Dried Plasma for Major Trauma: Past, Present, and Future.

Uncontrollable bleeding is recognized as the leading cause of preventable death among trauma patients. Early transfusion of blood products, especially plasma replacing crystalloid and colloid solutions, has been shown to increase survival of severely injured patients. However, the requirements for cold storage and thawing processes prior to transfusion present significant logistical challenges in prehospital and remote areas, resulting in a considerable delay in receiving thawed or liquid plasma, even in hospitals. In contrast, freeze- or spray-dried plasma, which can be massively produced, stockpiled, and stored at room temperature, is easily carried and can be reconstituted for transfusion in minutes, provides a promising alternative. Drawn from history, this paper provides a review of different forms of dried plasma with a focus on in vitro characterization of hemostatic properties, to assess the effects of the drying process, storage conditions in dry form and after reconstitution, their distinct safety and/or efficacy profiles currently in different phases of development, and to discuss the current expectations of these products in the context of recent preclinical and clinical trials. Future research directions are presented as well.

Post-Reconstitution Hemostatic Stability Profiles of Canadian and German Freeze-Dried Plasma.

Despite the importance of the hemostatic properties of reconstituted freeze-dried plasma (FDP) for trauma resuscitation, few studies have been conducted to determine its post-reconstitution hemostatic stability. This study aimed to assess the short- (≤24 h) and long-term (≥168 h) hemostatic stabilities of Canadian and German freeze-dried plasma (CFDP and LyoPlas) after reconstitution and storage under different conditions. Post-reconstitution hemostatic profiles were determined using rotational thromboelastometry (ROTEM) and a Stago analyzer, as both are widely used as standard methods for assessing the quality of plasma. When compared to the initial reconstituted CFDP, there were no changes in ROTEM measurements for INTEM maximum clot firmness (MCF), EXTEM clotting time (CT) and MCF, and Stago measurements for prothrombin time (PT), partial thromboplastin time (PTT), D-dimer concentration, plasminogen, and protein C activities after storage at 4 °C for 24 h and room temperature (RT) (22-25 °C) for 4 h. However, an increase in INTEM CT and decreases in fibrinogen concentration, factors V and VIII, and protein S activities were observed after storage at 4 °C for 24 h, while an increase in factor V and decreases in antithrombin and protein S activities were seen after storage at RT for 4 h. Evaluation of the long-term stability of reconstituted LyoPlas showed decreased stability in both global and specific hemostatic profiles with increasing storage temperatures, particularly at 35 °C, where progressive changes in CT and MCF, PT, PTT, fibrinogen concentration, factor V, antithrombin, protein C, and protein S activities were seen even after storage for 4 h. We confirmed the short-term stability of CFDP in global hemostatic properties after reconstitution and storage at RT, consistent with the shelf life of reconstituted LyoPlas. The long-term stability analyses suggest that the post-reconstitution hemostatic stability of FDP products would decrease over time with increasing storage temperature, with a significant loss of hemostatic functions at 35 °C compared to 22 °C or below. Therefore, the shelf life of reconstituted FDP should be recommended according to the storage temperature.

Past meets present: Reviving 80-year-old Canadian dried serum from World War II and its significance in advancing modern freeze-dried plasma for prehospital management of haemorrhage.

During World War II, Charles H. Best utilized Charles R. Drew's plasma isolation and drying technique to lead Canada's initiative to provide dried serum as a means of primary resuscitation for British casualties on the frontlines. Serum was likely utilized over plasma for its volume expansion properties without the risk of clotting during prolonged storage. We reconstituted dried serum from 1943 and discovered intact albumin, as well as anti-thrombin, plasminogen, protein C and protein S activity. Proteomic analysis identified 71 proteins, most prominent being albumin, and positive for hepatitis B by serological testing. Transmission of blood-borne diseases ended the programme, until modern advances in testing and pathogen reduction revived this technology. We tested the latest iteration of Canadian freeze-dried plasma (FDP), which was stored for 4 years, and demonstrated that its clotting capacity remained equivalent to fresh frozen plasma. We recommend that FDP is a strong alternative to contemporary prehospital resuscitation fluids (e.g. normal saline/lactated Ringer's) in managing prehospital haemorrhage where whole blood is unavailable.

