A prospective observational study of the rapid detection of clinically-relevant plasma direct oral anticoagulant levels following acute traumatic injury.

In urgent clinical situations, such as trauma, urgent surgery or before thrombolysis, rapid quantification of direct oral anticoagulant plasma drug levels is warranted. Using the ClotPro® analyser, we assessed two novel viscoelastic tests for detection of clinically-relevant plasma drug levels in trauma patients. The ecarin clotting time was used to assess the plasma concentration of dabigatran and Russell´s viper venom clotting time to determine the plasma concentration of direct factor Xa inhibitors. In parallel, plasma concentrations were analysed using plasma-based chromogenic assays. A total of 203 simultaneous measurements were performed. Strong to very strong linear correlations were detected between ecarin clotting time and plasma concentration of dabigatran (r = 0.9693), and between Russell´s viper venom clotting time and plasma concentrations of apixaban (r = 0.7391), edoxaban (r = 0.9251) and rivaroxaban (r = 0.8792), all p < 0.001. An ecarin clotting time ≥ 189 seconds provided 100% sensitivity and 90% specificity for detecting plasma dabigatran concentrations ≥ 50 ng.ml-1 . Corresponding Russell´s viper venom clotting time cut-off values were ≥ 136 seconds for apixaban (80% sensitivity, 88% specificity), ≥ 168 seconds for edoxaban (100% sensitivity, 100% specificity) and ≥ 177 seconds for rivaroxaban (90% sensitivity, 100% specificity). Detection of drug levels ≥ 100 ng.ml-1 was also investigated: for dabigatran, an ecarin clotting time ≥ 315 seconds yielded 92% sensitivity and 100% specificity; while Russell´s viper venom clotting time cut-offs of 191, 188 and 196 seconds were calculated for apixaban (67% sensitivity, 88% specificity), edoxaban (100% sensitivity, 75% specificity) and rivaroxaban (100% sensitivity, 91% specificity), respectively. We have demonstrated strong positive correlations between plasma drug levels and clotting time values in the specific ClotPro assays. Cut-off values for detecting clinically-relevant drug levels showed high levels of sensitivity and specificity.

Reversal of dabigatran by intraosseous or intravenous idarucizumab in a porcine polytrauma model.

BACKGROUND: Idarucizumab is licensed to reverse dabigatran in life-threatening haemorrhage. Establishment of venous access can be challenging, and the intraosseous (IO) route is a potentially life-saving alternative. In this study, we compared the efficacy and safety of IO or intravenous (i.v.) idarucizumab for dabigatran reversal in a porcine polytrauma model. METHODS: Male pigs (n=21) received oral dabigatran etexilate (30 mg kg-1 bid) for 3 days. On the 4th day, animals received dabigatran infusion and were randomised 1:1:1 to receive IO saline (control), i.v. idarucizumab (60 mg kg-1), or IO idarucizumab (60 mg kg-1), or animals were included in a sham group (n=7). Study treatment was administered after polytrauma and the animals were monitored for 240 min, or until death. Coagulation status was monitored by thromboelastometry, thromboelastography, and thrombin measurements. RESULTS: Total blood loss was lowest in sham animals [521 (52) ml, P<0.01 vs all other groups], and comparable in the two idarucizumab groups [IO: 1085 (102) ml vs i.v.: 1142 (125) ml], and highest in the control group [4065 (557) ml, P<0.001 vs all other groups]. Survival to 240 min was 100% in the sham group and both idarucizumab groups, and 14% in the control group. IO and i.v. idarucizumab promptly normalised global coagulation assays and thrombin generation. Thromboelastography showed a strong correlation between dabigatran concentrations and R-time (R2=0.90 and 0.89) in idarucizumab-treated animals. CONCLUSIONS: Intravenous and intraosseous idarucizumab were comparable for reversing dabigatran in a porcine trauma model. Dabigatran reversal could be monitored using fully automated thromboelastography.

[Rotational thromboelastometry for the diagnosis of coagulation disorders]. / Diagnose von Gerinnungsstörungen mit Rotationsthromboelastometrie.

