[Prehospital management of acute coronary syndrome in patients on long-term direct oral anticoagulant treatment]. / Prähospitale Behandlung des akuten Koronarsyndroms unter DOAK-Dauertherapie.

BACKGROUND: Despite an increasing incidence of patients suffering from acute coronary syndrome (ACS) under simultaneous treatment with direct oral anticoagulants (DOAC), neither sufficient scientific data nor uniform guidelines for the anticoagulation treatment of these patients are currently available. OBJECTIVE: The aim of this study was to determine the current practice of preclinical treatment of ACS in patients under DOAC treatment. MATERIAL AND METHODS: An internet and paper-based survey of emergency physicians, specialists of internal medicine, anesthesiologists, emergency and intensive care physicians was performed concerning the prehospital treatment of ACS in patients under long-term DOAC treatment. RESULTS: Overall, 284 questionnaires were answered. Substantial differences in the current treatment of ACS under long-term DOAC therapy were identified. While 39% of the respondents stated that they administer a combination treatment of heparin and acetylsalicylic acid (ASA), 36% renounced the administration of heparin. If a dose reduction was performed, 71% answered that they reduce the heparin dosage. Also, in cases of ST-segment elevation myocardial infarction 48% of the physicians renounced the administration of heparin. CONCLUSION: In Germany there is currently a heterogeneous practice of emergency treatment of ACS patients under DOAC therapy with respect to the administration of heparin and ASA. Therefore, guidelines of the specialist medical societies should address the prehospital emergency anticoagulation management of ACS in patients under therapy with DOAC, which correspond to the needs of patients and emergency physicians.

Assessment of standard laboratory tests and rotational thromboelastometry for the prediction of postoperative bleeding in liver transplantation.

BACKGROUND: Perioperative bleeding remains a major challenge in liver transplantation. We aimed to compare standard laboratory tests with thromboelastometry (ROTEM ® ) with regard to their ability to predict postoperative non-surgical bleeding. METHODS: Data from 243 adult liver transplant recipients from January 2012 to May 2014 were evaluated retrospectively. Upon admission to the intensive care unit, coagulation status was assessed using standard laboratory tests [prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration, and platelet count] and ROTEM ® whole blood coagulation assays. Bleeding was defined as transfusion of ≥ 3 units of red blood cells or reoperation for non-surgical bleeding within 48 h after transplantation. Coagulation test results were analysed using receiver operating characteristics (ROC) in order to identify variables predictive of postoperative bleeding. Coagulation management was based on ROTEM ® -guided factor concentrate treatment. RESULTS: The overall incidence of bleeding was 12.3% ( n =30). Twenty-three (9.5%) patients underwent reoperation and seven (2.9%) received ≥3 units of red blood cells and non-operative management. Standard laboratory tests predictive of postoperative bleeding were aPTT and PT [area under the ROC curve (AUC) 0.688 and 0.623, respectively]. Tests predictive of bleeding with ROTEM ® were CT EXTEM , CFT INTEM , A10 FIBTEM , and MCF FIBTEM , with AUCs of 0.682, 0.615, 0.615, and 0.611, respectively. Fibrinogen concentration, platelet count, and other ROTEM ® variables failed to demonstrate predictive value for postoperative bleeding (AUC <0.6). Dialysis-dependent kidney failure, 30 day mortality, and median model for endstage liver disease score were all significantly higher in bleeding patients. CONCLUSIONS: Although both postoperative standard laboratory tests and ROTEM ® assays could identify patients at risk for postoperative bleeding, ROTEM ® assays demonstrated a greater predictive value for impaired fibrinogen polymerization-related coagulopathy.

Bleeding risk assessment in patients undergoing elective cardiac surgery using ROTEM(®) platelet and Multiplate(®) impedance aggregometry.

Impaired platelet function is a major risk factor for peri-operative bleeding and transfusion. This prospective, observational study enrolled 101 consecutive patients undergoing elective cardiac surgery with cardiopulmonary bypass. Platelet function was assessed by two whole blood impedance aggregometers (ROTEM(®) platelet and Multiplate(®) ), using three different activators (arachidonic acid, adenosine diphosphate and thrombin receptor-activating peptide-6), at three peri-operative time points (before anaesthesia, after aortic declamping and 5-10 min after protamine administration). Platelet function was impaired over the time-course in all assays. Results after protamine administration demonstrated the best correlation with postoperative chest tube drainage. Patients with a chest tube drainage exceeding the 75th percentile of the entire study population, during the first 24 postoperative hours, were characterised to have excessive bleeding. Both devices provided similar predictability for postoperative chest tube drainage and red blood cell transfusion requirements. The latter was associated with the degree of platelet inhibition and the number of pathways inhibited determined respective cut-off values.

