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.

Haemostatic profile of reconstituted blood in a proposed 1:1:1 ratio of packed red blood cells, platelet concentrate and four different plasma preparations.

The concept of haemostatic resuscitation implies early and high-volume plasma transfusion. We investigated the haemostatic profile of reconstituted whole blood prepared in a 1:1:1 ratio of blood, platelets and plasma. This consisted of packed red blood cells, platelet concentrate and four different plasma variants: fresh frozen; solvent-detergent; lyophilised quarantine; and lyophilised methylene blue-inactivated plasma. Haematocrit, platelet count, endogenous thrombin potential and coagulation factor activity were significantly lower in reconstituted blood compared with citrated whole blood (p < 0.01). Except for lyophilised methylene blue-inactivated plasma, no substantial differences between plasma variants in coagulation factor activity, endogenous thrombin potential and standard coagulation tests were observed. After reconstitution, haematocrit and platelet counts were slightly above recommended transfusion triggers, most thromboelastometry (ROTEM(®)) parameters were within the normal range and fibrinogen concentrations were between 1.57 g.l(-1) and 1.91 g.l(-1). Reconstitution of whole blood in a 1:1:1 ratio resulted in significant dilution of haematocrit and platelet count, but values remained above limits recommended by transfusion guidelines. Fibrinogen concentrations of reconstituted whole blood were also significantly reduced, and these were below the threshold value for supplementation recommended by recent guidelines.

Management of traumatic haemorrhage--the European perspective.

Trauma-induced coagulopathy represents a life-threatening complication in severely injured patients. To avoid exsanguination, rapid surgical bleeding control coupled with immediate and aggressive haemostatic treatment is mandatory. In most trauma centres, coagulation therapy is established with transfusion of high volumes of fresh frozen plasma. Due to logistic issues, only busy trauma facilities store pre-thawed plasma ready for immediate transfusion. Thus, substantial time delays have been reported between the first unit of red blood cells transfused and the administration of fresh frozen plasma. An alternative for rapid improvement of haemostatic capacity is purified coagulation factor concentrates. They contain a well-defined concentration of coagulation proteins, carry a low risk for transfusion-related lung injury and virus transmission, and are available for immediate use without the need for blood group matching. In some European trauma centres, treatment algorithms have been developed for the administration of coagulation factor concentrates based on visco-elastic test results.

Fibrinogen measurement in cardiac surgery with cardiopulmonary bypass: analysis of repeatability and agreement of Clauss method within and between six different laboratories.

Plasma fibrinogen concentration is important for coagulopathy assessment, and is most commonly measured using the Clauss method. Several factors, including device type and reagent, have been shown to affect results. The study objective was to evaluate performance and repeatability of the Clauss method and to assess differences between measurements performed during and after cardiopulmonary bypass (CPB), by testing plasma samples from patients undergoing cardiac surgery with CPB. Samples were collected from 30 patients before surgery, approximately 20 minutes before weaning from CPB, and 5 minutes after CPB and protamine. Fibrinogen concentration was determined using the Clauss method at six quality-controlled specialised laboratories, according to accredited standard operating procedures. Regarding within-centre agreement for Clauss measurement, mean differences between duplicate measurements were between 0.00 g/l and 0.15 g/l, with intervals for 95% limits of agreement for mean Bland-Altman differences up to 1.3 g/l. Regarding between-centre agreement, some mean differences between pairs of centres were above 0.5 g/l. Differences of up to ~2 g/l were observed with individual samples. Increased variability was observed between centres, with inter-class correlation values below 0.5 suggesting only fair agreement. There were no significant differences in fibrinogen concentration before weaning from CPB and after CPB for most centres and methods. In conclusion, considerable differences exist between Clauss-based plasma fibrinogen measured using different detection methods. Nevertheless, the similarity between measurements shortly before weaning from CPB and after CPB within centres suggests that on-pump measurements could provide an early estimation of fibrinogen deficit after CPB and thus guidance for haemostatic therapy.

[Perioperative coagulation management in multiple trauma patients based on viscoelastic test results]. / Gerinnungsmanagement bei Polytrauma mit Hilfe viskoelastischer Tests.