BACKGROUND: Compared to conventional coagulation assays, as prothrombin time (PT) or activated partial thromboplastin time (aPTT), viscoelastic methods of coagulation analysis, including rotational thromboelastometry (ROTEM®, Tem International GmbH, Munich, Germany), yield prognostic benefits. Results of ROTEM® in citrated whole blood could be generated within 10-12 min and allow for a qualitative and semiquantitative characterisation of clot kinetics. Based on ROTEM® results, the switch between empiric approaches of treating coagulopathy to a goal-directed approach could be accelerated. Introduction of ROTEM® reduces transfusion requirements and the need for single factor concentrates. Thus, ROTEM® reduces transfusion-related adverse events, and additionally implement therapeutic cost effectiveness. OBJECTIVES: This review provides a short introduction in the methodology of ROTEM®, showing how the combination of assays with different commercially available ROTEM® reagents allows for rapid differential diagnosis of common coagulopathies in clinical practice. Furthermore, prognostic benefits and limitations of ROTEM® diagnostics are described. Finally, we discuss the potential fields of ROTEM® application in different surgical settings. CONCLUSION: ROTEM® appears to be a contemporary, applicable and effective method in diagnosing coagulopathy and for subsequent algorithm-based goal-directed therapy.

[Management of hemorrhage in patients treated with direct oral anticoagulants]. / Management von Blutungen unter Therapie mit direkten oralen Antikoagulanzien.

The introduction of nonvitamin K antagonistic, direct oral anticoagulants (DOAC) made thromboembolic prophylaxis easier for patients. For many physicians, however, there is still uncertainty about monitoring, preoperative discontinuation, and restarting of DOAC therapy. Guidelines for the management of bleeding are provided, but require specific therapeutic skills in the management of diagnostics and therapy of acute hemorrhage. Small clinical studies and case reports indicate that unspecific therapy with prothrombin complex concentrates (PCC) and activated PCC (aPCC) concentrate may reverse DOAC-induced anticoagulation. However, PCC or aPCC at higher doses potentially provoke thromboembolic complications. However, idarucizumab, a specific, fast-acting, antidote for dabigatran, provides immediate and sustained reversal with no intrinsic or prohemostatic activity. This review article provides an overview of the pharmacology and potential risk of DOAC and the management in the perioperative period with a focus of current concepts in the treatment of DOAC-associated bleeding.

[Dealing with massive bleeding and associated perioperative coagulopathy: recommendations for action of the German Society of Anaesthesiology and Intensive Care Medicine]. / Umgang mit Massivblutungen und assoziierten perioperativen Gerinnungsstörungen : Handlungsempfehlung der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin.

Massive bleeding with coagulopathy and hemorrhagic shock poses a potential threat to life in numerous clinical settings. Optimal treatment including the prevention of exsanguination necessitates a standardized and interdisciplinary approach. Several studies have shown the importance of massive transfusion protocols and standardized coagulation algorithms to improve survival of severely bleeding patients and to avoid secondary complications. Thus, the Helsinki declaration for patient safety in anesthesiology demands the implementation of clinical practice guidelines for the treatment of patients requiring massive transfusion. This paper introduces a standardized algorithm for the treatment of patients with massive bleeding which was developed in consensus with the German Society of Anaesthesiology and Intensive Care Medicine (DGAI).

Influence of a freeze-thaw cycle on the stress-stretch curves of tissues of porcine abdominal organs.

The paper investigates both fresh porcine spleen and liver and the possible decomposition of these organs under a freeze-thaw cycle. The effect of tissue preservation condition is an important factor which should be taken into account for protracted biomechanical tests. In this work, tension tests were conducted for a large number of tissue specimens from twenty pigs divided into two groups of 10. Concretely, the first group was tested in fresh state; the other one was tested after a freeze-thaw cycle which simulates the conservation conditions before biomechanical experiments. A modified Fung model for isotropic behavior was adopted for the curve fitting of each kind of tissues. Experimental results show strong effects of the realistic freeze-thaw cycle on the capsule of elastin-rich spleen but negligible effects on the liver which virtually contains no elastin. This different behavior could be explained by the autolysis of elastin by elastolytic enzymes during the warmer period after thawing. Realistic biomechanical properties of elastin-rich organs can only be expected if really fresh tissue is tested. The observations are supported by tests of intestines.

