Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution.

BACKGROUND: Idarucizumab is a humanized Fab fragment that specifically reverses dabigatran anticoagulation. In trauma, volume expanders are used for resuscitation to compensate for blood loss and hemorrhagic shock, but it is unknown whether volume expanders influence the binding of dabigatran to its antidote. Using a porcine dilutional coagulopathy model, this study investigated whether volume replacement strategies affect binding of dabigatran to idarucizumab. METHODS: Twenty-five male pigs were treated orally with dabigatran etexilate (30 mg/kg bid) for 3 days. The following day, animals were anesthetized, infused with dabigatran (total dose 0.645 mg/kg) to achieve supratherapeutic concentrations, and randomized 1:1:1:1:1 (n = 5 per group) to control (no hemodilution) or hemodilution where ~50% of blood volume was substituted with Ringer's solution, 6% hydroxyethyl starch 130/0.4, 6% hydroxyethyl starch 200/0.5 or 4% gelatin. Idarucizumab was then administered intravenously (30 mg/kg) and serial blood samples were taken for up to 24 hours to measure diluted thrombin time (corresponding with dabigatran activity), total dabigatran (bound to antidote and free drug) and a panel of coagulation parameters. RESULTS: Mean plasma dabigatran levels were 617 ± 16 ng/mL after infusion and 600 ± 114 ng/mL after ~50% hemodilution with no significant differences between groups. Following treatment with idarucizumab, plasma concentrations of unbound dabigatran decreased markedly, with similar reductions in all groups. Dabigatran-induced prolongation of coagulation parameters was rapidly reversed in all groups. CONCLUSION: This study indicates that several volume expanders used for resuscitation in trauma do not interfere with the binding of idarucizumab to dabigatran.

Hemostatic Therapy Using Tranexamic Acid and Coagulation Factor Concentrates in a Model of Traumatic Liver Injury.

BACKGROUND: The potential clinical benefits of targeted therapy with coagulation factor concentrates (e.g., fibrinogen) and antifibrinolytic agents (e.g., tranexamic acid [TXA]) for the treatment of trauma-induced coagulopathy are increasingly recognized. We hypothesized that human fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC), administered as combined therapy with TXA, would provide additive effects for reducing blood loss in an animal trauma model. METHODS: Thirty-six pigs were subjected to 2 consecutive blunt liver injuries, resulting in severe hemorrhagic shock and coagulopathy. Intervention comprised saline (control group); TXA (15 mg kg, TXA group); TXA and FC (90 mg kg, TXA-FC); or TXA, FC, and PCC (20 U kg, TXA-FC-PCC). Blood loss, thromboelastometry (ROTEM), measures of thrombin generation, platelet activation, and global coagulation variables were monitored for 4 hours. Tissue sections were examined to determine the occurrence of thromboembolic events. RESULTS: Total blood loss was similar in the TXA-FC and TXA-FC-PCC groups (mean ± SD: 1012 ± 86 mL and 1037 ± 118 mL, respectively; P = 1.000). These values were both lower (P < 0.001) than the TXA group (1579 ± 306 mL). Blood loss in all 3 intervention groups was lower (P < 0.001) than in the control group (2376 ± 478 mL). After trauma and resuscitation, but before study intervention, plasma fibrinogen levels were severely depleted (median for the whole study population: 66 mg dL; interquartile range: 51-108 mg dL) and clot strength was decreased (EXTEM whole-blood maximum clot firmness [MCF]: 53 ± 5 mm). Compared with controls, TXA inhibited fibrinolysis and stabilized MCF and clotting time. The addition of FC restored and stabilized hemostasis to a greater extent than TXA alone; the addition of PCC had no statistically significant impact on blood loss, clot strength (MCF), or clotting time, but it increased thrombin generation. There were no significant differences among the study groups regarding platelet activation. No thrombi or microthrombi were observed in any group at necropsy. CONCLUSIONS: The early use of TXA and FC reduced blood loss and improved coagulation measurements in a porcine model of blunt liver injury and hemorrhagic shock. FC, administered in addition to TXA, was highly effective in reducing blood loss. The lack of statistically significant reduction in blood loss when PCC was added to TXA and FC may be attributable to the absence of thrombin generation impairment in this model.

Effects of Fibrinogen Concentrate on Thrombin Generation, Thromboelastometry Parameters, and Laboratory Coagulation Testing in a 24-Hour Porcine Trauma Model.

