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BACKGROUND In long-term left ventricular assist device (LVAD) therapy, recurrent bleeding events may justify cessation of anticoagulation therapy (AT). However, data about THE safety and risks of AT cessation in LVAD patients are scarce.Methods and Results:Between 2010 and 2015, 128 patients received a HeartMate II (HMII). Following recurrent bleeding events, we ceased vitamin K antagonist (VKA) therapy in 13 patients (10%) (no-VKA group). To characterize the hemostatic profile, we performed von Willebrand factor (vWF), platelet function (PF), and other hemostatic tests in all HMII patients. The incidence of pump thrombosis (PT), ischemic stroke (IS) and bleeding events in this HMII population was 4.7 %, 6.2% and 36.7%, respectively. Median survival without VKA was 435 days. No cases of PT and only 1 of IS occurred after AT discontinuation. All patients had impaired PF and acquired von Willebrand syndrome (AvWS). However, the vWF collagen-binding activity to antigen ratio before and after VKA cessation was significantly lower in the no-VKA group compared with the HMII population (0.60±0.12 vs. 0.73±0.14, P=0.006). The thrombin-antithrombin III complex (TAT) value was significantly higher in the no-VKA group (P=0.0005). CONCLUSIONS We experienced good results with AT cessation in specific HMII patients. The simultaneous onset of AvWS and high TAT values could explain at least in part the low thromboembolic rate in HMII patients without VKA.

Die Einfuhrung der „nicht-Vitamin-K-abhangigen“, direkten oralen Antikoagulanzien (DOAK) bewirkte eine Vereinfachung der thrombembolischen Pravention fur die Patienten. Auf arztlicher Seite herrscht allerdings zum einen immer noch eine grose Unsicherheit im Rahmen des pra- und postoperativen Ab- und Wiederansetzens der Antikoagulation. Zum anderen erfordern Blutungen unter DOAK-Therapie spezifische Kenntnisse hinsichtlich diagnostischer und therapeutischer Optionen. Bisherige Therapiestrategien basierten vornehmlich auf Expertenempfehlungen und waren im Rahmen von Plasmasubstitution oder der Verwendung von Faktorenpraparaten relativ unspezifisch. Zudem muss davon ausgegangen werden, dass bei der Verwendung von prokoagulatorischen Substanzen, wie Prothrombinkomplex-Konzentrat (PPSB), das thrombogene Risiko nach erfolgter Therapie potenziell ansteigt. Ein neuer Ansatz resultiert aus der Einfuhrung von Idarucizumab, das als spezifisches, schnell wirkendes und gerinnungsinertes Antidot fur den Thrombininhibitor Dabigatran zur Verfugung steht. Die vorliegende Ubersichtsarbeit soll einen Uberblick uber pharmakologische Daten, Moglichkeiten der Therapie DOAK-assoziierter Blutungen und spezifische Reversierungsmoglichkeiten geben.

The direct oral anticoagulants (DOACs) provide a number of clinical advantages over vitamin K antagonists for the treatment of thromboembolism, including improved efficacy and safety, as well as no need for regular monitoring of anticoagulant effect. However, as with all anticoagulants, bleeding complications may occur, and anticoagulant reversal may be required in specific clinical situations, such as in patients experiencing spontaneous or traumatic bleeds, or in anticoagulated patients requiring emergency surgery or other invasive procedures. Therefore, several reversal agents for the DOACs are in development. This includes the specific reversal agent idarucizumab, which has been approved by the U.S. Food and Drug Administration and the European Medicines Agency for use in patients treated with dabigatran when urgent reversal of its anticoagulant effects is needed. Idarucizumab is a humanized monoclonal antibody fragment that binds with high affinity to free and thrombin-bound dabigatran, resulting in an almost irreversibly bound idarucizumab–dabigatran complex and thereby neutralizing dabigatran's anticoagulant activity. The reversal of the anticoagulant effects of dabigatran by idarucizumab has been demonstrated in animal bleeding models, in healthy volunteers with a range of ages and renal function, and in anticoagulated patients. In the phase 1 trials, at doses of 2 g or greater, idarucizumab resulted in immediate and complete reversal of the dabigatran anticoagulant effects and was well tolerated. In the absence of dabigatran, idarucizumab showed no effect on coagulation parameters or thrombin formation. These findings provide initial evidence that idarucizumab could provide a safe and effective means of reversing anticoagulant activity in patients treated with dabigatran in need of emergency surgery or in emergency bleeding situations.