[Treatment of massive bleeding: summary of the updated European guidelines]. / Behandlung von polytraumatisierten Patienten : Zusammenfassung der aktualisierten europäischen Leitlinien.

Despite improved strategies in the treatment of polytraumatized patients the mortality rate of severely injured patients remains high. Thus, worldwide 5 million patients die due to trauma or trauma-related complications each year. As the majority of early trauma-related deaths are attributed to or caused by exsanguination the prevention and treatment of coagulopathy is of paramount significance. With the aim of developing guidelines and improve strategies to treat polytraumatized patients the multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2005. Under consideration of new clinical studies, an updated version of the original publication from 2007 has recently been published. Based on a systematic review of published literature the recommendations were formed according to "Grading of Recommendations Assessment, Development and Evaluation" (GRADE). This publication summarizes the main recommendations with a special emphasis on revisions and new aspects.

Recombinant factor VIIa reduces bleeding after blunt liver injury in coagulopathic, hypofibrinogenaemic pigs.

BACKGROUND: Recombinant factor VIIa (rFVIIa) has been successfully used in various clinical conditions to treat severe coagulopathy, but its efficacy may be affected by the underlying conditions. We therefore investigated the efficacy of rFVIIa treatment under conditions of hypofibrinogenaemia in a pig model of blunt liver injury. METHODS: Severe haemodilution was instigated in four groups of seven anaesthetized pigs. Before inflicting liver injury, animals were assigned to receive either 70 mg kg(-1) fibrinogen (fibrinogen group) or placebo (control group). Thirty seconds after injury, rFVIIa (180 µg kg(-1)) (rFVIIa and fibrinogen+rFVIIa groups) or vehicle (control and fibrinogen groups) was administered. Haemodynamic variables, coagulation parameters, and blood loss were monitored for 2 h. Histology was examined to evaluate the presence of thrombi and the consistency of liver injury. RESULTS: At the end of the observation period, total blood loss [median (range)] decreased in all intervention groups [fibrinogen: 1275 (1221-1439) ml, P=0.036; rFVIIa: 966 (923-1136) ml, P=0.008; fibrinogen+rFVIIa: 678 (475-756) ml, P=0.008] when compared with control animals [blood loss: 1752 (1735-2221) ml]. The mortality rate in the control group was 100%, whereas only 42% of fibrinogen-substituted animals died (P=0.023). All animals treated with rFVIIa or fibrinogen+rFVIIa (P<0.001) survived and no signs of thromboembolism were observed. CONCLUSIONS: rFVIIa under conditions of hypofibrinogenaemia exhibited a positive impact on coagulation parameters and a reduction in blood loss. These effects were significantly improved after prior substitution with fibrinogen.

Comparison of early cognitive function and recovery after desflurane or sevoflurane anaesthesia in the elderly: a double-blinded randomized controlled trial.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is being recognized as a complication contributing to perioperative morbidity and mortality of the elderly. We hypothesized that the use of the shorter-acting volatile anaesthetic desflurane would be associated with less incidence of POCD when compared with sevoflurane. METHODS: Approved by the local ethical committee, 80 patients (aged 65-75 yr) were enrolled in this randomized, double-blinded study. Patients were allocated to either the desflurane (n=40) or the sevoflurane (n=40) group. The primary outcome was the cognitive Test for Attentional Performance with its subtests Alertness, Divided Attention, Visual Scanning, Working Memory, and Reaction Change. In addition, Paper-Pencil Tests [Well-being Test BF-S, Recall of Digit Span (DST), Digit-Symbol-Substitution Test, Trail Making Tests A and B, and Spielberg State-Trait Anxiety Inventory] were measured. After baseline assessment 12-24 h before operation, patients were followed up 6-8 and 66-72 h after operation. Among other outcome parameters, emergence times from anaesthesia and modified Aldrete scores were recorded. RESULTS: There was no difference in the incidence of POCD. However, according to the Paper-Pencil Tests, significant improvements for the desflurane group could be detected (Well-being Test at 6-8 h, DST at 6-8 h, and Trail Making Test at 66-72 h). Emergence was significantly faster in the desflurane group for 'time to open eyes' and 'time to extubation'. CONCLUSIONS: The total incidence of POCD showed no differences between the desflurane and the sevoflurane groups. However, the tests Well-being scale, DST, and Trail Making Test, emergence times, and patients' satisfaction were in favour of desflurane.