INTRODUCTION: In a 24-hour porcine model of liver injury, we showed that fibrinogen supplementation does not downregulate endogenous fibrinogen synthesis. Here we report data from the same study showing the impact of fibrinogen on coagulation variables. MATERIALS AND METHODS: Coagulopathy was induced in 20 German land race pigs by hemodilution and blunt liver injury. Animals randomly received fibrinogen concentrate (100 mg/kg) or saline. Coagulation parameters were assessed and thromboelastometry (ROTEM) was performed. RESULTS: Fibrinogen concentrate significantly reduced the prolongations of EXTEM clotting time, EXTEM clot formation time, and prothrombin time induced by hemodilution and liver injury. A decrease in clot strength was also ameliorated. Endogenous thrombin potential was significantly higher in the fibrinogen group than in the control group, 20 minutes (353 ± 24 vs 289 ± 22 nmol/L·min; P < .05) and 100 minutes (315 ± 40 vs 263 ± 38 nmol/L·min; P < .05) after the start of infusion. However, no significant between-group differences were seen in other thrombin generation parameters or in d-dimer or thrombin-antithrombin levels. Fibrinogen-platelet binding was reduced following liver injury, with no significant differences between groups. No significant between-group differences were observed in any parameter at ∼12 and ∼24 hours. CONCLUSION: This study suggests that, in trauma, fibrinogen supplementation may shorten some measurements of the speed of coagulation initiation and produce a short-lived increase in endogenous thrombin potential, potentially through increased clotting substrate availability. Approximately 12 and 24 hours after starting fibrinogen concentrate/saline infusion, all parameters measured in this study were comparable in the 2 study groups.

Fibrinogen concentrate does not suppress endogenous fibrinogen synthesis in a 24-hour porcine trauma model.

BACKGROUND: Fibrinogen concentrate may reduce blood loss after trauma. However, its effect on endogenous fibrinogen synthesis is unknown. The authors investigated the effect of exogenous human fibrinogen on endogenous fibrinogen metabolism in a 24-h porcine trauma model. METHODS: Coagulopathy was induced in 20 German Landrace pigs by hemodilution and blunt liver injury. Animals were randomized to receive fibrinogen concentrate (100 mg/kg; infusion beginning 20 min postinjury and lasting approximately 10 min) or saline. Fibrinogen concentration, thromboelastometry, and quantitative reverse transcriptase polymerase chain reaction of fibrinogen genes in liver tissue samples were recorded. Internal organs were examined histologically for emboli. RESULTS: Coagulation parameters were impaired and plasma fibrinogen concentrations were reduced before starting infusion of fibrinogen concentrate/saline. Twenty minutes after starting infusion, exogenous fibrinogen supplementation had increased plasma fibrinogen concentration versus controls (171 ± 19 vs. 63 ± 10 mg/dl [mean ± SD for Multifibren U]; 185 ± 30 vs. 41 ± 4 mg/dl [Thrombin reagent]; P < 0.05 for both comparisons). The between-group difference in plasma fibrinogen concentration diminished thereafter, with maximum concentrations in both groups observed at approximately 24 h, that is, during the acute-phase reaction after trauma. Fibrinogen supplementation did not down-regulate endogenous fibrinogen synthesis (no between-group differences in fibrinogen messenger RNA). Total postinjury blood loss was significantly lower in the fibrinogen group (1,062 ± 216 vs. 1,643 ± 244 ml; P < 0.001). No signs of thromboembolism were observed. CONCLUSIONS: Administration of human fibrinogen concentrate did not down-regulate endogenous porcine fibrinogen synthesis. The effect on plasma fibrinogen concentration was most pronounced at 20 min but nonsignificant at approximately 24 h.

Fibrin patch in a pig model with blunt liver injury under severe hypothermia.

BACKGROUND: Rapid control of hemorrhage is one of the key aspects in trauma handling. To cope with bleeding, local hemostatic approaches are useful, along with surgical and systemic homostatic therapy. In this experimental study, we investigated the efficacy of a fibrinogen/thrombin containing collagen patch (TachoSil) in a coagulopathic pig model with blunt liver trauma under severe hypothermia. METHODS: Eighteen anesthetized pigs underwent hemodilution by exchanging 70% of the blood volume with Ringer Lactate solution and hydroxyethyl starch 130/0.4 (1:1). Ten minutes after induction of a grade III blunt liver trauma, the animals randomly received treatment with TachoSil (FT-patch, n = 9) or a collagen patch (Tachotop, control group, n = 9). Blood loss, hemodynamics, and coagulation parameters were observed for 2 h. To confirm the consistency of liver trauma, pathologic examination of the liver tissue was performed. RESULTS: Hypothermia (33.5°C ± 0.5°C) and hemodilution led to severe coagulopathy as measured by thromboelastometry and coagulation parameters. After trauma and patch application, thromboelastometry and coagulation parameters in the control group showed further deterioration compared with the stable parameters in the FT-patch group. The total blood loss was significantly reduced in the FT-patch group (FT-patch: 1195 mL; control group: 2495 mL; P < 0.001). Concordantly, the control animals were hemodynamically jeopardized to a higher degree. Microscopy confirmed a similar degree of liver injury. CONCLUSIONS: Despite severe hypothermia and coagulopathy, TachoSil provided effective hemorrhage control in pigs with blunt liver injury. Therefore, TachoSil demonstrated usefulness as an additional early therapy in cases of uncontrolled bleeding following severe trauma.