Artificial intelligence and machine learning for hemorrhagic trauma care.

Artificial intelligence (AI), a branch of machine learning (ML) has been increasingly employed in the research of trauma in various aspects. Hemorrhage is the most common cause of trauma-related death. To better elucidate the current role of AI and contribute to future development of ML in trauma care, we conducted a review focused on the use of ML in the diagnosis or treatment strategy of traumatic hemorrhage. A literature search was carried out on PubMed and Google scholar. Titles and abstracts were screened and, if deemed appropriate, the full articles were reviewed. We included 89 studies in the review. These studies could be grouped into five areas: (1) prediction of outcomes; (2) risk assessment and injury severity for triage; (3) prediction of transfusions; (4) detection of hemorrhage; and (5) prediction of coagulopathy. Performance analysis of ML in comparison with current standards for trauma care showed that most studies demonstrated the benefits of ML models. However, most studies were retrospective, focused on prediction of mortality, and development of patient outcome scoring systems. Few studies performed model assessment via test datasets obtained from different sources. Prediction models for transfusions and coagulopathy have been developed, but none is in widespread use. AI-enabled ML-driven technology is becoming integral part of the whole course of trauma care. Comparison and application of ML algorithms using different datasets from initial training, testing and validation in prospective and randomized controlled trials are warranted for provision of decision support for individualized patient care as far forward as possible.

Freeze-dried plasma: From damage control resuscitation to coronavirus disease 2019 therapy.

BACKGROUND: Freeze-dried plasma (FDP) is a promising blood component for prehospital resuscitation given its logistic advantages over fresh frozen plasma (FFP). COVID-19 convalescent (CC) plasma has been used to treat coronavirus disease 2019 (COVID-19) patients, and its corresponding FDP has potential use during future pandemics. Therefore, we conducted the study to determine if the hemostatic and immunological properties of plasma can be retained after lyophilization. STUDY DESIGN AND METHODS: Hemostatic tests were conducted with Rotational Thromboelastometry (ROTEM) and a Stago analyzer. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG (Immunoglobulin G) and neutralizing activity were analyzed using Meso Scale Diagnostics immunoassay kits. RESULTS: There were no differences in ROTEM parameters and Stago measurements for prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and D-dimer concentrations, and antithrombin, factor V, VIII, and protein S activities between FFP and FDP for either pre-COVID-19 or CC samples. Differences were observed in INTEM clotting time and PT and PTT when comparing reconstituted FDP stored at 4°C for 24 h or room temperature for 4 h to healthy control. Both CC-FFP and CC-FDP showed two orders of magnitude higher concentrations of IgG antibodies against SARS-CoV-2 antigens than pre-COVID-19-FFP and pre-COVID-19-FDP and healthy control. Similarly, the CC samples showed approximately 4-fold higher %-inhibition of receptor binding than the pre-COVID-19 samples. There were no differences in either the antibody levels or neutralization activity between CC-FFP and CC-FDP. DISCUSSION: We demonstrated that FDP and CC-FDP retained the same hemostatic and antibody functional activities relative to their initial plasma sources, supporting clinical evaluation of their benefits in severe trauma and COVID-19 patients.

Correction: Convalescent Plasma for the Prevention and Treatment of COVID-19: A Systematic Review and Quantitative Analysis.

[This corrects the article DOI: 10.2196/25500.].

Evaluation of trauma-induced coagulopathy in the fibrinogen in the initial resuscitation of severe trauma trial.