A new model for blunt liver injuries in the swine.

BACKGROUND: To elaborate the impact of new haemostatic agents we developed an instrument for the pressure-controlled induction of blunt liver injuries in a porcine animal model. MATERIALS AND METHODS: A dilutional coagulopathy of 80% of animal blood volume was induced in 9 anaesthetized pigs. Animals were randomly assigned to be injured with a force of 112 Newton (N) (n = 1), 224 +/- 19 N (n = 4) or 355 +/- 35 N (n = 4). The impact of injury was measured by blood loss, survival time and coagulation parameters. Liver histology was obtained to evaluate the degree of liver injury. RESULTS: The profound haemodilution resulted in a significant alteration of all coagulation parameters. After inflicting the injury with 355 +/- 35 N, both the survival time (30 +/- 9 min; p = 0.006) and blood loss (68 +/- 16 ml min(-1), p = 0.002) were significantly different as compared to injuries with 224 +/- 19 N (survival time: 76 +/- 20 min, blood loss: 23 +/- 4 ml min(-1)). In contrast, an injury with 112 N led to an insignificant blood loss of only 239 ml. CONCLUSION: We developed a pressure-controlled clamp that allows for the induction of blunt liver traumas with highly reproducible injuries with a positive correlation with blood loss and survival.

Virtual reality-based simulator for training in regional anaesthesia.

BACKGROUND: The safe performance of regional anaesthesia (RA) requires theoretical knowledge and good manual skills. Virtual reality (VR)-based simulators may offer trainees a safe environment to learn and practice different techniques. However, currently available VR simulators do not consider individual anatomy, which limits their use for realistic training. We have developed a VR-based simulator that can be used for individual anatomy and for different anatomical regions. METHODS: Individual data were obtained from magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) without contrast agent to represent morphology and the vascular system, respectively. For data handling, registration, and segmentation, an application based on the Medical Imaging Interaction Toolkit was developed. Suitable segmentation algorithms such as the fuzzy c-means clustering approach were integrated, and a hierarchical tree data structure was created to model the flexible anatomical structures of peripheral nerve cords. The simulator was implemented in the VR toolkit ViSTA using modules for collision detection, virtual humanoids, interaction, and visualization. A novel algorithm for electric impulse transmission is the core of the simulation. RESULTS: In a feasibility study, MRI morphology and MRA were acquired from five subjects for the inguinal region. From these sources, three-dimensional anatomical data sets were created and nerves modelled. The resolution obtained from both MRI and MRA was sufficient for realistic simulations. Our high-fidelity simulator application allows trainees to perform virtual peripheral nerve blocks based on these data sets and models. CONCLUSIONS: Subject-specific training of RA is supported in a virtual environment. We have adapted segmentation algorithms and developed a VR-based simulator for the inguinal region for use in training for different peripheral nerve blocks. In contrast to available VR-based simulators, our simulation offers anatomical variety.

[Procedure for critical nonsurgical bleeding]. / Vorgehen bei kritischer nichtchirurgischer Grossblutung.

