Summary
The severely injured trauma patient often arrives in the emergency department bleeding, coagulopathic and in need of a blood transfusion. The diagnosis and management of these patients has ...vastly improved with a better understanding of acute traumatic coagulopathy (ATC). In the emergency setting, traditional laboratory coagulation screens are of limited use in the diagnosis and management of life‐threatening bleeding. Whole blood assays, such as thrombelastography (TEG) and rotational thrombelastometry (ROTEM) provide a rapid evaluation of clot formation, strength and lysis. Rapid diagnosis of ATC and aggressive haemostatic transfusion strategies utilizing early high doses of plasma are associated with improved outcomes in trauma. At present there is no accurate guide for transfusion in trauma, therefore blood and clotting products are administered on an empiric basis. Targeted transfusion therapy for major trauma haemorrhage based on comprehensive and rapid measures of coagulation e.g. TEG/ROTEM may lead to improved outcomes while optimizing blood utilization. Evidence for the clinical application of TEG and ROTEM in trauma is emerging with a number of studies evaluating their ability to diagnose coagulopathy early and facilitate goal‐directed transfusion. This review explores current controversies and best practice in the diagnosis and management of major haemorrhage in trauma.
Trauma-induced coagulopathy (TIC) is present soon after injury and is associated with increased transfusion requirements and worse outcomes. The pathophysiological mechanisms, which result in the ...widespread derangements of hemostasis following major trauma hemorrhage, are as yet not fully defined. Profound activation of fibrinolytic pathways and fibrinogen depletion appear to be fundamental processes in the development of TIC and offer potential therapeutic targets. Collaborative and multi-disciplinary scientific study is thus a research priority in order to characterize the primary drivers of TIC and develop targeted and efficacious treatment strategies.
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer (rs9349379-G allele), chromosome 6 (PHACTR1/EDN1). We performed a ...multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD).
Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013. The G allele was associated with higher plasma serum ET-1 least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005. Patients with rs9349379-G allele had over double the odds of CMD odds ratio (OR) 2.33, 95% CI 1.10-4.96; P = 0.027. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status.
We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina.
ClinicalTrials.gov: NCT03193294.
The prior existence of human ACE2 protein-expressing mice used to study SARS-CoV and the rapid development of mouse-adapted virus strains have allowed the study of SARS-CoV-2 in mice, even as we are ...still learning about its natural pathology in humans. With myriad genetically altered strains on the C57BL/6 background and the abundance of immunological reagents available to interrogate its immune responses, the C57BL/6 mice may provide useful insight into the immunology of SARS-CoV-2 infection and vaccination. To conduct more detailed studies on their T cell responses to vaccines and infection, the epitopes eliciting those responses must be characterized in further detail. In this study, we mapped CD8 T cell epitopes within the receptor binding domain of the SARS-CoV-2 spike protein in C57BL/6 mice. Our study identified five major CD8 T cell epitopes in immunized C57BL/6 mice, including one, VVLSFELL, presented by H-2K
and common between SARS-CoV and SARS-CoV-2.
Purpose of review
The use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) to temporarily control bleeding and improve central perfusion in critically injured trauma patients ...remains a controversial topic. In the last decade, select trauma services around the world have gained experience with REBOA. We discuss the recent observational data together with the initial results of the first randomized control trial and provide a view on the next steps for REBOA in trauma resuscitation.
Recent findings
While the observational data continue to be conflicting, the first randomized control trial signals that in the UK, in-hospital REBOA is associated with harm. Likely a result of delays to haemorrhage control, views are again split on whether to abandon complex interventions in bleeding trauma patients and to only prioritize transfer to the operating room or to push REBOA earlier into the post injury phase, recognizing that some patients will not survive without intervention.
Summary
Better understanding of cardiac shock physiology provides a new lens in which to evaluate REBOA through. Patient selection remains a huge challenge. Invasive blood pressure monitoring, combined with machine learning aided decision support may assist clinicians and their patients in the future. The use of REBOA should not delay definitive haemorrhage control in those patients without impending cardiac arrest.