BACKGROUND: Coagulopathic bleeding is frequently present after major trauma. However, trauma-induced coagulopathy (TIC) remains incompletely understood. This laboratory analysis of blood samples derived from our completed trial on fibrinogen in the initial resuscitation of severe trauma (FiiRST) was conducted to evaluate TIC and associated responses to fibrinogen replacement. STUDY DESIGN AND METHODS: We conducted a retrospective evaluation of TIC in 45 FiiRST trial patients based on rotational thromboelastometry (ROTEM), international normalized ratio (INR), and biomarkers for hemostasis and endotheliopathy. Whole blood was analyzed by ROTEM. Plasma was analyzed for INR and biomarkers. RESULTS: Overall, 19.0% and 30.0% of the FiiRST trial patients were coagulopathic on admission defined by EXTEM maximum clot firmness out of the range of 40-71 mm and INR >1.2, respectively. The FiiRST patients showed lower fibrinogen, factor II and V levels, protein C and antiplasmin activities, higher activated protein C, tissue plasminogen activator, d-dimer, and thrombomodulin concentrations at admission than healthy controls. Most of the biomarkers changed their activities during 48-h hospitalization, but were at abnormal levels even 48-h after admission. The fibrinogen treatment reduced hypofibrinogenemia and increased factor XIII level, but had no significant effects on other biomarkers levels. Limited development of endotheliopathy was indicated by syndean-1, thrombomodulin, and sE-selectin. CONCLUSIONS: About 19%-30% of the trauma patients in the FiiRST trial were coagulopathic on hospital admission depending on the definition of TIC. Analyses of the TIC biomarkers demonstrated that hemostasis would not return to normal after 48-h hospitalization, and fibrinogen replacement improved hypofibrinogenemia.

Ex vivo hemostatic and immuno-inflammatory profiles of freeze-dried plasma.

BACKGROUND: Hemorrhage is a leading cause of preventable death in civilian and military trauma. Freeze-dried plasma is promising for hemostatic resuscitation in remote prehospital settings, given its potential benefits in reducing blood loss and mortality, long storage at ambient temperatures, high portability, and rapid reconstitution for transfusion in austere environments. Here we assess the ex vivo characteristics of a novel Terumo's freeze-dried plasma product (TFDP). STUDY DESIGN AND METHODS: Rotational thromboelastometry (ROTEM) tests (INTEM, EXTEM, and FIBTEM) were conducted on plasma samples at 37°C with a ROTEM delta-machine using standard reagents and procedures. The following samples were analyzed: pooled plasma to produce TFDP, TFDP reconstituted, and stored immediately at -80°C, reconstituted TFDP stored at 4°C for 24 h and room temperature (RT) for 4 h before freezing at -80°C. Analysis of plasma concentrations of selected cytokines, chemokines, and vascular molecules was performed using a multiplex immunoassay system. One-way ANOVA with post hoc tests assessed differences in hemostatic and inflammatory properties. RESULTS: No significant differences in ROTEM variables (coagulation time [CT], clot formation time, α-angle, maximum clot firmness, and lysis index 30) between the TFDP-producing plasma and reconstituted TFDP samples were observed. Compared to control plasma, reconstituted TFDP stored at 4°C for 24 h or RT for 4 h showed a longer INTEM CT. Levels of immuno-inflammatory mediators were similar between frozen plasma and TFDP. CONCLUSIONS: TFDP is equivalent to frozen plasma with respect to global hemostatic and immuno-inflammatory mediator profiles. Further investigations of TFDP in trauma-induced coagulopathy models and bleeding patients are warranted.

Convalescent Plasma for the Prevention and Treatment of COVID-19: A Systematic Review and Quantitative Analysis.