Factor Xa inhibitors prevent thrombosis but are associated with severe or life-threatening bleeding. Here, the authors present data on four-factor prothrombin complex concentrates in management of anticoagulation-associated bleeding and restoring hemostasis, including recent results from the UPRATE study.

Trauma care providers are facing an increasing number of elderly patients on direct oral anticoagulants prior to injury. For dabigatran etexilate (DAB), the specific antagonist idarucizumab (IDA) has been approved since 2015 as a reversal agent. However, only limited data regarding the use of IDA in trauma patients are available. We performed a retrospective analysis of trauma patients under DAB for whom IDA administration was deemed necessary to reverse DAB’s antithrombotic effect. A total of 15 (9 male) patients were treated with IDA during the study period. The mean age was 81 ± 10 years. Intracranial haemorrhage (n = 7) and long bone fractures (n = 5) were the most common types of injury. Three patients were diagnosed as polytrauma. In all but one patient, atrial fibrillation was the indication for DAB intake. The median dose of IDA was 2.5 g (IQR 2.5–5). IDA administration decreased DAB plasma levels from 112.4 (IQR 73.4–123.4) to 5 (IQR 4–12) ng/mL (p = 0.031), thrombin time from 114.8 ± 48.3 to 16.2 ± 0.5 s (p

Editor’s Perspective What We Already Know about This Topic What this Article Tells Us That Is New Background The risk of thromboembolic complications with prothrombin complex concentrates (PCCs) appears low when used for reversal of vitamin K antagonists but might be different in other indications (e.g., trauma). A difference in risk could arise from the plasma ratio of pro- versus anticoagulant proteins. This study used a porcine trauma model to investigate combined treatment with PCC and antithrombin. The hypothesis was that antithrombin can modulate prothrombotic effects and prevent adverse events of PCC. Methods Nine treatment groups (n = 7 per group) were included: control (placebo), PCC (50 IU/kg), PCC plus antithrombin (three groups, with antithrombin doses of 12.5, 25, or 50 IU/kg), fibrinogen concentrate (100 mg/kg) plus PCC, fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg, tranexamic acid (15 mg/kg) plus fibrinogen concentrate plus PCC, and tranexamic acid plus fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg. In each group, bilateral femur fractures and thorax contusion were followed 60 min later by blunt liver injury. Study treatment was then administered, and animals were subsequently observed for 210 min. Results Total blood loss (mean ± SD) was statistically significantly lower in all three PCC plus antithrombin groups (PCC plus antithrombin dose of 50 IU/kg, 672 ± 63 ml; PCC plus antithrombin dose of 25 IU/kg, 535 ± 72 ml; and PCC plus antithrombin dose of 12.5 IU/kg, 538 ± 50 ml) than in the PCC group (907 ± 132 ml), which in turn had statistically significantly reduced bleeding versus the control group (1,671 ± 409 ml). Signs of disseminated intravascular coagulation were apparent with PCC monotherapy, and early deaths occurred with fibrinogen concentrate plus PCC, attributable to pulmonary emboli. Antithrombin was protective against both of these effects: signs of disseminated intravascular coagulation were absent from the PCC plus antithrombin groups, and there were no early deaths in the group with fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg. Conclusions According to this trauma model, 50 IU/kg PCC increases the risk of disseminated intravascular coagulation and other thromboembolic complications, most notably when coadministered with fibrinogen concentrate. The addition of antithrombin appears to reduce this risk.

