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Abstract: Background: Blood type O is the most common blood type and has lower von Willebrand factor (vWF) levels (25%-35% lower than non-O blood types). von Willebrand factor is important for initiating platelet attachment and binding factor VIII. We hypothesized that patients with type O blood are at an increased risk of trauma-induced coagulopathy and bleeding post injury. Study Design: Adult trauma activations with known blood type at a level I trauma center with field systolic blood pressure < 90 mm Hg were studied retrospectively. The relationships of blood group O versus non-O to coagulation assays, massive transfusion (MT), ventilator-free days, and mortality were adjusted for confounders. Hyperfibrinolysis (HF) was defined as thromboelastogram of percent lysis in 30 min > 3%, and fibrinolysis shutdown was defined as percent lysis in 30 min < 0.9%. von Willebrand factor activity was quantified on 212 injured patients using a STAGO apparatus. Results: Overall, 268 patients met criteria. Type O patients were more likely to develop HF than non-type O blood patients (43% vs. 29%, P = 0.06) and had significantly lower vWF activity (222% vs. 249%, P = 0.01). After adjustment for New Injury Severity Score and blunt mechanism, type O had higher odds of HF (odds ratio, 1.94, 95% confidence interval, 1.09-3.47) and increased odds of MT (odds ratio, 3.02; 95% confidence interval, 1.22-7.49). Other outcomes were not significantly affected. Conclusion: Type O patients with hypotension had increased HF and MT post injury, and these were associated with lower vWF activity. These findings have implications for the monitoring of HF in patients receiving type O whole-blood transfusions post injury., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by the Shock Society.)

Background: The rationale for resuscitative endovascular balloon occlusion of the aorta (REBOA) is to control life-threatening subdiaphragmatic bleeding and facilitate resuscitation; however, incorporating this into the resuscitative practices of a trauma service remains challenging. The objective of this study is to describe the process of successful implementation of REBOA use in an academic urban Level I trauma center. All REBOA procedures from April 2014 through December 2019 were evaluated; REBOA was implemented after surgical faculty attended a required and internally developed Advanced Endovascular Strategies for Trauma Surgeons course. Success was defined by sustained early adoption rates., Methods: An institutional protocol was published, and a REBOA supply cart was placed in the emergency department with posters attached to depict technical and procedural details. A focused professional practice evaluation was utilized for the first three REBOA procedures performed by each faculty member, leading to internal privileging., Results: Resuscitative endovascular balloon occlusion of the aorta was performed in 97 patients by nine trauma surgeons, which is 1% of the total trauma admissions during this time. Each surgeon performed a median of 12 REBOAs (interquartile range, 5-14). Blunt (77/97, 81%) or penetrating abdominopelvic injuries (15/97, 15%) comprised the main injury mechanisms; 4% were placed for other reasons (4/97), including ruptured abdominal aortic aneurysms (n = 3) and preoperatively for a surgical oncologic resection (n = 1). Overall survival was 65% (63/97) with a steady early adoption trend that resulted in participation in a Department of Defense multicenter trial., Conclusion: Strategies for how departments adopt new procedures require clinical guidelines, a training program focused on competence, and a hospital education and privileging process for those acquiring new skills., Level of Evidence: Therapeutic, level V., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Venous thromboembolism (VTE) in patients with major pelvic fractures who undergo preperitoneal pelvic packing (PPP) has not been investigated. We hypothesized that patients who undergo PPP are at high risk for VTE, thus early prophylactic anticoagulation and screening duplex are warranted., Study Design: All patients requiring PPP from 2015 to 2019 were reviewed. Management and outcomes were analyzed., Results: During the study period, 79 patients underwent PPP. Excluding the early deaths, 17 patients had deep venous thrombosis (DVT) and 6 had pulmonary emboli (PE); 4 patients had both DVT/PE. Overall mortality was 15%. Thirty-two patients underwent screening duplex within 72 h of admission and 10 were positive for DVT., Conclusion: Patients with complex pelvic trauma undergoing PPP have a 23% incidence of DVT and an additional 8% incidence of PE. 31% of screening ultrasounds are positive. The overall mortality was 15%. With a high incidence of VTE in this patient population, we recommend screening duplex ultrasounds., (Copyright © 2020. Published by Elsevier Inc.)

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.

Background: Mobilization of intra and extracellular calcium is required for platelet activation, aggregation, and degranulation. However, the importance of alterations in the calcium-platelet axis after injury is unknown. We hypothesized that in injured patients, in vivo initial calcium concentrations (pretransfusion) predict ex vivo platelet activation and aggregation, viscoelastic clot strength, and transfusion of blood products. We additionally hypothesized that increasing calcium concentrations ex vivo increases the expression of platelet activation surface receptors and platelet aggregation responses to agonist stimulation in healthy donor blood., Methods: Blood samples were collected from 538 trauma patients on arrival to the emergency department. Standard assays (including calcium), platelet aggregometry (PA) and thromboelastometry (ROTEM) were performed. In PA, platelet activation (prestimulation impedance [Ω]) and aggregation responses to agonist stimulation (area under the aggregation curve [AUC]) with adenosine diphosphate (ADP), thrombin receptor-activating peptide, arachidonic acid (AA), and collagen (COL) were measured. Multivariable regression tested the associations of calcium with PA, ROTEM, and transfusions. To further examine the calcium-platelet axis, calcium was titrated in healthy blood. Platelet aggregometry and ROTEM were performed, and expression of platelet glycoprotein IIb/IIIa and P-selectin was measured by flow cytometry., Results: The patients were moderately injured with normal calcium and platelet counts. Higher calcium on arrival (pretransfusion) was independently associated with increased platelet activation (prestimulation, Ω; p < 0.001), aggregation (ADP-stimulated, AUC; p = 0.002; thrombin receptor-activating peptide-stimulated, AUC; p = 0.038), and clot strength (ROTEM max clot firmness; p < 0.001), and inversely associated with 24-hour transfusions of blood, plasma, and platelets (all p < 0.005). Up-titrating calcium in healthy blood increased platelet activation (prestimulation, Ω; p < 0.001), aggregation (ADP, AA, COL-stimulated AUCs; p < 0.050), and expression of P-selectin (p = 0.003)., Conclusion: Initial calcium concentrations (pretransfusion) are independently associated with platelet activation, aggregation, clot-strength, and transfusions after injury. These changes may be mediated by calcium driven expression of surface receptors necessary for platelet activation and aggregation. However, the therapeutic benefit of early, empiric calcium repletion in trauma patients remains undefined., Level of Evidence: Prognostic, level V.

Background: Massive transfusion protocols to treat postinjury hemorrhage are based on predefined blood product transfusion ratios followed by goal-directed transfusion based on patient's clinical evolution. However, it remains unclear how these transfusion ratios impact patient outcomes over time from injury., Methods: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) is a phase 3, randomized controlled trial, across 12 Level I trauma centers in North America. From 2012 to 2013, 680 severely injured patients required massive transfusion. We used semiparametric machine learning techniques and causal inference methods to augment the intent-to-treat analysis of PROPPR, estimating the dynamic relationship between transfusion ratios and outcomes: mortality and hemostasis at different timepoints during the first 24 hours after admission., Results: In the intention-to-treat analysis, the 1:1:1 group tended to have decreased mortality, but with no statistical significance. For patients in whom hemostasis took longer than 2 hours, the 1:1:1 ratio was associated with a higher probability of hemostasis, statistically significant from the 4 hour on. In the per-protocol, actual-transfusion-ratios-received analysis, during four successive time intervals, no significant association was found between the actual ratios and mortality. When comparing patient groups who received both high plasma/PRBC and high platelet/PRBC ratios to the group of low ratios in both, the relative risk of achieving hemostasis was 2.49 (95% confidence interval, 1.19-5.22) during the third hour after admission, suggesting a significant beneficial impact of higher transfusion ratios of plasma and platelets on hemostasis., Conclusion: Our results suggest that the impact of transfusion ratios on hemostasis is dynamic. Overall, the transfusion ratios had no significant impact on mortality over time. However, receiving higher ratios of platelets and plasma relative to red blood cells hastens hemostasis in subjects who have yet to achieve hemostasis within 3 hours after hospital admission., Level of Evidence: Therapeutic IV.