Fast interpretation of thromboelastometry in non-cardiac surgery: reliability in patients with hypo-, normo-, and hypercoagulability.

BACKGROUND: Conventional coagulation test are not useful to guide haemostatic therapy in severe bleeding due to their long turn-around time. In contrast, early variables assessed by point-of-care thromboelastometry (ROTEM(®)) are available within 10-20 min and increasingly used to guide haemostatic therapy in liver transplantation and severe trauma. However, the reliability of early ROTEM(®) variables to predict maximum clot firmness (MCF) in non-cardiac surgery patients with subnormal, normal, and supranormal MCF has not yet been evaluated. METHODS: Retrospective data of 14,162 ROTEM(®) assays (3939 EXTEM(®), 3654 INTEM(®), 3287 FIBTEM(®), and 3282 APTEM(®) assays) of patients undergoing non-cardiac surgery were analysed. ROTEM(®) variables [clotting time (CT), clot formation time (CFT), α-angle, A5, A10, and A15] were related to MCF by linear or non-linear regression, as appropriate. The Bland-Altman analyses to assess the bias between early ROTEM(®) variables and MCF and receiver operating characteristics (ROC) were also performed. RESULTS: Taking the best and worst correlation coefficients for each assay type, CT (r=0.18-0.49) showed the worst correlation to MCF. In contrast, α-angle (r=0.85-0.88) and CFT (r=0.89-0.92) demonstrated good but non-linear correlation with MCF. The best and linear correlations were found for A5 (r=0.93-0.95), A10 (r=0.96), and A15 (r=0.97-0.98). ROC analyses provided excellent area under the curve (AUC) values for A5, A10, and A15 (AUC=0.962-0.985). CONCLUSIONS: Early values of clot firmness allow for fast and reliable prediction of ROTEM(®) MCF in non-cardiac patients with subnormal, normal, and supranormal MCF values and therefore can be used to guide haemostatic therapy in severe bleeding.

Early thromboelastometric variables reliably predict maximum clot firmness in patients undergoing cardiac surgery: a step towards earlier decision making.

BACKGROUND: While much effort has been spent on guiding coagulation and transfusion therapy in patients undergoing cardiopulmonary bypass (CPB) surgery, the use of conventional laboratory-based coagulation tests is hampered by long turnaround times and interference with heparin and protamine. To allow faster assessment of maximum clot firmness (MCF) by point-of-care thromboelastometry (ROTEM®, TEM International GmbH, Munich, Germany), we tested whether clotting time (CT), clot formation time (CFT), or early values of clot firmness (CF) predict MCF. METHODS: Results of 437 ROTEM® assays (EXTEM®, INTEM®, FIBTEM®, and HEPTEM®) from 84 patients undergoing CPB surgery were analyzed. Measurements were performed prior to and after heparin administration, as well as after protamine administration and CT, CFT, and CF after 5, 10, and 15 min (A5, A10, and A15) after initial clotting (CT) were related to MCF. STATISTICS: Regression and Bland-Altman analyses and receiver-operating characteristics (ROCs). RESULTS: CFT (r = 0.87-0.95), A5 (r = 0.84-0.98; P < 0.0001), A10 (r = 0.86-0.98; P < 0.0001), and A15 (r = 0.86-0.98; P < 0.0001) demonstrated high correlation coefficients with MCF, whereas CT correlated weakly (r = 0.07-0.41). As expected, correlation coefficients increased with the time allowed to assess a specific variable. ROC analyses demonstrated excellent accuracy for CFT, A5, A10, and A15 [area under the curve (AUC): 0.9476-0.9931] to predict a subnormal MCF, whereas CT demonstrated poor accuracy (AUC: 0.5796-0.6774). CONCLUSION: Taking into account specific bias, early values of CF (A5-A15) reliably predict maximum CF under all conditions and, therefore, allow for marked time savings in the interpretation of ROTEM® measurements. This may guide earlier and more specific treatment of CPB-related coagulation disorders.

Development and longitudinal validation of the overall benefit of analgesia score: a simple multi-dimensional quality assessment instrument.