Exsanguination represents the most common and potentially preventable cause of death in major trauma patients. Rapid surgical intervention coupled with an early and aggressive hemostatic therapy not only results in survival benefits of coagulopathic trauma patients, but also reduces the incidence of complications and costs. Standard coagulation tests are not suitable to adequately characterize the complexity of trauma-induced coagulopathy (TIC). This fact has led to a renaissance of viscoelastic tests, such as rotational thromboelastometry (ROTEM®) and thrombelastography (TEG®), which can be used as point-of-care monitors. In some trauma centers treatment algorithms have been developed, where hemostatic therapy is based on viscoelastic test results. Shock and tissue trauma activate profibrinolytic pathways which in turn result in premature dissolution of formed clots. Tranexamic acid rapidly and inexpensively blocks hyperfibrinolysis. ROTEM®/TEG® measurements revealed that diminished clot strength is associated with an increased bleeding tendency. Depending on the underlying cause, administration of fibrinogen concentrate and/or platelet concentrate administration improves clot firmness. Thrombin generation is initially less compromised and can be improved by the administration of plasma, prothrombin complex concentrate, or with restrictiveness by recombinant activated factor VII.

Comparison of Ringer's solution with 0.4% glucose or without in intraoperative infusion regimens for the prevention of hypoglycemia in juvenile pigs.

Juvenile pigs are prone to hypoglycemia, nevertheless they are commonly used in preclinical studies. The optimal perioperative fluid management with crystalloid solutions in such settings has not yet been studied. The aim of the current study was to correlate the perioperative fluid administration of Ringer's solution, with and without the addition of a minimal amount of glucose (0.4% glucose) to the blood glucose, and the incidence of perioperative hypoglycemia in 20 juvenile pigs (31.7 ± 5.2 kg) undergoing surgery for approximately one hour. Infusion of Ringer's solution without glucose (group Ri, n = 10) led to a significant decrease of the serum blood glucose level from 105.7 ± 27.1 mg/dL at baseline compared with 87.8 ± 31.7 mg/dL post surgery. The pigs (50%) in group Ri were observed to be hypoglycemic (<72 mg/dL). The second group received Ringer's solution containing a final concentration of 0.4% glucose (group Ri-Glu, n = 10) and showed a significant increase in blood glucose level from 104.4 ± 15.8 mg/dL at baseline compared with 122.3 ± 14.3 mg/dL post surgery. No animal in group Ri-Glu was observed to be hypoglycemic. In conclusion, we showed that even minor changes in perioperative crystalloid fluid management significantly influence blood glucose levels. In order to avoid hypoglycemia in juvenile pigs we recommend adding a minimal amount of glucose (0.4% final concentration) to the Ringer's solution given perioperatively during surgery of approximately one hour.

The role of fibrinogen in trauma-induced coagulopathy.

Fibrinogen plays an essential role in clot formation and stability. Importantly it seems to be the most vulnerable coagulation factor, reaching critical levels earlier than the others during the course of severe injury. A variety of causes of fibrinogen depletion in major trauma have been identified, such as blood loss, dilution, consumption, hyperfibrinolysis, hypothermia and acidosis. Low concentrations of fibrinogen are associated with an increased risk of diffuse microvascular bleeding. Therefore, repeated measurements of plasma fibrinogen concentration are strongly recommended in trauma patients with major bleeding. Recent guidelines recommend maintaining plasma fibrinogen concentration at 1.5-2 g/l in coagulopathic patients. It has been shown that early fibrinogen substitution is associated with improved outcome.

A novel coagulation assay incorporating adherent endothelial cells in thromboelastometry.

Following vascular injury or activation, endothelial cells (ECs) participate in the modulation of haemostasis and fibrinolysis. Viscoelastic tests (VETs) are a potent bedside monitoring tool that reports haemostatic parameters in real time. However, VETs neglect the influence of the surrounding endothelium. Our aim was therefore to establish an assay that incorporates ECs in a whole blood VET and to assess the impact of ECs on coagulation parameters. Outgrowth endothelial cells (OECs) and human umbilical vein endothelial cells (HUVECs) were seeded onto microbeads to create transferable EC-microcarriers. Microbeads were then added to citrated whole blood in the measurement cup of a thromboelastometry device (ROTEM). After the addition of CaCl2 (star-TEM®) to the blood sample (NATEM assay), standard ROTEM parameters were analysed. Scanning electron microscopy (SEM) was carried out to visualise the interactions of the beads, whole blood components and the ROTEM pin after clotting. SEM showed that the added microbeads were effectively incorporated into the final blood clot. In the presence of activated ECs, the clotting time (CT) of the blood was shortened fourfold compared to that in uncoated control beads. A significant reduction in CT was also observed in the presence of unstimulated ECs. Interestingly, CT was also reduced by the addition of purified EC culture supernatant. CT shortening was prevented by incubating the supernatant with an inhibiting antibody against tissue factor (TF). Our findings demonstrate that ECs can be incorporated into a ROTEM assay via coated microbeads, and whole blood clotting initiation is accelerated by non-activated and activated ECs.