Background: Impaired postinjury platelet aggregation is common, but the effect of transfusion on this remains unclear. Data suggest that following injury platelet transfusion may not correct impaired platelet aggregation, and impaired platelet aggregation may not predict the need for platelet transfusion. We sought to further investigate platelet aggregation responses to transfusions, using regression statistics to isolate the independent effects of transfusions given in discrete time intervals from injury on both immediate and longitudinal platelet aggregation. We hypothesized that platelet aggregation response to platelet transfusion increases over time from injury., Methods: Serial (0-96 hours) blood samples were collected from 248 trauma patients. Platelet aggregation was assessed in vitro with impedance aggregometry stimulated by adenosine diphosphate, collagen, and thrombin receptor-activating peptide-6. Using regression, transfusion exposure was modeled against platelet aggregation at each subsequent timepoint and adjusted for confounders (Injury Severity Score, international normalized ratio (INR), base deficit, platelet count, and interval transfusions). The expected change in platelet aggregation at each timepoint under the intervention of transfusion exposure was calculated and compared with the observed platelet aggregation., Results: The 248 patients analyzed were severely injured (Injury Severity Score, 21 ± 19), with normal platelet counts (mean, 268 × 10/L ± 90), and 62% were transfused in 24 hours. The independent effect of transfusions on subsequent platelet aggregation over time was modeled with observed platelet aggregation under hypothetical treatment of one unit transfusion of blood, plasma, or platelets. Platelet transfusions had increasing expected effects on subsequent platelet aggregation over time, with the maximal expected effect occurring late (4-5 days from injury)., Conclusion: Controversy exists on whether transfusions improve impaired postinjury platelet aggregation. Using regression modeling, we identified that expected transfusion effects on subsequent platelet aggregation are maximal with platelet transfusion given late after injury. This is critical for tailored resuscitation, identifying a potential early period of resistance to platelet transfusion that resolves by 96 hours., Level of Evidence: Therapeutic, level V.

Background: Multi-detector computed tomography imaging is now the reference standard for identifying solid organ injuries, with a high sensitivity and specificity. However, delayed splenic hemorrhage (DSH), defined as no identified injury to the spleen on the index scan but delayed bleeding from a splenic injury, has been reported. We hypothesized that the occurrence of DSH would be minimized by utilization of modern imaging techniques., Methods: Data was retrospectively collected from 2006 to 2016 in 12 adult Level I and II trauma centers. All patients had an initial CT scan demonstrating no splenic injury but subsequently were diagnosed with splenic bleeding. Demographic, injury characteristics, imaging parameters and results, interventions and outcomes were collected., Results: Of 6867 patients with splenic injuries, 32 cases (0.4%) of blunt splenic hemorrage were identified. Patients were primarily male, had blunt trauma, severely injured (ISS 32 (9-57) and with associated injuries. Injuries of all grades were identified up to 16 days following admission. Overall, half of patients required splenectomy. All index images were obtained using multi-detector CT (16-320 slice). Secondary review of imaging by two trauma radiologists judged 72% (n = 23) of scans as suboptimal. This was due to poor scan quality primary from artifact(23), single phase contrast imaging (16), and/or poor contrast bolus timing or volume (6). Notably, only 28% of scans in patients with DSH were performed with optimal scanning techniques., Conclusion: This is the largest reported series of DSH in the era of modern imaging. Although the incidence of DSH is low, it still occurs despite the use of multi-detector imaging and when present, is associated with a high rate of splenectomy. Most cases of DSH can be attributed to missed diagnosis from suboptimal index imaging and ultimately be avoided., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Backdrop: Clinicians intuitively recognize that faster time to hemostasis is important in bleeding trauma patients, but these times are rarely reported., Methods: Prospectively collected data from the Pragmatic Randomized Optimal Platelet and Plasma Ratios trial were analyzed. Hemostasis was predefined as no intraoperative bleeding requiring intervention in the surgical field or resolution of contrast blush on interventional radiology (IR). Patients who underwent an emergent (within 90 minutes) operating room (OR) or IR procedure were included. Mixed-effects Poisson regression with robust error variance (controlling for age, Injury Severity Score, treatment arm, injury mechanism, base excess on admission [missing values estimated by multiple imputation], and time to OR/IR as fixed effects and study site as a random effect) with modified Bonferroni corrections tested the hypothesis that decreased time to hemostasis was associated with decreased mortality and decreased incidence of acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), multiple-organ failure (MOF), sepsis, and venous thromboembolism., Results: Of 680 enrolled patients, 468 (69%) underwent an emergent procedure. Patients with decreased time to hemostasis were less severely injured, had less deranged base excess on admission, and lower incidence of blunt trauma (all p < 0.05). In 408 (87%) patients in whom hemostasis was achieved, every 15-minute decrease in time to hemostasis was associated with decreased 30-day mortality (RR, 0.97; 95% confidence interval [CI], 0.94-0.99), AKI (RR, 0.97; 95% CI, 0.96-0.98), ARDS (RR, 0.98; 95% CI, 0.97-0.99), MOF (RR, 0.94; 95% CI, 0.91-0.97), and sepsis (RR, 0.98; 95% CI, 0.96-0.99), but not venous thromboembolism (RR, 0.99; 95% CI, 0.96-1.03)., Conclusion: Earlier time to hemostasis was independently associated with decreased incidence of 30-day mortality, AKI, ARDS, MOF, and sepsis in bleeding trauma patients. Time to hemostasis should be considered as an endpoint in trauma studies and as a potential quality indicator., Level of Evidence: Therapeutic/care management, level III.

Background: Elevated d-dimers in injured patients with paradoxically low fibrinolysis activity measured by viscoelastic assays have been speculated to be "occult" fibrinolysis. However, an alternative explanation is that these patients have previously activated their fibrinolytic system and have shut it down by the time of blood draw, and would gain no benefit in clot strength with tranexamic acid (TXA). We hypothesize that TXA will not increase clot strength in injured patients with low fibrinolytic activity measured by thrombelastography (TEG), despite biomarkers of fibrinolysis activation., Study Design: Three TEG assays (rapid, tissue plasminogen activator, and functional fibrinogen) were run on trauma patients. The tissue plasminogen activator TEG served as a functional assay to quantify depletion of fibrinolysis inhibitors (DFI). Patients were stratified by DFI vs non-DFI and then by rapid TEG lysis at 30 minutes phenotype cutoffs. Response to TXA was evaluated with functional fibrinogen TEG by calculating percent change in clot strength with the addition of exogenous TXA in the TEG cup., Results: Six hundred and thirty patients with a median new injury severity score of 20 were analyzed. Depletion of fibrinolysis inhibitors was present in 116 (18%). The DFI patients had significantly increased d-dimer (p < 0.001) and lower fibrinogen (p < 0.001). The DFI patients had increased rates of massive transfusion (33% vs 3.3%; p < 0.001) and mortality (40% vs 6.2%; p < 0.001). Among DFI patients, TXA significantly improved fibrin clot strength with hyperfibrinolysis (+19% clot strength; p < 0.001) but not with shutdown (+1.2%) or physiologic (-2.5%)., Conclusions: Patients with DFI have multiple abnormalities of their coagulation system, but only DFI patients with hyperfibrinolysis have improved fibrin clot strength with TXA., (Copyright © 2019. Published by Elsevier Inc.)

Background: Viscoelastic tests (VETs), specifically thromboelastography (TEG) and rotational thromboelastometry (ROTEM), are gaining popularity in the management of critically ill surgical patients with hemorrhage or thrombosis due to their comprehensive characterization of the coagulation process and point-of-care availability in comparison to conventional coagulation tests (CCTs). We review current evidence for VET use in patients in the surgical intensive care unit (SICU)., Methods: We searched PUBMED, EMBASE and the Cochrane Library through May 30, 2018 for articles that evaluated the use of VETs in patient populations and clinical scenarios germane to the surgical intensivist. Individual articles were critically evaluated for relevance and appropriate methodology using a structured technique. Information on patient characteristics, timing and methods of CCTs/VETs, and outcomes was collected and summarized in narrative form., Results: Of 2,589 identified articles, 36 were included. Five (14%) were interventional studies and 31 (86%) were observational. Twenty-five (69%) evaluated TEG, 11 (31%) ROTEM and 18 (50%) CCTs. Investigated outcomes included quantitative blood loss (13 (36%)), blood product transfusion (9 (25%)), thromboembolic events (9 (25%)) and mortality (6 (17%)). We identified 12 clinical scenarios with sufficient available evidence, much of which was of limited quantity and poor methodological quality. Nonetheless, research supports the use of VETs for guiding early blood product administration in severe traumatic hemorrhage and for the prediction of abstract excess bleeding following routine cardiac surgery. In contrast, evidence suggests VET-based heparin dosing strategies for venous thromboembolism prophylaxis are not superior to standard dosing in SICU patients., Conclusion: While VETs have the potential to impact the care of critically ill surgical patients in many ways, current evidence for their use is limited, mainly because of poor methodological quality of most available studies. Further high-quality research, including several ongoing randomized controlled trials, is needed to elucidate the role of TEG/ROTEM in the SICU population., Level of Evidence: Systematic review, level IV.