BACKGROUND: The goal of this study was to develop and validate the overall benefit of analgesic score (OBAS), which assesses pain intensity and the opioid-related adverse effects. METHODS: The score was developed and validated in four trials (n=1470 patients). Data from randomized trial I were used to develop the OBAS (factor analysis). Data from randomized trial II were used to compare the resolution of rofecoxib's analgesic effects between OBAS and pain scores. Randomized trial III (spine surgery) was conducted to evaluate prospectively the reliability of the OBAS and to compare its resolution of analgesic treatment with the opioid-related symptom distress scale (OR-SDS) and the modified brief pain inventory short form (m-BPI-sf). Trial IV was conducted to evaluate in patients with a moderate-to-high level of postoperative pain (after major abdominal surgery) the relation of OBAS and pain scores for patients' satisfaction with analgesic therapy. RESULTS: The seven-item OBAS yielded a higher resolution of analgesic treatment effects than pain scores, the OR-SDS and m-BPI-sf. The OBAS has a fair inter-rater reliability (concordance correlation of 0.71 c) and is more sensitive (P=0.03) in indicating the delivery of opioid boluses than the dedicated OR-SDS. The OBAS, but not pain scores at rest or pain scores during movement, explained significant variance in patients' satisfaction with postoperative pain therapy. CONCLUSIONS: The OBAS is a simple, multi-dimensional quality assessment instrument to measure patients' benefit from postoperative pain therapy. Opioid symptom distress, pain relief, and patients' satisfaction are combined in a reliable and valid tool.

Whole blood coagulation and platelet activation in the athlete: a comparison of marathon, triathlon and long distance cycling.

INTRODUCTION: Serious thrombembolic events occur in otherwise healthy marathon athletes during competition. We tested the hypothesis that during heavy endurance sports coagulation and platelets are activated depending on the type of endurance sport with respect to its running fraction. MATERIALS AND METHODS: 68 healthy athletes participating in marathon (MAR, running 42 km, n = 24), triathlon (TRI, swimming 2.5 km + cycling 90 km + running 21 km, n = 22), and long distance cycling (CYC, 151 km, n = 22) were included in the study. Blood samples were taken before and immediately after completion of competition to perform rotational thrombelastometry. We assessed coagulation time (CT), maximum clot firmness (MCF) after intrinsically activation and fibrin polymerization (FIBTEM). Furthermore, platelet aggregation was tested after activation with ADP and thrombin activating peptide 6 (TRAP) by using multiple platelet function analyzer. RESULTS: Complete data sets were obtained in 58 athletes (MAR: n = 20, TRI: n = 19, CYC: n = 19). CT significantly decreased in all groups (MAR -9.9%, TRI -8.3%, CYC -7.4%) without differences between groups. In parallel, MCF (MAR +7.4%, TRI +6.1%, CYC +8.3%) and fibrin polymerization (MAR +14.7%, TRI +6.1%, CYC +8.3%) were significantly increased in all groups. However, platelets were only activated during MAR and TRI as indicated by increased AUC during TRAP-activation (MAR +15.8%) and increased AUC during ADP-activation in MAR (+50.3%) and TRI (+57.5%). DISCUSSION: While coagulation is activated during physical activity irrespective of type we observed significant platelet activation only during marathon and to a lesser extent during triathlon. We speculate that prolonged running may increase platelet activity, possibly, due to mechanical alteration. Thus, particularly prolonged running may increase the risk of thrombembolic incidents in running athletes.

Diadenosine-5-phosphate exerts A1-receptor-mediated proarrhythmic effects in rabbit atrial myocardium.

(1) Diadenosine polyphosphates have been described to be present in the myocardium and exert purinergic- and nonreceptor-mediated effects. Since the electrophysiological properties of atrial myocardium are effectively regulated by A(1) receptors, we investigated the effect of diadenosine pentaphosphate (Ap(5)A) in rabbit myocardium. (2) Parameters of supraventricular electrophysiology and atrial vulnerability were measured in Langendorff-perfused rabbit hearts. Muscarinic potassium current (I(K(ACh/Ado))) and ATP-sensitive potassium current (I(K(ATP))) were measured by using the whole-cell voltage clamp method. (3) Ap(5)A prolonged the cycle length of spontaneously beating Langendorff perfused hearts from 225+/-14 (control) to 1823+/-400 ms (Ap(5)A 50 micro M; n=6; P<0.05). This effect was paralleled by higher degree of atrio-ventricular block. Atrial effective refractory period (AERP) in control hearts was 84+/-14 ms (n=6). Ap(5)A>/=1 micro M reduced AERP (100 micro M, 58+/-11 ms; n=6). (4) Extrastimuli delivered to hearts perfused with Ap(5)A- or adenosine (>/= micro M)-induced atrial fibrillation, the incidence of which correlated to the concentration added to the perfusate. The selective A(1)-receptor antagonist CPX (20 micro M) inhibited the Ap(5)A- and adenosine-induced decrease of AERP. Atrial fibrillation was no longer observed in the presence of CPX. (5) The described Ap(5)A-induced effects in the multicellular preparation were enhanced by dipyridamole (10 micro M), which is a cellular adenosine uptake inhibitor. Dipyridamole-induced enhancement was inhibited by CPX. (6) Ap(5)A (

Perioperative use of modified thrombelastography in factor XI deficiency: a helpful method to assess drug effects.