The improvement of surgical and nonsurgical approaches to control bleeding offers new strategies for overcoming coagulopathy. Massive hemorrhage is usually caused by a combination of surgical and coagulopathic bleeding. Coagulopathy is multifactorial and results from the dilution and consumption of both platelets and coagulation factors and dysfunction of the coagulation system. Blood component therapy continues to be a mainstay for this coagulopathy-related bleeding. However, the transfusion of red blood cells has been shown to be associated with post-injury infection and multiple organ failure. Therefore it is crucial to develop a clear strategy for correcting coagulopathy, preventing exsanguination, and minimizing the need for blood transfusion.

[Coagulopathy in multiple trauma: new aspects of therapy]. / Koagulopathie. Bedeutung beim polytraumatisierten Patienten und aktuelle Aspekte der Gerinnungstherapie.

Coagulopathy after trauma is a major cause for uncontrolled hemorrhage in trauma victims. Approximately 40% of trauma related deaths are attributed to or caused by exsanguination. Therefore the prevention of coagulopathy is regarded as the leading cause of avoidable death in these patients. Massive hemorrhage after trauma is usually caused by a combination of surgical and coagulopathic bleeding. Coagulopathic bleeding is multifactorial, including dilution and consumption of both platelets and coagulation factors, as well as dysfunction of the coagulation system. Because of the high mortality associated with hypothermia, acidosis and progressive coagulopathy, this vicious circle is often referred to as the lethal triad, potentially leading to exsanguination. To overcome this coagulopahty-related bleeding an empiric therapy is often instituted by replacing blood components. However, the use of transfusion of red blood cells has been shown to be associated with post-injury infection and multiple organ failure. In the management of mass bleeding it is therefore crucial to have a clear strategy to prevent coagulopathy and to minimize the need for blood transfusion.

[Comparison of premedication with clonidine and midazolam combined with TCI for orthopaedic shoulder surgery]. / Vergleich der Prämedikationsqualität unterschiedlicher Clonidinkonzentrationen und Midazolam im Rahmen einer TCI bei orthopädischen Schulteroperationen.

OBJECTIVE: The most frequently used drugs for premedication are benzodiazepines and alpha (2)-adrenoceptor agonists. In this study we examined midazolam and clonidine for premedication in combination with target controlled infusion anaesthesia (TCI) in patients undergoing orthopaedic shoulder surgery and analysed the effects on the peri- and postoperative course. METHODS: Forty-five Patients (ASA I-III) were included in this prospective randomized, double blind study. Sixty minutes prior to anaesthetic induction the patients received clonidine in a dosage of 2 microg x kg(-1) (group ND) or 5 microg x kg(-1) (group HD) or 0.1 mg x kg(-1) midazolam (group midazolam) per orally. Anaesthesia was performed as TCI with propofol (plasma concentration 2.0-4.0 microg x ml(-1)) und remifentanil (plasma concentration 0.2-0.4 microg x ml(-1) x min(-1)). 15 minutes before the operation was finished, all patients received a bolus dose of 0.1 mg x kg(-1) piritramid i.v., followed by administration of piritramid via a PCA pump (patient controlled analgesia) for a duration of 24 hours. During the time of the operation the influence of premedication on the anaesthetic course was determined by vital parameters and ranking scales. For statistic evaluation we used the Kruskal-Wallis test, ANOVA with Tukey as post hoc test and the test named after Fisher (p < 0.05). RESULTS: The effects of premedication on haemodynamic parameters and ranking scales for sedation as well as anaesthetic requirements were comparable in all three groups. In the postoperative period the incidence of postoperative nausea and vomiting (PONV) (ND: n = 8, HD: n = 2, midazolam: n = 6) and the use of pritramid were lower in the clonidine HD group (HD: 38.7 +/- 30.7 mg, ND: 51.7 +/- 25.1 mg, midazolam: 45.1 +/- 30.4 mg) than in the other groups. CONCLUSIONS: Premedication with the alpha(2)-adrenoceptor agonist clonidine is as good as with benzodiazepines in combination with TCI. Because of the lower incidence of PONV and the need of piritramid in the postoperative period patients premedicated with 5 microg x kg(-1) clonidine may benefit from this premedication.