BACKGROUND: The COVID-19 pandemic, caused by a novel coronavirus termed SARS-CoV-2, has spread quickly worldwide. Convalescent plasma (CP) obtained from patients following recovery from COVID-19 infection and development of antibodies against the virus is an attractive option for either prophylactic or therapeutic treatment, since antibodies may have direct or indirect antiviral activities and immunotherapy has proven effective in principle and in many clinical reports. OBJECTIVE: We seek to characterize the latest advances and evidence in the use of CP for COVID-19 through a systematic review and quantitative analysis, identify knowledge gaps in this setting, and offer recommendations and directives for future research. METHODS: PubMed, Web of Science, and Embase were continuously searched for studies assessing the use of CP for COVID-19, including clinical studies, commentaries, reviews, guidelines or protocols, and in vitro testing of CP antibodies. The screening process and data extraction were performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Quality appraisal of all clinical studies was conducted using a universal tool independent of study designs. A meta-analysis of case-control and randomized controlled trials (RCTs) was conducted using a random-effects model. RESULTS: Substantial literature has been published covering various aspects of CP therapy for COVID-19. Of the references included in this review, a total of 243 eligible studies including 64 clinical studies, 79 commentary articles, 46 reviews, 19 guidance and protocols, and 35 in vitro testing of CP antibodies matched the criteria. Positive results have been mostly observed so far when using CP for the treatment of COVID-19. There were remarkable heterogeneities in the CP therapy with respect to patient demographics, donor antibody titers, and time and dose of CP administration. The studies assessing the safety of CP treatment reported low incidence of adverse events. Most clinical studies, in particular case reports and case series, had poor quality. Only 1 RCT was of high quality. Randomized and nonrandomized data were found in 2 and 11 studies, respectively, and were included for meta-analysis, suggesting that CP could reduce mortality and increase viral clearance. Despite promising pilot studies, the benefits of CP treatment can only be clearly established through carefully designed RCTs. CONCLUSIONS: There is developing support for CP therapy, particularly for patients who are critically ill or mechanically ventilated and resistant to antivirals and supportive care. These studies provide important lessons that should inform the planning of well-designed RCTs to generate more robust knowledge for the efficacy of CP in patients with COVID-19. Future research is necessary to fill the knowledge gap regarding prevention and treatment for patients with COVID-19 with CP while other therapeutics are being developed.

Stability of Reconstituted Fibrinogen Concentrate in Hemostatic Function and Concentration.

INTRODUCTION: Canadian Armed Forces adopted fibrinogen concentrate (RiaSTAP) for hemostatic resuscitation in the far-forward combat setting, given its potential benefits of reducing blood loss, blood transfusion and mortality, and its long storage stability and high portability. The current guidance recommends that RiaSTAP should be administered within 8 hours after reconstitution when stored at room temperature. However, little information about its stability is available. There is also a need to investigate the stability and efficacy of RiaSTAP after reconstitution and exposure to extreme temperatures in which our forces may operate. MATERIALS AND METHODS: RiaSTAP was reconstituted as per manufacturer's instruction and stored at specific temperatures (-20°C, 4°C, 22°C, 35°C, 42°C, or 50°C) for up to 6 months. Reconstituted RiaSTAP was also oscillated on a rocker at 18 rpm under 22°C and 50°C. Its hemostatic function was measured using rotational thromboelastometry performed with RiaSTAP-spiked whole blood. Fibrinogen concentrations were measured by a commercial enzyme-linked immunosorbent assay (ELISA) kit. Gel electrophoresis was also conducted for initial and stored samples. RESULTS: We found no change to the hemostatic function of reconstituted RiaSTAP after storage at -20°C for 6 months. At 4°C, no obvious changes to the hemostatic effect of reconstituted RiaSTAP relative to 0 hours were seen until 1,680 hours. At 22°C, a remarkable decrease began after storage for 168 hours. Storage at 35°C significantly decreased the hemostatic effect after 144 hours, while the storage at 42°C resulted in decreased hemostatic function after 72 hours. Finally, storage at 50°C for 8 hours resulted in complete loss of hemostatic function. Compared to the hemostatic activity, the fibrinogen concentration for reconstituted RiaSTAP showed less change over time. No apparent decline in fibrinogen concentration was seen after storage at -20°C for 6 months and at 4°C for 1,680 hours. At 22°C, there were no clear alterations until 792 hours. There was a decline in fibrinogen concentration at 35°C and 42°C after 672 and 600 hours of storage, respectively. At 50°C, little amount of fibrinogen was detected by ELISA at 8 hours. Similar changes in the hemostatic effect and fibrinogen concentration over time were observed under the rocking condition in comparison with the static condition at the same temperature. The gel electrophoresis confirmed fibrinogen degradation which increased with storage temperature and time. CONCLUSIONS: The stability of reconstituted RiaSTAP decreases with increasing storage temperature. The hemostatic function deteriorated before fibrinogen concentration and integrity were significantly altered at all temperatures for the study period except at 50°C where there was a rapid decline in both hemostatic function and fibrinogen concentration. Sample oscillation did not significantly affect its stability. The shelf life of reconstituted RiaSTAP may, therefore, be recommended accordingly when stored at different temperatures and extended to 6 days at room temperature provided that sterility is maintained.