Introduction: Goal-directed hemostatic resuscitation based on thrombelastography (TEG) has a survival benefit compared with conventional coagulation assays such as international normalized ratio, activated partial thromboplastin time, fibrinogen level, and platelet count. While TEG-based transfusion thresholds for patients at risk for massive transfusion (MT) have been defined using rapid TEG, cutoffs have not been defined for TEG using other activators such as kaolin. The purpose of this study was to develop thresholds for blood product transfusion using citrated kaolin TEG (CK-TEG) in patients at risk for MT., Methods: CK-TEG was assessed in trauma activation patients at two Level 1 trauma centers admitted between 2010 and 2017. Receiver operating characteristic (ROC) curve analyses were performed to test the predictive performance of CK-TEG measurements in patients requiring MT, defined as >10 units of red blood cells or death within the first 6 hours. The Youden Index defined optimal thresholds for CK-TEG-based resuscitation., Results: Of the 825 trauma activations, 671 (81.3%) were men, 419 (50.8%) suffered a blunt injury, and 62 (7.5%) received a MT. Patients who had a MT were more severely injured, had signs of more pronounced shock, and more abnormal coagulation assays. CK-TEG R-time was longer (4.9 vs. 4.4 min, p = 0.0084), angle was lower (66.2 vs. 70.3 degrees, p < 0.0001), maximum amplitude was lower in MT (57 vs. 65.5 mm, p < 0.0001), and LY30 was greater (1.8% vs. 1.2%, p = 0.0012) in patients with MT compared with non-MT. To predict MT, R-time yielded an area under the ROC curve (AUROC) = 0.6002 and a cut point of >4.45 min. Angle had an AUROC = 0.6931 and a cut point of <67 degrees. CMA had an AUROC = 0.7425, and a cut point of <60 mm. LY30 had an AUROC = 0.623 with a cut point of >4.55%., Conclusion: We have identified CK-TEG thresholds that can guide MT in trauma. We propose plasma transfusion for R-time >4.45 min, fibrinogen products for an angle <67 degrees, platelet transfusion for MA <60 mm, and antifibrinolytics for LY30 >4.55%., Level of Evidence: Therapeutic study, level V.

Background: To address deficiencies associated with the classic definition of massive transfusion (MT), critical administration threshold (CAT) and resuscitation intensity (RI) were developed to better quantify the overall severity of illness and predict the need for transfusions and early mortality. We sought to evaluate these as more appropriate replacements for MT in defining mortality risk in patients undergoing major transfusions., Methods: Patients predicted to receive MT at 12 Level I trauma centers were randomized in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial. MT of 10 U or greater red blood cell (RBC) in 24 hours; CAT+, 3 U or greater RBC in the first hour; and RI, total products in the first 30 minutes (1 U RBC, 1 U plasma, 1000 mL crystalloid, 500 mL colloid each valued at 1 U). Resuscitation intensity was evaluated as a continuous variable and dichotomized as RI4+, where RI is 4 U or greater. Each metric was evaluated for its ability to predict mortality at 3 hours, 6 hours, and 24 hours, and at 30 days., Results: Of the 680 patients, 301 patients met MT definition, 521 were CAT+, and 445 were RI4+. Of those that died, 23% never reached MT threshold, but all were captured by CAT+ and RI4+. The 3-hour (9% vs. 9%), 6-hour (14% vs. 14%), 24-hour (17% vs. 18%), and 30-day mortality rates (28% vs. 29%) were similar between CAT+ and RI4+ patients. When RI was evaluated as a continuous variable, each unit increase was associated with a 20% increase in hemorrhage-related mortality (odds ratio, 1.20; 95% confidence interval, 1.15-1.29; p < 0.05)., Conclusion: Both RI and CAT are valid surrogates for early mortality in patients undergoing major transfusion, capturing patients omitted by the MT definition. The CAT+ showed the best sensitivity; RI4+ demonstrated better specificity and good positive predictive values and negative predictive values. While CAT+ may be suited for patients receiving an RBC-dominant resuscitation, RI4+ is more comprehensive. RI can also be used as a continuous variable to provide quantitative as well as qualitative risk of death., Level of Evidence: Prognostic, level III.

Background: Resuscitation guided by thrombelastography improves survival after injury. If bleeding is rapid, however, or if no thrombelastography data are available, the optimal strategy remains controversial. Our current practice gives fresh frozen plasma and red blood cells (1:2) empirically in patients with life-threatening hemorrhage, with subsequent administration based on rapid thrombelastography. We identified patients at risk of massive transfusion at 1 hour, examined their initial rapid thrombelastography, and used this value to provide empiric recommendations about transfusions., Methods: Massive transfusion was defined as >4 units of red blood cells in the first hour. Patients managed by a trauma activation (2014-2017) had an admission rapid thrombelastography analyzed to determine what proportion met thresholds for administration of cryoprecipitate or platelets., Results: Overall, 35 patients received >4 units of red blood cells in the first hour. Based on the admission rapid thrombelastography, 37% met criteria for both platelets and cryoprecipitate, 35% for either platelets or cryoprecipitate and 29% for neither. Kaplan-Meier analysis showed a significant delay in the administration of cryoprecipitate and platelets compared to fresh frozen plasma., Conclusion: Patients who require >4 units of red blood cells within the first hour should receive cryoprecipitate and platelets if thrombelastography results are not available. Point-of-care devices are needed for optimal care of trauma-induced-coagulopathy, but these data offer guidance in their absence., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Open pelvic fractures are life-threatening injuries. Preperitoneal pelvic packing (PPP) has been suggested to be ineffective for hemorrhage control in open pelvic fractures. We hypothesize that PPP is effective at hemorrhage control in patients with open pelvic fractures and reduces mortality., Methods: Patients undergoing PPP from 2005 to 2015 were analyzed. Patients with open pelvic fractures were defined as direct communication of the bony injury with overlying soft tissue, vagina, or rectum., Results: During the 10-year study, 126 patients underwent PPP; 14 (11%) sustained an open pelvic fracture. After PPP, 1 patient (7%) underwent angioembolization with a documented arterial blush. PPP controlled pelvic hemorrhage in all patients. Overall mortality rate was 7% with one death due to traumatic brain injury., Conclusions: PPP is effective for hemorrhage control in patients with open pelvic fractures. PPP should be used in a standard protocol for hemodynamically unstable patients with pelvic fractures regardless of associated perineal injuries., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this research agenda on the acute and critical care management of trauma patients, we concentrate on the major factors leading to death, namely haemorrhage and traumatic brain injury (TBI). In haemostasis biology, the results of randomised controlled trials have led to the therapeutic focus moving away from the augmentation of coagulation factors (such as recombinant factor VIIa) and towards fibrinogen supplementation and administration of antifibrinolytics such as tranexamic acid. Novel diagnostic techniques need to be evaluated to determine whether an individualised precision approach is superior to current empirical practice. The timing and efficacy of platelet transfusions remain in question, while new blood products need to be developed and evaluated, including whole blood variants, lyophilised products and novel red cell storage modalities. The current cornerstones of TBI management are intracranial pressure control, maintenance of cerebral perfusion pressure and avoidance of secondary insults (such as hypotension, hypoxaemia, hyperglycaemia and pyrexia). Therapeutic hypothermia and decompressive craniectomy are controversial therapies. Further research into these strategies should focus on identifying which subgroups of patients may benefit from these interventions. Prediction of the long-term outcome early after TBI remains challenging. Early magnetic resonance imaging has recently been evaluated for predicting the long-term outcome in mild and severe TBI. Novel biomarkers may also help in outcome prediction and may predict chronic neurological symptoms. For trauma in general, rehabilitation is complex and multidimensional, and the optimal timing for commencement of rehabilitation needs investigation. We propose priority areas for clinical trials in the next 10 years.

Background: The resuscitation of severely injured bleeding patients has evolved into a multi-modal strategy termed damage control resuscitation (DCR). This guideline evaluates several aspects of DCR including the role of massive transfusion (MT) protocols, the optimal target ratio of plasma (PLAS) and platelets (PLT) to red blood cells (RBC) during DCR, and the role of recombinant activated factor VII (rVIIa) and tranexamic acid (TXA)., Methods: Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, a subcommittee of the Practice Management Guidelines (PMG) Section of EAST conducted a systematic review using MEDLINE and EMBASE. Articles in English from1985 through 2015 were considered in evaluating four PICO questions relevant to DCR., Result: A total of 37 studies were identified for analysis, of which 31 met criteria for quantitative meta-analysis. In these studies, mortality decreased with use of an MT/DCR protocol vs. no protocol (OR 0.61, 95% CI 0.43-0.87, p = 0.006) and with a high ratio of PLAS:RBC and PLT:RBC (relatively more PLAS and PLT) vs. a low ratio (OR 0.60, 95% CI 0.46-0.77, p < 0.0001; OR 0.44, 95% CI 0.28-0.71, p = 0.0003). Mortality and blood product use were no different with either rVIIa vs. no rVIIa or with TXA vs. no TXA., Conclusion: DCR can significantly improve outcomes in severely injured bleeding patients. After a review of the best available evidence, we recommend the use of a MT/DCR protocol in hospitals that manage such patients and recommend that the protocol target a high ratio of PLAS and PLT to RBC. This is best achieved by transfusing equal amounts of RBC, PLAS, and PLT during the early, empiric phase of resuscitation. We cannot recommend for or against the use of rVIIa based on the available evidence. Finally, we conditionally recommend the in-hospital use of TXA early in the management of severely injured bleeding patients.