The relationship between late clinical outcomes after injury and early dynamic changes between fibrinolytic states is not fully understood. The authors hypothesized that temporal transitions in ...fibrinolysis states using rotational thromboelastometry (ROTEM) would aid stratification of adverse late clinical outcomes and improve understanding of how tranexamic acid modulates the fibrinolytic response and impacts mortality.
The authors conducted a secondary analysis of previously collected data from trauma patients enrolled into an ongoing prospective cohort study (International Standard Randomised Controlled Trial Number ISRCTN 12962642) at a major trauma center in the United Kingdom. ROTEM was performed on admission and at 24 h with patients retrospectively grouped into three fibrinolysis categories: tissue factor-activated ROTEM maximum lysis of less than 5% (low); tissue factor-activated ROTEM maximum lysis of 5 to 15% (normal); or tissue factor-activated ROTEM maximum lysis of more than 15% (high). Primary outcomes were multiorgan dysfunction syndrome and 28-day mortality.
Seven-hundred thirty-one patients were included: 299 (41%) were treated with tranexamic acid and 432 (59%) were untreated. Two different cohorts with low-maximum lysis at 24 h were identified: (1) severe brain injury and (2) admission shock and hemorrhage. Multiple organ dysfunction syndrome was greatest in those with low-maximum lysis on admission and at 24 h, and late mortality was four times higher than in patients who remained normal during the first 24 h (7 of 42 17% vs. 9 of 223 4%; P = 0.029). Patients that transitioned to or remained in low-maximum lysis had increased odds of organ dysfunction (5.43 95% CI, 1.43 to 20.61 and 4.85 95% CI, 1.83 to 12.83, respectively). Tranexamic acid abolished ROTEM hyperfibrinolysis (high) on admission, increased the frequency of persistent low-maximum lysis (67 of 195 34%) vs. 8 of 79 10%; P = 0.002), and was associated with reduced early mortality (28 of 195 14% vs. 23 of 79 29%; P = 0.015). No increase in late deaths, regardless of fibrinolysis transition patterns, was observed.
Adverse late outcomes are more closely related to 24-h maximum lysis, irrespective of admission levels. Tranexamic acid alters early fibrinolysis transition patterns, but late mortality in patients with low-maximum lysis at 24 h is not increased.
Purpose
Contemporary trauma resuscitation prioritizes control of bleeding and uses major haemorrhage protocols (MHPs) to prevent and treat coagulopathy. We aimed to determine whether augmenting MHPs ...with Viscoelastic Haemostatic Assays (VHA) would improve outcomes compared to Conventional Coagulation Tests (CCTs).
Methods
This was a multi-centre, randomized controlled trial comparing outcomes in trauma patients who received empiric MHPs, augmented by either VHA or CCT-guided interventions. Primary outcome was the proportion of subjects who, at 24 h after injury, were alive and free of massive transfusion (10 or more red cell transfusions). Secondary outcomes included 28-day mortality. Pre-specified subgroups included patients with severe traumatic brain injury (TBI).
Results
Of 396 patients in the intention to treat analysis, 201 were allocated to VHA and 195 to CCT-guided therapy. At 24 h, there was no difference in the proportion of patients who were alive and free of massive transfusion (VHA: 67%, CCT: 64%, OR 1.15, 95% CI 0.76–1.73). 28-day mortality was not different overall (VHA: 25%, CCT: 28%, OR 0.84, 95% CI 0.54–1.31), nor were there differences in other secondary outcomes or serious adverse events. In pre-specified subgroups, there were no differences in primary outcomes. In the pre-specified subgroup of 74 patients with TBI, 64% were alive and free of massive transfusion at 24 h compared to 46% in the CCT arm (OR 2.12, 95% CI 0.84–5.34).