Hemostatic agents for prehospital hemorrhage control: a narrative review.

Hemorrhage is the leading cause of preventable death in combat trauma and the secondary cause of death in civilian trauma. A significant number of deaths due to hemorrhage occur before and in the first hour after hospital arrival. A literature search was performed through PubMed, Scopus, and Institute of Scientific Information databases for English language articles using terms relating to hemostatic agents, prehospital, battlefield or combat dressings, and prehospital hemostatic resuscitation, followed by cross-reference searching. Abstracts were screened to determine relevance and whether appropriate further review of the original articles was warranted. Based on these findings, this paper provides a review of a variety of hemostatic agents ranging from clinically approved products for human use to newly developed concepts with great potential for use in prehospital settings. These hemostatic agents can be administered either systemically or locally to stop bleeding through different mechanisms of action. Comparisons of current hemostatic products and further directions for prehospital hemorrhage control are also discussed.

A comparative study of viscoelastic hemostatic assays and conventional coagulation tests in trauma patients receiving fibrinogen concentrate.

BACKGROUND: Both thrombelastography (TEG) and rotational thromboelastometry (ROTEM) have been investigated for diagnosis of coagulopathy and guidance of resuscitation in trauma and surgery. Given similarities between the two systems, it is important to determine whether one is superior to the other and how comparable they are to conventional coagulation tests (CCTs). Therefore, we conducted a comparative study of functional fibrinogen and coagulation assays using TEG and ROTEM and CCTs to determine their capability to monitor coagulation profiles, diagnose coagulopathy and predict blood transfusion requirements in trauma patients. METHODS: Blood samples were collected from 45 patients at admission and during 48-h hospitalization as part of a randomized control trial on early fibrinogen replacement in trauma. Functional fibrinogen (FF) TEG, ROTEM FIBTEM and EXTEM, and CCTs were performed and compared. RESULTS: We found significant differences between the placebo and fibrinogen groups over hospitalization time in FF TEG MA, ROTEM CT, MCF and LI30. FF TEG MA and ROTEM FIBTEM MCF mirrored plasma fibrinogen profiles, reached a maximum difference between the two groups 1-3 h after fibrinogen administration. In comparison, CCTs detected minimal hemostatic changes by fibrinogen treatment. TEG and ROTEM showed various degrees of correlations with CCTs. TEG MA and ROTEM MCF provided better predictions for plasma and RBC transfusions than CCTs, but poor accuracy for cryoprecipitate transfusion. Both TEG and ROTEM well predicted hypofibrinogenemia (fibrinogen concentration < 1 g/L), but poorly detected coagulopathy (INR ≥ 1.2). CONCLUSIONS: TEG and ROTEM detected increases in clot strength following early use of fibrinogen. ROTEM also detected changes in coagulation time and clot lysis. Both were better than CCTs for monitoring coagulation profiles and predicting transfusion requirements.

Biological Response to Stress During Battlefield Trauma Training: Live Tissue Versus High-Fidelity Patient Simulator.