Background: Major trauma is a leading cause of morbidity and mortality worldwide with hemorrhage accounting for 40% of deaths. Acute traumatic coagulopathy exacerbates bleeding, but controversy remains over the degree to which inhibition of procoagulant pathways (anticoagulation), fibrinogen loss, and fibrinolysis drive the pathologic process. Through a combination of experimental study in a murine model of trauma hemorrhage and human observation, the authors' objective was to determine the predominant pathophysiology of acute traumatic coagulopathy., Methods: First, a prospective cohort study of 300 trauma patients admitted to a single level 1 trauma center with blood samples collected on arrival was performed. Second, a murine model of acute traumatic coagulopathy with suppressed protein C activation via genetic mutation of thrombomodulin was used. In both studies, analysis for coagulation screen, activated protein C levels, and rotational thromboelastometry (ROTEM) was performed., Results: In patients with acute traumatic coagulopathy, the authors have demonstrated elevated activated protein C levels with profound fibrinolytic activity and early depletion of fibrinogen. Procoagulant pathways were only minimally inhibited with preservation of capacity to generate thrombin. Compared to factors V and VIII, proteases that do not undergo activated protein C-mediated cleavage were reduced but maintained within normal levels. In transgenic mice with reduced capacity to activate protein C, both fibrinolysis and fibrinogen depletion were significantly attenuated. Other recognized drivers of coagulopathy were associated with less significant perturbations of coagulation., Conclusions: Activated protein C-associated fibrinolysis and fibrinogenolysis, rather than inhibition of procoagulant pathways, predominate in acute traumatic coagulopathy. In combination, these findings suggest a central role for the protein C pathway in acute traumatic coagulopathy and provide new translational opportunities for management of major trauma hemorrhage., Competing Interests: of conflicts of interest The authors declare no competing financial interests.

Coagulopathy is common after injury and develops independently from iatrogenic, hypothermic, and dilutional causes. Despite considerable research on the topic over the past decade, trauma-induced coagulopathy (TIC) continues to portend poor outcomes, including decreased survival. We review the current evidence regarding the diagnosis and mechanisms underlying trauma induced coagulopathy and summarize the debates regarding optimal management strategy including product resuscitation, potential pharmacologic adjuncts, and targeted approaches to hemostasis. Throughout, we will identify areas of continued investigation and controversy in the understanding and management of TIC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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.

Improving the treatment of trauma, a leading cause of death worldwide, is of great clinical and public health interest. This analysis introduces flexible statistical methods for estimating center-level effects on individual outcomes in the context of highly variable patient populations, such as those of the PRospective, Observational, Multi-center Major Trauma Transfusion study. Ten US level I trauma centers enrolled a total of 1,245 trauma patients who survived at least 30 minutes after admission and received at least one unit of red blood cells. Outcomes included death, multiple organ failure, substantial bleeding, and transfusion of blood products. The centers involved were classified as either large or small-volume based on the number of massive transfusion patients enrolled during the study period. We focused on estimation of parameters inspired by causal inference, specifically estimated impacts on patient outcomes related to the volume of the trauma hospital that treated them. We defined this association as the change in mean outcomes of interest that would be observed if, contrary to fact, subjects from large-volume sites were treated at small-volume sites (the effect of treatment among the treated). We estimated this parameter using three different methods, some of which use data-adaptive machine learning tools to derive the outcome models, minimizing residual confounding by reducing model misspecification. Differences between unadjusted and adjusted estimators sometimes differed dramatically, demonstrating the need to account for differences in patient characteristics in clinic comparisons. In addition, the estimators based on robust adjustment methods showed potential impacts of hospital volume. For instance, we estimated a survival benefit for patients who were treated at large-volume sites, which was not apparent in simpler, unadjusted comparisons. By removing arbitrary modeling decisions from the estimation process and concentrating on parameters that have more direct policy implications, these potentially automated approaches allow methodological standardization across similar comparativeness effectiveness studies.

Background: Trauma-induced coagulopathy following severe injury is associated with increased bleeding and mortality. Injury may result in alteration of cellular phenotypes and release of cell-derived microparticles (MP). Circulating MPs are procoagulant and support thrombin generation (TG) and clotting. We evaluated MP and TG phenotypes in severely injured patients at admission, in relation to coagulopathy and bleeding., Methods: As part of the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, research blood samples were obtained from 180 trauma patients requiring transfusions at 5 participating centers. Twenty five healthy controls and 40 minimally injured patients were analyzed for comparisons. Laboratory criteria for coagulopathy was activated partial thromboplastin time (APTT) ≥ 35 sec. Samples were analyzed by Calibrated Automated Thrombogram to assess TG, and by flow cytometry for MP phenotypes [platelet (PMP), erythrocyte (RMP), leukocyte (LMP), endothelial (EMP), tissue factor (TFMP), and Annexin V positive (AVMP)]., Results: 21.7% of patients were coagulopathic with the median (IQR) APTT of 44 sec (37, 53), and an Injury Severity Score of 26 (17, 35). Compared to controls, patients had elevated EMP, RMP, LMP, and TFMP (all p<0.001), and enhanced TG (p<0.0001). However, coagulopathic PROMMTT patients had significantly lower PMP, TFMP, and TG, higher substantial bleeding, and higher mortality compared to non-coagulopathic patients (all p<0.001)., Conclusions: Cellular activation and enhanced TG are predominant after trauma and independent of injury severity. Coagulopathy was associated with lower thrombin peak and rate compared to non-coagulopathic patients, while lower levels of TF-bearing PMPs were associated with substantial bleeding., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Forty percent of in-hospital deaths among injured patients involve massive truncal haemorrhage. These deaths may be prevented with rapid haemorrhage control and improved resuscitation techniques. The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial was designed to determine if there is a difference in mortality between subjects who received different ratios of FDA approved blood products. This report describes the design and implementation of PROPPR., Study Design: PROPPR was designed as a randomized, two-group, Phase III trial conducted in subjects with the highest level of trauma activation and predicted to have a massive transfusion. Subjects at 12 North American level 1 trauma centres were randomized into one of two standard transfusion ratio interventions: 1:1:1 or 1:1:2, (plasma, platelets, and red blood cells). Clinical data and serial blood samples were collected under Exception from Informed Consent (EFIC) regulations. Co-primary mortality endpoints of 24h and 30 days were evaluated., Results: Between August 2012 and December 2013, 680 patients were randomized. The overall median time from admission to randomization was 26min. PROPPR enrolled at higher than expected rates with fewer than expected protocol deviations., Conclusion: PROPPR is the largest randomized study to enrol severely bleeding patients. This study showed that rapidly enrolling and successfully providing randomized blood products to severely injured patients in an EFIC study is feasible. PROPPR was able to achieve these goals by utilizing a collaborative structure and developing successful procedures and design elements that can be part of future trauma studies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Trauma remains the leading cause of death and morbidity worldwide and bleeding is the primary reason for this mortality. Over the past 11 years there has been a paradigm shift in our understanding of coagulopathy after trauma. Specifically its incidence, biological drivers, clinical sequelae have been elucidated. From this understanding a concurrent change in resuscitation practices has occurred. This manuscript will review the history of resuscitation after injury, the discovery and clinical and biological characterization of acute traumatic coagulopathy and the changes in resuscitation practices aimed at combating coagulopathy and inflammatory perturbation after trauma. Finally it will discuss the ongoing state of the science and suggest topics for continued biological and clinical study., (Copyright © 2014. Published by Elsevier Ltd.)

Background: Although minimization of crystalloids is a widely adopted practice in the resuscitation of patients with severe hemorrhage, its direct impact on high-ratio resuscitation (HRR) outcomes has not been analyzed. We hypothesize that HRR patients will have worse outcomes from crystalloid use., Methods: This was a 4-year retrospective multi-institutional analysis (MIA) of patients who received massive transfusion protocol (MTP) managed with damage-control laparotomy. Ratios of fresh frozen plasma-packed red blood cell (PRBC) were calculated and divided in two groups: HRR (1-1:2) and low-ratio resuscitation (LRR < 1:2). Major outcome of interest was to analyze the direct impact of 24-hour crystalloid volume on HRR MTP patients who received 10 or more units of PRBC. Statistical analysis included analysis of variance, Fisher's exact, Kaplan-Meier (KM) survival curves, and multiple logistic regression., Results: Total of five Level I trauma centers participated with 451 patients who received MTP with 10 or more units of PRBC (fresh frozen plasma/PRBC ratios, n = 365 (80.9%) HRR vs. n = 86 (19.0%) LRR. Overall 24-hour KM survival for the HRR versus LRR was 85.2% versus 68.6% (p = 0.0004). The volume of crystalloids on KM survival curve in HRR MTP patients was not significant for mortality (p = 0.52). Morbidity odds ratios (95% confidence interval) for complications were not significant for HRR but were for crystalloids: bacteremia, 1.05 (1.0-1.1); adult respiratory distress syndrome, 1.13 (1.0-1.2), and acute renal failure, 1.05 (1.0-1.1)., Conclusion: Our MIA results support previous studies with decreased mortality in HRR group when compared with LRR. This is the first MIA to demonstrate increased morbidity from crystalloid use in HRR. Within all MTPs with 10 or more units of PRBC, HRR was not a predictor of morbidity, but crystalloid volume was. Caution in overzealous use of crystalloid during HRR is warranted., Level of Evidence: Therapeutic study, level IV.