Conclusion
There was no difference in overall outcomes between VHA- and CCT-augmented-major haemorrhage protocols.
OBJECTIVE:To characterize the relationship between tranexamic acid (TXA) use and patient outcomes in a severely injured civilian cohort, and to determine any differential effect between patients who ...presented with and without shock.
BACKGROUND:TXA has demonstrated survival benefits in trauma patients in an international randomized control trial and the military setting. The uptake of TXA into civilian major hemorrhage protocols (MHPs) has been variable. The evidence gap in mature civilian trauma systems is limiting the widespread use of TXA and its potential benefits on survival.
METHODS:Prospective cohort study of severely injured adult patients (Injury severity score > 15) admitted to a civilian trauma system during the adoption phase of TXA into the hospitalʼs MHP. Outcomes measured were mortality, multiple organ failure (MOF), venous thromboembolism, infection, stroke, ventilator-free days (VFD), and length of stay.
RESULTS:Patients receiving TXA (n = 160, 42%) were more severely injured, shocked, and coagulopathic on arrival. TXA was not independently associated with any change in outcome for either the overall or nonshocked cohorts. In multivariate analysis, TXA was independently associated with a reduction in MOF odds ratio (OR) = 0.27, confidence interval (CI)0.10–0.73, P = 0.01 and was protective for adjusted all-cause mortality (OR = 0.16 CI0.03–0.86, P = 0.03) in shocked patients.
CONCLUSIONS:TXA as part of a major hemorrhage protocol within a mature civilian trauma system provides outcome benefits specifically for severely injured shocked patients.
OBJECTIVE:To identify an appropriate diagnostic tool for the early diagnosis of acute traumatic coagulopathy and validate this modality through prediction of transfusion requirements in trauma ...hemorrhage.
DESIGN:Prospective observational cohort study.
SETTING:Level 1 trauma center.
PATIENTS:Adult trauma patients who met the local criteria for full trauma team activation. Exclusion criteria included emergency department arrival >2 hrs after injury, >2000 mL of intravenous fluid before emergency department arrival, or transfer from another hospital.
INTERVENTIONS:None.
MEASUREMENTS:Blood was collected on arrival in the emergency department and analyzed with laboratory prothrombin time, point-of-care prothrombin time, and rotational thromboelastometry. Prothrombin time ratio was calculated and acute traumatic coagulopathy defined as laboratory prothrombin time ratio >1.2. Transfusion requirements were recorded for the first 12 hrs following admission.
MAIN RESULTS:Three hundred patients were included in the study. Laboratory prothrombin time results were available at a median of 78 (62–103) mins. Point-of-care prothrombin time ratio had reduced agreement with laboratory prothrombin time ratio in patients with acute traumatic coagulopathy, with 29% false-negative results. In acute traumatic coagulopathy, the rotational thromboelastometry clot amplitude at 5 mins was diminished by 42%, and this persisted throughout clot maturation. Rotational thromboelastometry clotting time was not significantly prolonged. Clot amplitude at a 5-min threshold of ≤35 mm had a detection rate of 77% for acute traumatic coagulopathy with a false-positive rate of 13%. Patients with clot amplitude at 5 mins ≤35 mm were more likely to receive red cell (46% vs. 17%, p < .001) and plasma (37% vs. 11%, p < .001) transfusions. The clot amplitude at 5 mins could identify patients who would require massive transfusion (detection rate of 71%, vs. 43% for prothrombin time ratio >1.2, p < .001).
CONCLUSIONS:In trauma hemorrhage, prothrombin time ratio is not rapidly available from the laboratory and point-of-care devices can be inaccurate. Acute traumatic coagulopathy is functionally characterized by a reduction in clot strength. With a threshold of clot amplitude at 5 mins of ≤35 mm, rotational thromboelastometry can identify acute traumatic coagulopathy at 5 mins and predict the need for massive transfusion.