INTRODUCTION: Tactical Combat Casualty Care (TCCC) training imposes psychophysiological stress on medics. It is unclear whether these stress levels vary with the training modalities selected. It is also unclear how stress levels could have an impact on medical performance and skill uptake. MATERIALS AND METHODS: We conducted a pilot study to compare the effects of live tissue (LT) with a high-fidelity patient simulator (SIM) on the level of stress elicited, performance, and skill uptake during battlefield trauma training course in an operating room (OR) and in a simulated battlefield scenario (field). In the report, we studied the effects of training modalities and their changes on stress levels by measuring different biomarkers (salivary amylase, plasma catecholamines, and neuropeptide Y) at various time points during the trauma training course. RESULTS: We found that the training resulted in significant psychophysiological stress as indicated by elevated levels of various biomarkers relative to baseline immediately after both OR and field assessment (p < 0.05). Compared with pre-OR levels, the LT training in the OR resulted in significant increases in the plasma levels of epinephrine, norepinephrine, and neuropeptide (p = 0.013, 0.023, 0.004, respectively), whereas the SIM training in the OR resulted in significant increases in the plasma levels of norepinephrine and neuropeptide (p = 0.003 and 0.008). Compared with pre-field levels, we found significant increases in plasma epinephrine concentration in the SIM group (p = 0.016), plasma norepinephrine concentration in the LT group (p = 0.015), and plasma neuropeptide Y concentration in both LT (p = 0.006) and SIM groups (p = 0.029). No differences in the changes of biomarker levels were found between LT and SIM groups in the OR and field. Compared with pre-field levels, the testing on the same modality as that in the OR in the simulated battlefield resulted in significant increases in norepinephrine and neuropeptide levels (p = 0.013 and 0.015), whereas the testing on different modalities resulted in significant increases in amylase, epinephrine, and neuropeptide levels (p = 0.016, 0.05, 0.018, respectively). There was a significantly larger increase in plasma norepinephrine concentration (p = 0.031) and a trend toward a greater increase in the salivary amylase level (p = 0.052) when the field testing involved a different modality than the OR compared with when OR and field testing involved the same modality. Although most of the biomarkers returned to baseline levels after 24 h, plasma norepinephrine levels remained significantly higher regardless of whether field testing occurred on the same or different modality compared with OR (p = 0.040 and 0.002). CONCLUSION: TCCC training led to significant increase in psychophysiological stress, as indicated by elevated levels of various biomarkers. The training modalities did not result in any differences in stress levels, whereas the switch in training modalities appeared to elicit greater stress as evidenced by changes in specific biomarkers (amylase and norepinephrine). A comparative study with a larger sample size is warranted.

An improved model to predict performance under mental fatigue.

Fatigue has become an increasing problem in our modern society. Using MATLAB as a generic modelling tool, a fatigue model was developed based on an existing one and compared with a commercial fatigue software for prediction of cognitive performance under total and partial sleep deprivation. The flexibility of our fatigue model allowed additions of new algorithms and mechanisms for non-sleep factors and countermeasures and thus improved model predictions and usability for both civilian and military applications. This was demonstrated by model simulations of various scenarios and comparison with experimental studies. Our future work will be focused on model validation and integration with other modelling tools. Practitioner Summary: Mental fatigue affects health, safety and quality of life in our modern society. In this paper, we reported a cognitive fatigue model based on existing models with newly incorporated components taking both the operator's state of alertness and task demand into account. The model provided the additional capability for prediction of cognitive performance in scenarios involving pharmaceutical countermeasures, different task demands and shift work.

Thromboelastography and Thromboelastometry in Assessment of Fibrinogen Deficiency and Prediction for Transfusion Requirement: A Descriptive Review.

Fibrinogen is crucial for the formation of blood clot and clinical outcomes in major bleeding. Both Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM) have been increasingly used to diagnose fibrinogen deficiency and guide fibrinogen transfusion in trauma and surgical bleeding patients. We conducted a comprehensive and comparative review on the technologies and clinical applications of two typical functional fibrinogen assays using TEG (FF TEG) and ROTEM (FIBTEM) for assessment of fibrinogen level and deficiency, and prediction of transfusion requirement. Clot strength and firmness of FF TEG and ROTEM FIBTEM were the most used parameters, and their associations with fibrinogen levels as measured by Clauss method ranged from 0 to 0.9 for FF TEG and 0.27 to 0.94 for FIBTEM. A comparison of the interchangeability and clinical performance of the functional fibrinogen assays using the two systems showed that the results were correlated, but are not interchangeable between the two systems. It appears that ROTEM FIBTEM showed better associations with the Clauss method and more clinical use for monitoring fibrinogen deficiency and predicting transfusion requirements including fibrinogen replacement than FF TEG. TEG and ROTEM functional fibrinogen tests play important roles in the diagnosis of fibrinogen-related coagulopathy and guidance of transfusion requirements. Despite the fact that high-quality evidence is still needed, the two systems are likely to remain popular for the hemostatic management of bleeding patients.