Nonsurgical techniques to control massive bleeding.

Significant advancements in nonsurgical and surgical approaches to control bleeding in severely injured patients have also improved the treatment of critical trauma-related coagulopathy. Nonsurgical procedures such as angiographic embolization are progressively considered to terminate arterial bleeding from pelvic fractures. The disturbance of coagulation may aggravate bleeding and hamper surgical procedures. The administration of coagulation factors and factor concentrates may be useful for correcting systemic coagulopathy and reducing the need for fresh frozen plasma, platelet, and red blood cell transfusions, which are associated with various adverse outcomes. In this review, nonsurgical management of critical trauma bleeding is discussed.

Prediction of mortality using measures of cardiac autonomic dysfunction in the diabetic and nondiabetic population: the MONICA/KORA Augsburg Cohort Study.

OBJECTIVES: To evaluate whether reduced heart rate variability (HRV), prolonged corrected QT (QTc) interval, or increased QT dispersion (QTD) are predictors of mortality in the general diabetic and nondiabetic population. RESEARCH DESIGN AND METHODS: Nondiabetic (n = 1,560) and diabetic (n = 160) subjects aged 55-74 years were assessed to determine whether reduced HRV, prolonged QTc interval, and increased QTD may predict all-cause mortality. Lowest quartiles for the maximum-minimum R-R interval difference (max-min, as measured at baseline from a 20-s standard 12-lead resting electrocardiogram without controlling for depth and rate of respiration), QTc >440 ms and QTD >60 ms, were used as cutpoints. RESULTS: During a 9-year follow-up, 10.5% of the nondiabetic and 30.6% of the diabetic population deceased. In the nondiabetic individuals, multivariate Cox proportional hazard models adjusted for cardiovascular risk factors and demographic variables showed that prolonged QTc interval (hazard ratio 2.02 [95% CI 1.29-3.17]; P = 0.002) but not low max-min (0.93 [0.65-1.34]; P = 0.700), and increased QTD (0.98 [0.60-1.60]; P = 0.939) were associated with increased mortality. In the diabetic subjects, prolonged QTc was also a predictor of mortality (3.00 [1.34-6.71]; P = 0.007), while a trend for an increased risk was noted in those with low max-min (1.74 [0.95-3.18]; P = 0.075), whereas increased QTD did not predict mortality (0.42 [0.06-3.16]; P = 0.402). CONCLUSIONS: Prolonged QTc interval, but not increased QTD, is an independent predictor of a twofold and threefold increased risk of mortality in the nondiabetic and diabetic elderly general population, respectively. Low HRV during spontaneous breathing tends to be associated with excess mortality in the diabetic but not nondiabetic population.

Three-dimensional assessment of MR imaging-guided percutaneous cryotherapy using multi-performer repeated segmentations: the value of supervised learning.

RATIONALE AND OBJECTIVES: Accurate and reproducible segmentations of two-dimensional images are an important prerequisite for assessing tumor ablations three dimensionally (3D). We evaluated whether supervised learning methods would improve multiperformer repeated segmentations of magnetic resonance images (MRI) obtained before and after MRI-guided cryotherapy of renal cell carcinoma. MATERIALS AND METHODS: Three medical students independently performed five manual segmentations of a biopsy-proven renal cell carcinoma that was treated with percutaneous MRI-guided cryotherapy. Using pretreatment (T2-weighted fast recovery fast spin echo [FRFSE]) and posttreatment (T1-weighted, fat-suppressed, dynamically enhanced) MRIs, regions of tumor cryonecrosis were segmented. The same tasks were repeated after an experienced abdominal radiologist provided supervised learning. Segmentation sensitivity was compared with an estimated 3D-ground truth via voxel counts for regions of tumor, both before and after treatment, and for the regions of cryonecrosis. The sensitivity of each repeated segmentation was compared against the estimated ground truth using sensitivity, overlap index, and volume (mL). RESULTS: Supervised learning significantly improved posttreatment segmentation sensitivity (P = .03). With supervised learning, the ranges of the performance metrics over the segmentation performers were: pretreated tumor, sensitivity 0.902-0.999, overlap index 0.935-0.961, and volume 19.15-23.71 mL; posttreated tumor, sensitivity 0.923-0.991, overlap index 0.952-0.981, and volume 20.67-22.70 mL; in the ablation zone, sensitivity 0.938-0.969, overlap index 0.940-0.962, and volume 31.79-32.36 mL. CONCLUSIONS: Supervised learning improved multiperformer repeated segmentations of MRIs obtained before and after MRI-guided percutaneous cryotherapy of renal cell carcinoma. These methods may prove useful in aiding the 3D assessment of percutaneous tumor ablations.