Background: The trauma transfusion literature has yet to resolve which is more important for hemorrhaging patients, transfusing plasma and platelets along with red blood cells (RBCs) early in resuscitation or gradually balancing blood product ratios. In a previous report of PROMMTT results, we found (1) plasma and platelet:RBC ratios increased gradually during the 6 hours following admission, and (2) patients achieving ratios more than 1:2 (relative to ratios <1:2) had significantly decreased 6-hour to 24-hour mortality adjusting for baseline and time-varying covariates. To differentiate the association of in-hospital mortality with early plasma or platelet transfusion from that with delayed but gradually balanced ratios, we developed a separate analytic approach., Methods: Using PROMMTT data and multilevel logistic regression to adjust for center effects, we related in-hospital mortality to the early receipt of plasma or platelets within the first three to six transfusion units (including RBCs) and 2.5 hours of admission. We adjusted for the same covariates as in our previous report: Injury Severity Score (ISS), age, time and total number of blood product transfusions upon entry to the analysis cohort, and bleeding from the head, chest, or limb., Results: Of 1,245 PROMMTT patients, 619 were eligible for this analysis. Early plasma was associated with decreased 24-hour and 30-day mortality (adjusted odds ratios of 0.47 [p = 0.009] and 0.44 [p = 0.002], respectively). Too few patients (24) received platelets early for meaningful assessment. In the subgroup of 222 patients receiving no early plasma but continuing transfusions beyond Hour 2.5, achieving gradually balanced plasma and platelet:RBC ratios of 1:2 or greater by Hour 4 was not associated with 30-day mortality (adjusted odds ratios of 0.9 and 1.1, respectively). There were no significant center effects., Conclusion: Plasma transfusion early in resuscitation had a protective association with mortality, whereas delayed but gradually balanced transfusion ratios did not. Further research will require considerably larger numbers of patients receiving platelets early.

Background: There are few clinical data to guide the use of cryoprecipitate in severely injured trauma patients. Cryoprecipitate is a rich source of fibrinogen and has been associated with improved survival in animal as well as limited human studies. Our objectives were to identify patterns and predictors of cryoprecipitate use and determine whether transfusing cryoprecipitate was associated with improved survival., Methods: This secondary analysis of 1,238 of 1,245 PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study patients who had timed transfusion data included 359 (29%) who received cryoprecipitate. For this analysis, one dose of cryoprecipitate was defined as 10 U. Unadjusted predictors of cryoprecipitate use were identified using logistic regression. Multivariable time-dependent Cox models were performed to examine the association of cryoprecipitate on time to in-hospital death., Results: Cryoprecipitate use varied significantly by center, ranging from 7% to 82%. Among patients who received cryoprecipitate, the median number of units infused by 24 hours was 10 (interquartile range, 10-20). The median time from admission to first cryoprecipitate unit was 2.7 hours (interquartile range, 1.7-4.4 hours). Of those who died of a hemorrhagic death within 6 hours of admission, 72% received no cryoprecipitate. Other unadjusted predictors of cryoprecipitate use included Injury Severity Score (ISS), initial fibrinogen levels, base deficit, international normalized ratio, prothrombin time/partial thromboplastin time, hemoglobin, damage-control surgery, and surgical intervention of the chest and abdomen. Cryoprecipitate use was not associated with in-hospital mortality after adjusting for initial pH, initial hemoglobin, emergency department systolic blood pressure, emergency department Glasgow Coma Scale (GCS) score, blood product use, ISS, and center., Conclusion: Ten US Level 1 trauma centers vary greatly in their timing and use of cryoprecipitate in severely injured trauma patients. We could not identify any association of cryoprecipitate use with in-hospital mortality, although most patients did not receive this product. Randomized controlled studies are needed to determine if cryoprecipitate (or fibrinogen concentrates) have a beneficial effect.

Background: Acute lung injury following trauma resuscitation remains a concern despite recent advances. With the use of the PROMMTT study population, the risk of hypoxemia and potential modifiable risk factors are studied., Methods: Patients with survival for 24 hours or greater with at least one intensive care unit day were included in the analysis. Hypoxemia was categorized using the Berlin definition for adult respiratory distress syndrome: none (PaO₂-to-FIO₂ ratio [P/F] > 300 mm Hg), mild (P/F, 201-300 mm Hg), moderate (P/F, 101-200 mm Hg) or severe (P/F ≤ 100 mm Hg). The cohort was dichotomized into those with none or mild hypoxemia and those with moderate or severe injury. Early resuscitation was defined as that occurring 0 hour to 6 hours from arrival; late resuscitation was defined as that occurring 7 hours to 24 hours. Multivariate logistic regression models were developed controlling for age, sex, mechanisms of injury, arrival physiology, individual Abbreviated Injury Scale (AIS) scores, blood transfusions, and crystalloid administration., Results: Of the patients 58.7% (731 of 1,245) met inclusion criteria. Hypoxemia occurred in 69% (mild, 24%; moderate, 28%; severe, 17%). Mortality was highest (24%) in the severe group. During early resuscitation (0-6 h), logistic regression revealed age (odd ratio [OR], 1.02; 95% confidence interval [CI], 1.00-1.04), chest AIS score (OR, 1.31; 95% CI, 1.10-1.57), and intravenously administered crystalloid fluids given in 500 mL increments (OR, 1.12; 95% CI, 1.01-1.25) as predictive of moderate or severe hypoxemia. During late resuscitation, age (OR, 1.02; 95% CI, 1.00-1.04), chest AIS score (OR, 1.33; 95% CI, 1.11-1.59), and crystalloids given during this period (OR, 1.05; 95% CI, 1.01-1.10) were also predictive of moderate-to-severe hypoxemia. Red blood cell, plasma, and platelet transfusions (whether received during early or late resuscitation) failed to demonstrate an increased risk of developing moderate/severe hypoxemia., Conclusion: Severe chest injury, increasing age, and crystalloid-based resuscitation, but not blood transfusions, were associated with increased risk of developing moderate-to-severe hypoxemia following injury.

Background: The Focused Assessment with Sonography for Trauma (FAST) examination is an important variable in many retrospective trauma studies. The purpose of this study was to devise an imputation method to overcome missing data for the FAST examination. Owing to variability in patients' injuries and trauma care, these data are unlikely to be missing completely at random, raising concern for validity when analyses exclude patients with missing values., Methods: Imputation was conducted under a less restrictive, more plausible missing-at-random assumption. Patients with missing FAST examinations had available data on alternate, clinically relevant elements that were strongly associated with FAST results in complete cases, especially when considered jointly. Subjects with missing data (32.7%) were divided into eight mutually exclusive groups based on selected variables that both described the injury and were associated with missing FAST values. Additional variables were selected within each group to classify missing FAST values as positive or negative, and correct FAST examination classification based on these variables was determined for patients with nonmissing FAST values., Results: Severe head/neck injury (odds ratio [OR], 2.04), severe extremity injury (OR, 4.03), severe abdominal injury (OR, 1.94), no injury (OR, 1.94), other abdominal injury (OR, 0.47), other head/neck injury (OR, 0.57), and other extremity injury (OR, 0.45) groups had significant ORs for missing data; the other group's OR was not significant (OR, 0.84). All 407 missing FAST values were imputed, with 109 classified as positive. Correct classification of nonmissing FAST results using the alternate variables was 87.2%., Conclusion: Purposeful imputation for missing FAST examinations based on interactions among selected variables assessed by simple stratification may be a useful adjunct to sensitivity analysis in the evaluation of imputation strategies under different missing data mechanisms. This approach has the potential for widespread application in clinical and translational research, and validation is warranted.

Background: Missing data are inherent in clinical research and may be especially problematic for trauma studies. This study describes a sensitivity analysis to evaluate the impact of missing data on clinical risk prediction algorithms. Three blood transfusion prediction models were evaluated using an observational trauma data set with valid missing data., Methods: The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study included patients requiring one or more unit of red blood cells at 10 participating US Level I trauma centers from July 2009 to October 2010. Physiologic, laboratory, and treatment data were collected prospectively up to 24 hours after hospital admission. Subjects who received 10 or more units of red blood cells within 24 hours of admission were classified as massive transfusion (MT) patients. Correct classification percentages for three MT prediction models were evaluated using complete case analysis and multiple imputation. A sensitivity analysis for missing data was conducted to determine the upper and lower bounds for correct classification percentages., Results: PROMMTT study enrolled 1,245 subjects. MT was received by 297 patients (24%). Missing percentage ranged from 2.2% (heart rate) to 45% (respiratory rate). Proportions of complete cases used in the MT prediction models ranged from 41% to 88%. All models demonstrated similar correct classification percentages using complete case analysis and multiple imputation. In the sensitivity analysis, correct classification upper-lower bound ranges per model were 4%, 10%, and 12%. Predictive accuracy for all models using PROMMTT data was lower than reported in the original data sets., Conclusion: Evaluating the accuracy clinical prediction models with missing data can be misleading, especially with many predictor variables and moderate levels of missingness per variable. The proposed sensitivity analysis describes the influence of missing data on risk prediction algorithms. Reporting upper-lower bounds for percent correct classification may be more informative than multiple imputation, which provided similar results to complete case analysis in this study.