Hyperfibrinolysis is common in out-of-hospital cardiac arrest: results from a prospective observational thromboelastometry study.

BACKGROUND: Cardiocirculatory arrest (CCA) activates procoagulant pathways. It has also been reported to inhibit fibrinolysis, resulting in fibrin deposition and further impairment of blood flow. Until now, no studies have used whole-blood viscoelastic tests to characterize coagulation and the impact of fibrinolysis in out-of-hospital cardiac arrest (OHCA). METHODS: Patient with established OHCA who underwent cardiopulmonary resuscitation (CPR) were enrolled. Blood samples were obtained immediately after placement of an intravenous line at the scene, for full blood cell count, standard coagulation tests and rotational thromboelastometric (ROTEM(®)) analyses. Patients with return of spontaneous circulation (ROSC) were compared to non-ROSC patients. RESULTS: Fifty-three patients (median age 67 years, interquartile range: 56-73 years) were included in the study. ROSC was established in 25 patients. Prothrombin time index (PTI) was significantly lower and activated partial thromboplastin time (aPTT) was significantly prolonged in non-ROSC patients compared to ROSC patients. Clotting time (CT) in the extrinsically activated ROTEM test (EXTEM) was significantly longer in non-ROSC versus ROSC patients. For the remaining EXTEM parameters, there were no significant differences between ROSC and non-ROSC patients. Hyperfibrinolysis (maximum lysis>15% according to ROTEM test results) was observed in 19 patients (35.8%). There was no difference between ROSC and non-ROSC patients in the incidence of hyperfibrinolysis. CONCLUSIONS: PTI, aPTT and EXTEM CT revealed significant differences between ROSC and non-ROSC patients. Hyperfibrinolysis according to ROTEM test results was much more common than previously assumed. Routine use of fibrinolytic therapy in all patients with prolonged CPR cannot therefore be recommended.

[Clonidine for remifentanil-induced hyperalgesia: a double-blind randomized, placebo-controlled study of clonidine under intra-operative use of remifentanil in elective surgery of the shoulder]. / Clonidin bei Remifentanil-induzierter Hyperalgesie: Doppelblinde randomisierte, placebokontrollierte Studie mit Clonidin unter intraoperativer Analgesie mit Remifentanil bei Schultereingriffen.

BACKGROUND: In the postoperative period, α2-adrenergic agonists have an opioid sparing effect. In a previous, experimental study, it was also shown that clonidine attenuates remifentanil-induced hyperalgesia. In this study, we examined under clinical conditions whether early administration of a single dose of clonidine can inhibit remifentanil-induced hyperalgesia in patients undergoing elective surgery of the shoulder and with continuous intraoperative use of remifentanil. PATIENTS AND METHODS: In this study 40 patients received double-blind and randomized either 150 µg clonidine or placebo intravenously before skin incision. Anaesthesia was maintained with propofol and remifentanil (0.23 ± 0.09 µg/kg body weight/min) and morphine (0.1 mg/kg body weight) was administered 20 min before incision closure. Postoperatively, the patients were given a patient-controlled analgesia pump (PCA) with morphine. RESULTS: Overall morphine consumption as well as overall assessment of pain with the visual analogue scale in the first 24 h postoperatively did not differ significantly between the groups. Isolated pain scores at 12 h and 24 h were significantly enhanced in the clonidine group (p<0.05). CONCLUSION: An early single dose of 150 µg of clonidine did not reduce the postoperative morphine consumption and pain scores in patients undergoing elective surgery of the shoulder with remifentanil/propofol-based anaesthesia. After the effect of clonidine has presumably subsided the pain can even increase, therefore further studies with repetitive doses of clonidine should be carried out.

Assessment of reperfusion following thrombolysis with mean fibrillation and amplitude spectrum area in patients with sustained ventricular fibrillation.