In Trauma, Conventional ROTEM and TEG Results Are Not Interchangeable But Are Similar in Clinical Applicability.

BACKGROUND: There is growing interest in viscoelastic hemostatic assays rotational thromboelastometry (ROTEM) and thromboelastography (TEG) for trauma. Despite shared features, it is unknown whether their results are interchangeable and whether one is clinically superior in predicting mortality, blood transfusion, and diagnosing early trauma coagulopathy. METHODS: We conducted a prospective observational study comparing equivalent ROTEM and TEG parameters. Severely injured patients expected to receive massive transfusion were included. Assays were performed simultaneously on admission and repeated over subsequent 12 hours. International normalized ratio ≥1.2 or fibrinogen <1 g/L defined coagulopathy. TEG used kaolin as coagulation initiator and ROTEM used tissue factor (conventional). Spearman nonparametric analysis and Bland-Altman difference mean plot revealed parameter association. Logistic regression and receiver operating characteristic curves measured predictive values. RESULTS: 33 patients (74 ROTEM, 74 TEG) were included; 79% were male, mean Injury Severity Score was 23.5 ± 14, admission international normalized ratio was 1.33 ± 0.4, and 63.4% received blood transfusions. Overall, parameter agreement fell outside acceptable limits, with weak or no association. Clinically, ROTEM maximum clot firmness and TEG maximum amplitude showed reasonable predictive accuracy for mortality, strong accuracy for any or massive blood transfusion, reasonable for plasma transfusion and similar poor predictive accuracy for diagnosing coagulopathy. CONCLUSIONS: ROTEM and TEG results are not interchangeable, arguably due to different coagulation triggers. Assays had similar clinical performance.

Sympathoadrenal Activation is Associated with Acute Traumatic Coagulopathy and Endotheliopathy in Isolated Brain Injury.

BACKGROUND: Acute coagulopathy after traumatic brain injury (TBI) involves a complex multifactorial hemostatic response that is poorly characterized. OBJECTIVES: To examine early posttraumatic alterations in coagulofibrinolytic, endothelial, and inflammatory blood biomarkers in relation to sympathetic nervous system (SNS) activation and 6-month patient outcomes, using multivariate partial least-squares (PLS) analysis. PATIENTS AND METHODS: A multicenter observational study of 159 adult isolated TBI patients admitted to the emergency department at an urban level I trauma center, was performed. Plasma concentrations of 6 coagulofibrinolytic, 10 vascular endothelial, 19 inflammatory, and 2 catecholamine biomarkers were measured by immunoassay on admission and 24 h postinjury. Neurological outcome at 6 months was assessed using the Extended Glasgow Outcome Scale. PLS-discriminant analysis was used to identify salient biomarker contributions to unfavorable outcome, whereas PLS regression analysis was used to evaluate the covariance between SNS correlates (catecholamines) and biomarkers of coagulopathy, endotheliopathy, and inflammation. RESULTS: Biomarker profiles in patients with an unfavorable outcome displayed procoagulation, hyperfibrinolysis, glycocalyx and endothelial damage, vasculature activation, and inflammation. A strong covariant relationship was evident between catecholamines and biomarkers of coagulopathy, endotheliopathy, and inflammation at both admission and 24 h postinjury. CONCLUSIONS: Biomarkers of coagulopathy and endotheliopathy are associated with poor outcome after TBI. Catecholamine levels were highly correlated with endotheliopathy and coagulopathy markers within the first 24 h after injury. Further research is warranted to characterize the pathogenic role of SNS-mediated hemostatic alterations in isolated TBI.

Performance Evaluation of a Salivary Amylase Biosensor for Stress Assessment in Military Field Research.