Background: Prediction of outcome after injury is fraught with uncertainty and statistically beset by misspecified models. Single-time point regression only gives prediction and inference at one time, of dubious value for continuous prediction of ongoing bleeding. New statistical machine learning techniques such as SuperLearner (SL) exist to make superior prediction at iterative time points while evaluating the changing relative importance of each measured variable on an outcome. This then can provide continuously changing prediction of outcome and evaluation of which clinical variables likely drive a particular outcome., Methods: PROMMTT data were evaluated using both naive (standard stepwise logistic regression) and SL techniques to develop a time-dependent prediction of future mortality within discrete time intervals. We avoided both underfitting and overfitting using cross validation to select an optimal combination of predictors among candidate predictors/machine learning algorithms. SL was also used to produce interval-specific robust measures of variable importance measures (VIM resulting in an ordered list of variables, by time point) that have the strongest impact on future mortality., Results: Nine hundred eighty patients had complete clinical and outcome data and were included in the analysis. The prediction of ongoing transfusion with SL was superior to the naive approach for all time intervals (correlations of cross-validated predictions with the outcome were 0.819, 0.789, 0.792 for time intervals 30-90, 90-180, 180-360, >360 minutes). The estimated VIM of mortality also changed significantly at each time point., Conclusion: The SL technique for prediction of outcome from a complex dynamic multivariate data set is superior at each time interval to standard models. In addition, the SL VIM at each time point provides insight into the time-specific drivers of future outcome, patient trajectory, and targets for clinical intervention. Thus, this automated approach mimics clinical practice, changing form and content through time to optimize the accuracy of the prognosis based on the evolving trajectory of the patient.

Background: Several predictive models have been developed to identify trauma patients who have had severe hemorrhage (SH) and may need a massive transfusion (MT) protocol. However, almost all these models define SH as the transfusion of 10 or more units of red blood cells (RBCs) within 24 hours of emergency department admission (also known as MT). This definition excludes some patients with SH, especially those who die before a 10th unit of RBCs could be transfused, which calls the validity of these prediction models into question. We show how a latent class model could improve the accuracy of identifying the SH patients., Methods: Modeling SH classification as a latent variable, we estimate the posterior probability of a patient in SH based on emergency department admission variables (systolic blood pressure, heart rate, pH, hemoglobin), the 24-hour blood product use (plasma/RBC and platelet/RBC ratios), and 24-hour survival status. We define the SH subgroup as those having a posterior probability of 0.5 or greater. We compare our new classification of SH with that of the traditional MT using data from PROMMTT study., Results: Of the 1,245 patients, 913 had complete data, which were used in the latent class model. About 25.3% of patients were classified as SH. The overall agreement between the MT and SH classifications was 83.8%. However, among 49 patients who died before receiving the 10th unit of RBCs, 41 (84%) were classified as SH. Seven (87.5%) of the remaining eight patients who were not classified as SH had head injury., Conclusion: Our definition of SH based on the aforementioned latent class model has an advantage of improving on the traditional MT definition by identifying SH patients who die before receiving the 10th unit of RBCs. We recommend further improvements to more accurately classify SH patients, which could replace the traditional definition of MT for use in developing prediction algorithms.

Background: In the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, waiver of consent was used because previous literature reported low response rates and subsequent bias. The goal of this article was to examine the rationale and tradeoffs of using waiver of consent in PROMMTT., Methods: PROMMTT enrolled trauma patients receiving at least 1 U of red blood cells within 6 hours after admission at 10 US Level 1 trauma centers. Local institutional review boards (IRBs) from all sites approved the study. Site 8 was required by their IRB to attempt consent but was allowed to retain data on patients unable to be consented., Results: Of 121 subjects enrolled at Site 8, 55 consents were obtained (46%), and no patient or legally authorized representative refused to give consent. Of the patients, 36 (30%) died, and 6 (5%) were discharged before consent could be attempted. Consent was attempted but not possible among 24 patients (20%). Of the 10 clinical sites, 6 of the local IRBs approved collection of residual blood samples, 1 had previous approval to collect timed blood samples under a separate protocol, and 3 reported that their local IRBs would not approve collection of residual blood under a waiver of consent., Conclusion: Waiver of consent was used in PROMMTT because of the potential adverse impact of consent refusals; however, there were no refusals. If the IRB for Site 8 had required withdrawal of patients unable to consent and destruction of their data, a serious bias would likely have been introduced. Other tradeoffs included a reduction in sites participating in residual blood collection and a smaller than expected amount of residual blood collected among sites operating under a waiver of consent. Noninterventional emergency research studies should consider these potential tradeoffs carefully before deciding whether waiver of consent would best achieve the goals of a study.

Background: Acute traumatic coagulopathy (ATC) occurs after severe injury and shock and is associated with increased bleeding, morbidity, and mortality. The effects of ATC and hemostatic resuscitation on outcome are not well-explored. The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study provided a unique opportunity to characterize coagulation and the effects of resuscitation on ATC after severe trauma., Methods: Blood samples were collected upon arrival on a subset of PROMMTT patients. Plasma clotting factor levels were prospectively assayed for coagulation factors. These data were analyzed with comprehensive PROMMTT clinical data., Results: There were 1,198 patients with laboratory results, of whom 41.6% were coagulopathic. Using international normalized ratio of 1.3 or greater, 41.6% of patients (448) were coagulopathic, while 20.5% (214) were coagulopathic using partial thromboplastin time of 35 or greater. Coagulopathy was primarily associated with a combination of an Injury Severity Score (ISS) of greater than 15 and a base deficit (BD) of less than -6 (p < 0.05). Regression modeling for international normalized ratio-based coagulopathy shows that prehospital crystalloid (odds ratio [OR], 1.05), ISS (OR, 1.03), Glasgow Coma Scale (GCS) score (OR, 0.93), heart rate (OR, 1.08), systolic blood pressure (OR, 0.96), BD (OR, 0.92), and temperature (OR, 0.84) were significant predictors of coagulopathy (all p < 0.03). A subset of 165 patients had blood samples collected and coagulation factor analysis performed. Elevated ISS and BD were associated with elevation of aPC and depletion of factors (all p < 0.05). Reductions in factors I, II, V, VIII and an increase in aPC drive ATC (all p < 0.04). Similar results were found for partial thromboplastin time-defined coagulopathy., Conclusion: ATC is associated with the depletion of factors I, II, V, VII, VIII, IX, and X and is driven by the activation of the protein C system. These data provide additional mechanistic understanding of the drivers of coagulation abnormalities after injury. Further understanding of the drivers of ATC and the effects of resuscitation can guide factor-guided resuscitation and correction of coagulopathy after injury.

Background: The classic definition of massive transfusion, 10 or more units of red blood cells (RBCs) in 24 hours, has never been demonstrated as a valid surrogate for severe hemorrhage and can introduce survival bias. In addition, the definition fails to capture other products that the clinician may have immediately available, and may use, during the initial resuscitation. Assuming that units of resuscitative fluids reflect patient illness, our objective was to identify a rate of resuscitation intensity (RI) that could serve as an early surrogate of sickness for patients with substantial bleeding after injury., Methods: Adult patients surviving at least 30 minutes after admission and receiving one or more RBCs within 6 hours of admission from 10 US Level 1 trauma centers were enrolled in the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Total fluid units were calculated as the sum of the number of crystalloid units (1 L = 1 U), colloids (0.5 L = 1 U), and blood products (1 RBC = 1 U, 1 plasma = 1 U, 6 pack platelets = 1 U). Univariable and multivariable logistic regressions were used to evaluate associations between RI and 6-hour mortality, adjusting for age, center, penetrating injury, weighted Revised Trauma Score (RTS), and Injury Severity Score (ISS)., Results: A total of 1,096 eligible patients received resuscitative fluids within 30 minutes, including 620 transfused with blood products. Despite varying products used, the total fluid RI was similar across all sites (3.2 ± 2.5 U). Patients who received four or more units of any resuscitative fluid had a 6-hour mortality rate of 14.4% versus 4.5% in patients who received less than 4 U. The adjusted odds ratio of 6-hour mortality for patients receiving 4 U or more within 30 minutes was 2.1 (95% confidence interval, 1.2-3.5)., Conclusion: Resuscitation with four or more units of any fluid was significantly associated with 6-hour mortality. This study suggests that early RI regardless of fluid type can be used as a surrogate for sickness and mortality in severely bleeding patients.