BACKGROUND: Improved microcirculatory reperfusion in patients with ventricular fibrillation (VF) enhances the electrical activity of the fibrillation process and increases the likelihood of successful defibrillation. METHODS: Changes in amplitude spectrum area (AMSA) and mean fibrillation (MF) in patients with sustained VF were analysed after administration of rt-PA variant tenecteplase in out-of-hospital cardiac arrest (OHCA) during cardiopulmonary resuscitation (CPR). RESULTS: A total of 69 ECG sequences from nine patients were evaluated. Patients who received tenecteplase showed significantly longer duration of VF (p = 0.016). While AMSA declined significantly during CPR (p = 0.001), MF did not differ between groups. There were two survivors in the treatment group and one in the control group. CONCLUSION: When tenecteplase was administered during CPR, VF lasted significantly longer than in controls. Changes in MF and AMSA did not indicate improved myocardial perfusion in patients who received tenecteplase during CPR.

Safety aspects for public access defibrillation using automated external defibrillators near high-voltage power lines.

BACKGROUND: Automated external defibrillators (AEDs) must combine easy operability and high-quality diagnosis even under unfavorable conditions. This study determined the influence of electromagnetic interference caused by high-voltage power lines with 16.7-Hz alternating current on the quality of AEDs' rhythm analysis. METHODS: Two AEDs frequently used in Austria were tested near high-voltage power lines (15 kV or 110 kV, alternating current with 16.7 Hz). The defibrillation electrodes were attached either to a proband with true sinus rhythm or to a resuscitation dummy with generated sinus rhythm, ventricular fibrillation, ventricular tachycardia or asystole. RESULTS: Electromagnetic interference was much more prominent in a human's than in a dummy's electrocardiogram and depended on the position of the electrodes and cables in relation to the power line. Near high-voltage power lines the AEDs showed a significant operational fault. One AED interpreted the interference as a motion artifact, even when underlying rhythms were clearly detectable. The other AED interpreted 16.7-Hz oscillation as ventricular fibrillation with consequent shock advice when no underlying rhythm was detected. CONCLUSION: The tested AEDs neither filter nor recognize a technical interference of 16.7 Hz caused by 15-kV power lines above railway tracks or 110-kV overland power lines, as run by railway companies in Austria, Germany, Norway, Sweden and Switzerland. These failures in AEDs' algorithms for rhythm analysis may cause substantial harm to patients undergoing public access defibrillation. The proper function of AEDs needs to be reconsidered to guarantee patients' safety near high-voltage power lines.

[Evaluation of an established course of hospital management through structured telephone survey of former participants]. / Evaluierung eines etablierten Universitätslehrganges für Krankenhausmanagement durch telefonische Befragung ehemaliger Teilnehmer.

AIM OF THE STUDY: Participation in courses for health and hospital management is increasingly becoming a conditio sine qua non for candidates for executive positions in the health professions. The aim of this study was thus to evaluate the two-semester university course for health and hospital management offered by the University of Innsbruck since 1994. METHODS: A structured telephone survey was conducted to poll the participants (n = 184) of previous courses concerning time invested, cost-benefit ratio, quality of the course as well as implementation of course content. RESULTS: The university courses (n = 7) for health and hospital management of the University of Innsbruck evaluated in this study were rated in the upper half of the of the five-part scale (scores 2 to 3) for overall quality, cost-benefit ratio and implementation of course content. Only approx. 25 % of the course participants reported that the course had a positive influence on their career. The relatively high course fee was borne in part by the local hospital operator, a fact that had a certain influence on the selection of course participants. Participation in the course was largely made possible by exemptions from job duties (approx. 75 %) and to a lesser extent by vacation time (approx. 20 %) or time off for overtime (approx. 5 %). Of total absences from the course (3.18 +/- 3.41 d) 75 % was for job-related reasons, 6 % for illness and 19 % for other reasons. Overall, participants were absent more often, the larger the number of personnel in their department or clinic. CONCLUSION: All in all, the courses were considered important and recommendable, particularly with regard to communication, organization, time management and cost awareness. Streamlining (i. e. more content in less time), stronger practical orientation and a switch from mainly local to more international speakers would be important steps toward improving course quality. Thanks to its demonstrated quality, it can be said that the university course for health and hospital management held by the University of Innsbruck and evaluated in this study is certainly a worthwhile course offered in a still emerging market, namely one that will come under increasing pressure from the candidates for executive positions in the health professions to provide what is best for their careers and the health services industry in general.