Factor XI deficiency is a rare, hereditary bleeding disorder associated with a trauma-related bleeding tendency, caused by insufficient generation of the thrombin activatable fibrinolysis inhibitor (TAFI) evoking increased fibrinolysis. We present the case of a five year old girl with homozygote, severe factor XI deficiency presenting for surgery on two occasions. Modified thrombelastography (ROTEM) was used to assess effects of factor XI deficiency on coagulation, endogenous fibrinolysis, and potential effects of tranexamic acid, aprotinin and recombinant, activated Factor VII in an in vitro model of hyperfibrinolysis. According to our data and in consideration of the mechanisms of factor XI deficiency we decided on prophylactic use of tranexamic acid.

Propranolol inhibits IK(Ado) by competitive A1-receptor interaction.

OBJECTIVES: Betablocking agents are known to exert anti-arrhythmic effects in ischemic myocardium due to blockade of myocardial beta-1-receptors. Since adenosine (Ado) induced muscarinic potassium current (IK(Ado)) and ATP sensitive potassium current (IK(ATP)) are discussed to be activated during ischemia we studied the effect of propranolol on IK(Ado) and IK(ATP). METHODS AND RESULTS: The effect of propranolol on muscarinic potassium current and IK(ATP) was studied in isolated rat atrial myocytes by means of the whole-cell voltage clamp tech- nique. Propranolol (50 microM) completely inhibited IK(Ado). IC50 was 7 microM. Inhibition of acetylcholine induced current (IK(ACh)) and GTP-gamma-S induced muscarinic potassium current was less potent (IC50 29 microM and 31 microM respectively). Propranolol was active from the outside only. Intracellular application did not significantly affect muscarinic potassium current. (+)-propranolol, an isomer without beta-blocking properties, was as effective as (+/-)-propranolol. The inwardly rectifying potassium current IK(ATP) showed minor sensitivity to the compound (10% current reduction, propranolol 50 microM). CONCLUSIONS: Propranolol inhibits IK(Ado). Inhibition is not due to beta-receptor blockade. Predominantly an interaction with A1-receptors seems to be involved. The observations in part might explain the anti-arrhythmic properties of the drug in ischemic/fibrillating myocardium based on the prolongation of refractoriness.

Inhibition of G protein-coupled and ATP-sensitive potassium currents by 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015), an amiodarone derivative.

2-Methyl-3- (3,5-diiodo-4-carboxymethoxybenzyl) benzofuran (KB130015; KB), a novel compound derived from amiodarone, has been proposed to have antiarrhythmic properties. Its effect on the G protein-coupled inward rectifying K+ current [IK(ACh) or IK(Ado)], ATP-sensitive K+ current [IK(ATP)], and background inward rectifying current (I(K1)) were studied in guinea pig atrial and ventricular myocytes by the whole-cell voltage-clamp technique. Receptor-activated IK(ACh/Ado), induced in atrial myocytes by the stimulation of either muscarinic or Ado receptors was concentration dependently (IC50 value of approximately 0.6-0.8 microM) inhibited by KB. Receptor-independent guanosine 5'-O-(3-thio)triphosphate-induced and background IK(ACh), which contributes to the resting conductance of atrial myocytes, were equally sensitive to KB (IC50 value of approximately 0.9 microM). IK(ATP) induced in atrial myocytes during metabolic inhibition with 2,4-dinitrophenol (DNP) was also suppressed by KB, whereas IK1 measured in ventricular myocytes was insensitive to the drug (KB < or =50 microM). Although being effective when applied from the outside, intracellular application of KB via the patch pipette affected neither IK(ACh) nor IK(ATP). 3,3',5-triodo-L-thyronin, which shares structural groups with KB, did not have an effect on the K+ currents. Consistent with the effects on single myocytes, KB did not depolarize the resting potential but antagonized the shortening of action potential duration by carbamylcholine-chloride or by DNP in multicellular preparations and antagonized the shortening of action potential duration by acetylcholine in single myocytes. It is concluded that KB inhibits IK(ACh) and IK(ATP) by direct drug-channel interaction at a site more easily accessible from extracellular side of the membrane.