Background: The impact of do-not-resuscitate (DNR) orders has not been systematically evaluated in acute trauma research. We determined the frequency, timing, and impact on mortality-based effect estimates for patients with DNR orders in the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study., Methods: Trauma patients surviving at least 30 minutes and transfused one or greater unit of red blood cell within 6 hours of admission (n = 1,245) from 10 Level 1 centers were enrolled. We report descriptive statistics and results from survival analysis to compare the association of blood product transfusion ratios with outcome defined as mortality and as a composite, DNR, and death., Results: DNRs were reported for 95 patients (7.6%), with 94 in-hospital deaths. There were 172 deaths without DNRs. Of 90 known DNR order times, the median was 53 hours (interquartile range, 9-186 hours) after admission; the median DNR-to-death time was 10 hours (2-32 hours). DNRs were for comfort measures only (43%), no cardiopulmonary resuscitation (40%), and no intubation or cardiopulmonary resuscitation (16%). Compared with the 116 non-DNR deaths that occurred after the earliest DNR order (2 hours), the DNR decedents were significantly older with a less severe base deficit, fewer red blood cell and plasma transfusions, and a later median time of death (98 [21-230] hours vs. 17 [4-91] hours). In multivariable Cox models that accounted for time-varying blood product ratios, the associations were consistent, regardless of whether outcome was defined as mortality or the composite., Conclusion: DNR orders were instituted after the 24-hour period of highest mortality risk and more often in older patients not in severe shock. Findings from the primary PROMMTT analyses of the impact of blood product ratios on survival did not materially change when the original mortality outcome was redefined as a composite of DNR or death. DNR orders are potentially an important mediating variable that should be systematically evaluated in trauma research.

Introduction: Focused assessment with sonography for trauma (FAST) is commonly used to facilitate the timely diagnosis of life-threatening hemorrhage in injured patients. Most patients with positive findings on FAST require laparotomy. Although it is assumed that an increasing time to operation (T-OR) leads to higher mortality, this relationship has not been quantified. This study sought to determine the impact of T-OR on survival in patients with a positive FAST who required emergent laparotomy., Methods: We retrospectively analyzed patients from the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study who underwent laparotomy within 90 minutes of presentation and had a FAST performed. Cox proportional hazards models including Injury Severity Score (ISS), age, base deficit, and hospital site were created to examine the impact of increasing T-OR on in-hospital survival at 24 hours and 30 days. The impact of time from the performance of the FAST examination to operation (TFAST-OR) on in-hospital mortality was also examined using the same model., Results: One hundred fifteen patients met study criteria and had complete data. Increasing T-OR was associated with increased in-hospital mortality at 24 hours (hazard ratio [HR], 1.50 for each 10-minute increase in T-OR; confidence interval [CI], 1.14-1.97; p = 0.003) and 30 days (HR, 1.41; CI, 1.18-2.10; p = 0.002). Increasing TFAST-OR was also associated with higher in-hospital mortality at 24 hours (HR, 1.34; CI, 1.03-1.72; p = 0.03) and 30 days (HR, 1.40; CI, 1.06-1.84; p = 0.02)., Conclusion: In patients with a positive FAST who required emergent laparotomy, delay in operation was associated with increased early and late in-hospital mortality. Delays in T-OR in trauma patients with a positive FAST should be minimized.

Background: Massive haemorrhage is a leading cause of preventable deaths in trauma. Traumatic coagulopathy is frequently present early after trauma, and is associated with increased mortality. A number of recent trials suggest that viscoelastic haemostatic assays (VHA), such as thromboelastography and thromboelastometry, are useful tools in guiding transfusion. Treatment algorithms exist for the use of VHAs but are not validated in traumatic haemorrhage. In this study we examined the inter-changeability of two commonly used VHAs, TEG(®) and RoTEM(®)., Methods: A total of 184 trauma patients over the age of 18, requiring full trauma team activation, were included at three different hospitals in three different countries (Copenhagen, Denmark, San Francisco, CA, USA and Oslo, Norway). Blood samples were drawn immediately upon arrival, and TEG(®) and RoTEM(®) analyzed simultaneously. Correlations were calculated using. Spearman's rank correlation coefficient. Agreement was evaluated by Bland-Altman plots and calculation of limits of agreement., Results: The mean ISS in the total population was 17, and the mortality was 16.5%. Mean base excess was -2.8 (SD: 4.2). The correlation coefficient for corresponding values for the two devices was 0.24 for the R-time vs CT in all centres combined. For the K-time vs CFT the correlation was 0.48, for the α-angleTEG vs α-angleRoTEM 0.44, and for MA vs MCF 0.76. Limits of agreement exceeded the preset clinically acceptable deviation of 10% for all variables in all centres except for MA/MCF in one centre (Copenhagen). Generally, correlation coefficients were lower and agreement poorer in the one centre (Oslo) where measurements were performed bedside by clinicians., Conclusion: Inter-changeability between TEG(®) and RoTEM(®) is limited in the trauma setting. Agreement seems poorer when clinicians operate the devices. Development and validation of separate treatment algorithms for the two devices is required., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To relate in-hospital mortality to early transfusion of plasma and/or platelets and to time-varying plasma:red blood cell (RBC) and platelet:RBC ratios., Design: Prospective cohort study documenting the timing of transfusions during active resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards models., Setting: Ten US level I trauma centers., Patients: Adult trauma patients surviving for 30 minutes after admission who received a transfusion of at least 1 unit of RBCs within 6 hours of admission (n = 1245, the original study group) and at least 3 total units (of RBCs, plasma, or platelets) within 24 hours (n = 905, the analysis group)., Main Outcome Measure: In-hospital mortality., Results: Plasma:RBC and platelet:RBC ratios were not constant during the first 24 hours (P < .001 for both). In a multivariable time-dependent Cox model, increased ratios of plasma:RBCs (adjusted hazard ratio = 0.31; 95% CI, 0.16-0.58) and platelets:RBCs (adjusted hazard ratio = 0.55; 95% CI, 0.31-0.98) were independently associated with decreased 6-hour mortality, when hemorrhagic death predominated. In the first 6 hours, patients with ratios less than 1:2 were 3 to 4 times more likely to die than patients with ratios of 1:1 or higher. After 24 hours, plasma and platelet ratios were unassociated with mortality, when competing risks from nonhemorrhagic causes prevailed., Conclusions: Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission. Among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or platelet ratios.

Background: Early predictors of massive transfusion (MT) would prevent undertriage of patients likely to require MT. This study validates triggers using the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study., Methods: All enrolled patients in PROMMTT were analyzed. The initial emergency department value for each trigger (international normalized ratio [INR], systolic blood pressure, hemoglobin, base deficit, positive result for Focused Assessment for the Sonography of Trauma examination, heart rate, temperature, and penetrating injury mechanism) was compared for patients receiving MT (≥ 10 U of packed red blood cells in 24 hours) versus no MT. Adjusted odds ratios (ORs) for MT are reported using multiple logistic regression. If all triggers were known, a Massive Transfusion Score (MTS) was created, with 1 point assigned for each met trigger., Results: A total of 1,245 patients were prospectively enrolled with 297 receiving an MT. Data were available for all triggers in 66% of the patients including 67% of the MTs (199 of 297). INR was known in 87% (1,081 of 1,245). All triggers except penetrating injury mechanism and heart rate were valid individual predictors of MT, with INR as the most predictive (adjusted OR, 2.5; 95% confidence interval, 1.7-3.7). For those with all triggers known, a positive INR trigger was seen in 49% receiving MT. Patients with an MTS of less than 2 were unlikely to receive MT (negative predictive value, 89%). If any two triggers were present (MTS ≥ 2), sensitivity for predicting MT was 85%. MT was present in 33% with an MTS of 2 greater compared with 11% of those with MTS of less than 2 (OR, 3.9; 95% confidence interval, 2.6-5.8; p < 0.0005)., Conclusion: Parameters that can be obtained early in the initial emergency department evaluation are valid predictors for determining the likelihood of MT., Level of Evidence: Diagnostic, level II.

Background: Coagulopathy is present in 25% to 38% of trauma patients on arrival to the hospital, and these patients are four times more likely to die than trauma patients without coagulopathy. Recently, a high ratio of fresh frozen plasma (FFP) to packed red blood cells (PRBCs) has been shown to decrease mortality in massively transfused trauma patients. Therefore, we hypothesized that patients with elevated International Normalized Ratio (INR) on arrival to the hospital may benefit more from transfusion with a high ratio of FFP:PRBC than those with a lower INR., Methods: Retrospective multicenter cohort study of 437 massively transfused trauma patients was conducted to determine whether the effect of the ratio of FFP:PRBC on death at 24 hours is modified by a patient's admission INR on arrival to the hospital. Contingency tables and logistic regression were used., Results: Trauma patients who arrived to the hospital with an elevated INR had a greater risk of death than those with a lower INR. However, as the ratio of FFP:PRBC transfused increased, mortality decreased similarly between the INR quartiles., Conclusions: The mortality benefit from a high FFP:PRBC ratio is similar for all massively transfused trauma patients. This is contrary to the current belief that only coagulopathic trauma patients benefit from a high FFP:PRBC ratio. Furthermore, it is unnecessary to determine whether INR is elevated before transfusing a high FFP:PRBC ratio. Future studies are needed to determine the mechanism by which a high FFP:PRBC ratio decreases mortality in all massively transfused trauma patients.