BACKGROUND: A convenient biosensor for real-time measurement of biomarkers for in-field psychophysiological stress research and military operations is desirable. We evaluated a hand-held device for measuring salivary amylase as a stress marker in medical technicians undergoing combat casualty care training using two different modalities in operating room and field settings. METHODS: Salivary amylase activity was measured by two biosensor methods: directly sampling saliva with a test strip placed under the tongue or pipetting a fixed volume of precollected saliva onto the test strip, followed by analyzing the sample on the strip using a biosensor. The two methods were compared for their accuracy and sensitivity to detect the stress response using an enzyme assay method as a standard. RESULTS: The measurements from the under-the-tongue method were not as consistent with those from the standard assay method as the values obtained from the pipetting method. The under-the-tongue method did not detect any significant increase in the amylase activity due to stress in the operating room (P > 0.1), in contrast to the significant increases observed using the pipetting method and assay method with a significance level less than 0.05 and 0.1, respectively. Furthermore, the under-the-tongue method showed no increased amylase activity in the field testing, while both the pipetting method and assay method showed increased amylase activity in the same group (P < 0.1). CONCLUSION: The accuracy and consistency of the biosensors need to be improved when used to directly measure salivary amylase activity under the tongue for stress assessment in military medical training.

Effects of Hyperbaric and Decompression Stress on Blood Coagulation and Fibrinolysis: Comparison of Thromboelastography and Thromboelastometry.

Hyperbaric and decompression stress from diving impairs blood coagulation and fibrinolysis. We hypothesized that thromboelastography (TEG) and rotational thromboelastometry (ROTEM) were suitable to characterize the effects of stress on global hemostatic profiles. We thus conducted a comparative study of the hyperbaric effects on human coagulation using TEG and ROTEM. Maximum clot strength (maximum amplitude [MA]) and clot lysis (lysis index at time 30 minutes [LI30]) were reduced as indicated by TEG MA and EXTEM LI30, respectively. The relative changes in coagulation and fibrinolysis by the hyperbaric effects of diving were indicated by reduced TEG reaction time R at 5 hours, MA at 24 hours postdive, and reduced EXTEM coagulation time at 15 minutes postdive as well as decreased fibrinolysis (EXTEM LI30) at all postdiving time points investigated. Comparison of the parameter values and the diving-induced changes in each parameter between TEG and ROTEM showed both differences and correlations. The discrepancies between the 2 systems may be due to the different assay reagents used. Future studies will seek to further elucidate the changes in blood coagulation and fibrinolysis following varying levels of hyperbaric and decompression stress.

A comparative study of tissue factor and kaolin on blood coagulation assays using rotational thromboelastometry and thromboelastography.

Rotational thromboelastometry (ROTEM) and thromboelastography (TEG) have been increasingly used to diagnose acute coagulopathy and guide blood transfusion. The tests are routinely performed using different triggering activators such as tissue factor and kaolin, which activate different pathways yielding different results. To optimize the global blood coagulation assays using ROTEM and TEG, we conducted a comparative study on the activation methods employing tissue factor and kaolin at different concentrations as well as standard reagents as recommended by the manufacturer of each device. Key parameter values were obtained at various assay conditions to evaluate and compare coagulation and fibrinolysis profiles of citrated whole blood collected from healthy volunteers. It was found that tissue factor reduced ROTEM clotting time and TEG R, and increased ROTEM clot formation time and TEG K in a concentration-dependent manner. In addition, tissue factor affected ROTEM alpha angle, and maximum clot firmness, especially in the absence of kaolin activation, whereas both ROTEM and TEG clot lysis (LI30, CL30, and LY30) remained unaffected. Moreover, kaolin reduced ROTEM clotting time and TEG R and K, but to a lesser extent than tissue factor, in-tem and ex-tem. Correlations in all corresponding parameters between ROTEM and TEG were observed, when the same activators were used in the assays compared with lesser correlations between standard kaolin TEG and ROTEM (INTEM/EXTEM). The two types of viscoelastic point-of-care devices provide different results, depending on the triggering reagent used to perform the assay. Optimal assay condition was obtained to reduce assay time and improve assay accuracy.