Background: Platelets play a central role in hemostasis after trauma. However, the platelet count of most trauma patients does not fall below the normal range (100-450 × 10(9)/L), and as a result, admission platelet count has not been adequately investigated as a predictor of outcome. The purpose of this study was to examine the relationship between admission platelet count and outcomes after trauma., Methods: A retrospective cohort study of 389 massively transfused trauma patients. Regression methods and the Kruskal-Wallis test were used to test the association between admission platelet count and 24-hour mortality and units of packed red blood cells (PRBCs) transfused., Results: For every 50 × 10(9)/L increase in admission platelet count, the odds of death decreased 17% at 6 hours (p = 0.03; 95% confidence interval [CI], 0.70-0.99) and 14% at 24 hours (p = 0.02; 95% CI, 0.75-0.98). The probability of death at 24 hours decreased with increasing platelet count. For every 50 × 10(9)/L increase in platelet count, patients received 0.7 fewer units of blood within the first 6 hours (p = 0.01; 95% CI, -1.3 to -0.14) and one less unit of blood within the first 24 hours (p = 0.002; 95% CI, -1.6 to -0.36). The mean number of units of PRBCs transfused within the first 6 hours and 24 hours decreased with increasing platelet count., Conclusions: Admission platelet count was inversely correlated with 24-hour mortality and transfusion of PRBCs. A normal platelet count may be insufficient after severe trauma, and as a result, these patients may benefit from a lower platelet transfusion threshold. Future studies of platelet number and function after injury are needed.

Background: The receptor for advanced glycation endproducts (RAGE) recognizes a variety of ligands that play an important role in the posttraumatic inflammatory response. However, whether soluble RAGE (sRAGE) is released early after trauma hemorrhage in humans and whether such a release is associated with the development of an inflammatory response and coagulopathy is not known and therefore constitutes the aim of this study., Methods: One hundred sixty-eight patients were studied as part of a prospective cohort study of severe trauma patients admitted to a single Level I Trauma center. Blood was drawn within 10 minutes of arrival to the emergency department before the administration of any fluid resuscitation. sRAGE, tumor necrosis factor-alpha, interleukin-6, von Willebrand factor, angiopoietin-2, prothrombin time, prothrombin fragments 1 + 2, soluble thrombomodulin, protein C, plasminogen activator inhibitor-1, and d-dimers (fibrin degradation products) were measured using standard techniques. Base deficit was used as a measure of tissue hypoperfusion. Measurements were compared with outcome measures obtained from the electronic medical record and trauma registry., Results: Plasma levels of sRAGE were increased within 30 minutes after severe trauma in humans and correlated with the severity of injury, early posttraumatic coagulopathy and hyperfibrinolysis, and endothelial cell activation (angiopoietin-1 and complement). Furthermore, we found that there was a significant relationship between plasma levels of sRAGE and the development of acute renal failure. This relationship was not quite significant for patients who developed acute lung injury (p = 0.11), although patients with <26 ventilator-free days had significantly higher plasma levels of sRAGE than those with >26 ventilator-free days. Finally, there was no relationship between plasma levels of sRAGE and mortality rate in trauma patients., Conclusion: The results of this study demonstrate that the release of sRAGE in the bloodstream of trauma patients requires severe injury and is associated with coagulation abnormalities and endothelial cell and complement activation.

Introduction: The massive-transfusion concept was introduced to recognize the dilutional complications resulting from large volumes of packed red blood cells (PRBCs). Definitions of massive transfusion vary and lack supporting clinical evidence. Damage-control resuscitation regimens of modern trauma care are targeted to the early correction of acute traumatic coagulopathy. The aim of this study was to identify a clinically relevant definition of trauma massive transfusion based on clinical outcomes. We also examined whether the concept was useful in that early prediction of massive transfusion requirements could allow early activation of blood bank protocols., Methods: Datasets on trauma admissions over a 1 or 2-year period were obtained from the trauma registries of five large trauma research networks. A fractional polynomial was used to model the transfusion-associated probability of death. A logistic regression model for the prediction of massive transfusion, defined as 10 or more units of red cell transfusions, was developed., Results: In total, 5,693 patient records were available for analysis. Mortality increased as transfusion requirements increased, but the model indicated no threshold effect. Mortality was 9% in patients who received none to five PRBC units, 22% in patients receiving six to nine PRBC units, and 42% in patients receiving 10 or more units. A logistic model for prediction of massive transfusion was developed and validated at multiple sites but achieved only moderate performance. The area under the receiver operating characteristic curve was 0.81, with specificity of only 50% at a sensitivity of 90% for the prediction of 10 or more PRBC units. Performance varied widely at different trauma centers, with specificity varying from 48% to 91%., Conclusions: No threshold for definition exists at which a massive transfusion specifically results in worse outcomes. Even with a large sample size across multiple trauma datasets, it was not possible to develop a transportable and clinically useful prediction model based on available admission parameters. Massive transfusion as a concept in trauma has limited utility, and emphasis should be placed on identifying patients with massive hemorrhage and acute traumatic coagulopathy.

Platelets are damage sentinels of the intravascular compartment, initiating and coordinating the primary response to tissue injury. Severe trauma and hemorrhage induce profound alterations in platelet behavior. During the acute post-injury phase, platelets develop a state of impaired ex vivo agonist responsiveness independent of platelet count, associated with systemic coagulopathy and mortality risk. In patients surviving the initial insult, platelets become hyper-responsive, associated with increased risk of thrombotic events. Beyond coagulation, platelets constitute part of a sterile inflammatory response to injury: both directly through release of immunomodulatory molecules, and indirectly through modifying behavior of innate leukocytes. Both procoagulant and proinflammatory aspects have implications for secondary organ injury and multiple-organ dysfunction syndromes. This review details our current understanding of adaptive and maladaptive alterations in platelet biology induced by severe trauma, mechanisms underlying these alterations, potential platelet-focused therapies, and existing knowledge gaps and their research implications.

Understanding the coagulation process is critical to developing treatments for trauma and coagulopathies. Clinical studies on tranexamic acid (TXA) have resulted in mixed reports on its efficacy in improving outcomes in trauma patients. The largest study, CRASH-2, reported that TXA improved outcomes in patients who received treatment prior to 3 hours after the injury, but worsened outcomes in patients who received treatment after 3 hours. No consensus has been reached about the mechanism behind the duality of these results. In this paper we use a computational model for coagulation and fibrinolysis to propose that deficiencies or depletions of key anti-fibrinolytic proteins, specifically antiplasmin, a1-antitrypsin and a2-macroglobulin, can lead to worsened outcomes through urokinase-mediated hyperfibrinolysis.

Trauma remains a leading cause of death worldwide, and most early preventable deaths in both the civilian and military settings are due to uncontrolled hemorrhage, despite paradigm advances in modern trauma care. Combined tissue injury and shock result in hemostatic failure, which has been identified as a multidimensional molecular, physiologic and clinical disorder termed trauma-induced coagulopathy (TIC). Understanding the biology of TIC is of utmost importance, as it is often responsible for uncontrolled bleeding, organ failure, thromboembolic complications, and death. Investigations have shown that TIC is characterized by multiple phenotypes of impaired hemostasis due to altered biology in clot formation and breakdown. These coagulopathies are attributable to tissue injury and shock, and encompass underlying endothelial, immune and inflammatory perturbations. Despite the recognition and identification of multiple mechanisms and mediators of TIC, and the development of targeted treatments, the mortality rates and associated morbidities due to hemorrhage after injury remain high. The purpose of this review is to examine the past and present understanding of the multiple distinct but highly integrated pathways implicated in TIC, in order to highlight the current knowledge gaps and future needs in this evolving field, with the aim of reducing morbidity and mortality after injury.

BackgroundHistorically, 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.MethodsEighteen 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.ResultsOne 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.ConclusionExsanguination 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 evidenceEpidemiologic, level II.

BackgroundThe Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) study evaluated the effects of plasma and platelets on hemostasis and mortality after hemorrhage. The pulmonary consequences of resuscitation strategies that mimic whole blood, remain unknown.MethodsA secondary analysis of the PROPPR study was performed. Injured patients predicted to receive a massive transfusion were randomized to 1:1:1 versus 1:1:2 plasma-platelet-red blood cell ratios at 12 Level I North American trauma centers. Patients with survival >24 h, an intensive care unit (ICU) stay, and a recorded PaO2/FiO2 (P/F) ratio were included. Acute respiratory distress syndrome (ARDS) was defined as a P/F ratio