Background Factor X (FX) deficiency (FXD) is an extremely rare autosomal recessive hereditary hematologic disorder, affecting approximately one in 1,000,000 of the general population. Case report This case report describes an infant with hereditary severe FXD who presented with a spontaneous, life-threatening intracranial hemorrhage and was treated with the first licensed plasma-derived FX (pdFX) concentrate. On admission, laboratory assays showed severe coagulopathy of unknown cause; the patient was empirically treated using a multimodal hemostatic approach with prothrombin complex concentrate, fresh-frozen plasma, and tranexamic acid. Subsequent single-factor coagulation and genetic analyses confirmed the hereditary FXD diagnosis, and the therapeutic regimen was changed to a targeted regimen of 250 IU pdFX daily. Based on careful monitoring of the coagulation profile, pdFX administration frequency was increased to twice daily, followed by a reduction to once every 18 hours. The patient was discharged after 7 weeks of hospitalization in good clinical condition and now receives prophylactic pdFX three times weekly.

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.

Clinical and applied thrombosis, hemostasis 22(8), 749-759 (2016). doi:10.1177/1076029615584662, Published by Sage, Thousand Oaks, Calif.

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(-1), TXA group); TXA and FC (90 mg kg(-1), TXA-FC); or TXA, FC, and PCC (20 U kg(-1), 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

Orale Antikoagulanzien sind fur die Schlaganfallpravention bei Vorhofflimmern sowie die Therapie und Prophylaxe venoser Thromboembolien unverzichtbar. In den letzten Jahren ist mit den nicht Vitamin-K-abhangigen oralen Antikoagulanzien (NOAKs) eine Wirkstoffgruppe in den Vordergrund geruckt, die hinsichtlich ihrer Wirksamkeit und Sicherheit gegenuber den klassischen Antikoagulanzien, wie Vitamin-K-Antagonisten, relevante Vorteile bietet. Blutungskomplikationen gehoren jedoch nach wie vor zu den moglichen Nebenwirkungen. Mit der Entwicklung NOAK-spezifischer Antidote wird nun ein weiterer Fortschritt in der Sicherheit der antithrombotischen Therapie erzielt: Mit Idarucizumab ist bereits ein spezifisch und rasch wirksames Antidot gegen den direkten Thrombininhibitor Dabigatran auf dem Markt verfugbar. Zur Wirkungsaufhebung der Faktor-Xa-Inhibitoren ist Andexanet alfa in Phase III der klinischen Entwicklung.

The licensed anesthetic xenon, which exerts organ protective properties, was recently added by the World Anti-Doping Agency to the list of prohibited substances. Xenon is supposed to trigger the production of hypoxia-inducible factor 1α (HIF-1α) and subsequently erythropoietin, but data are limited to in vivo experimental work. Therefore we evaluated the effect of xenon on erythropoietin levels in healthy persons. Twenty-four healthy volunteers were randomly assigned either to a group spontaneously breathing xenon 30 % (Xe/O2 30 %/60 %) or a group breathing control gas (N2/O2 40 %/60 %) for 45 min. Primary outcome parameters were erythropoietin levels at several time-points after exposure. Secondary outcome parameters were serum levels of testosterone, cytokines, and growth factors as well as concentrations of xenon in blood and exhalation samples measured at several time-points after exposure. In addition, hemodynamic safety parameters were monitored during exposure. The administration of xenon significantly increased erythropoietin levels 8 h after exposure (1.34 [±0.368]; p = 0.008), peaking at 24 h compared to the baseline values (1.45 [±0.498]; p = 0.01) and remained traceable in blood and exhalation probes until 24 h after exposure. In contrast, no significant change was observed in the control group. Measurement of stromal cell-derived factor 1 (SDF-1) revealed a significant increase of SDF-1 levels (p = 0.005), whereas no differences were observed with respect to growth factors, cytokines, or androgens. In an in vitro chemotaxis assay, endothelial progenitor cells (EPCs) showed a trend towards increased migration in serum samples received from participants after xenon exposure (p = 0.080). The present study presents first evidence about a xenon-induced effect on increased erythropoietin levels in healthy volunteers. The study was registered at the European Medicines Agency (EudraCT-number: 2014-000973-38) and at ClinicalTrials.gov (NCT number: 02129400).

Veno-venous extracorporeal lung assist (ECLA) can provide sufficient gas exchange even in most severe cases of acute respiratory distress syndrome. Commercially available systems are manually controlled, although an automatically controlled ECLA could allow individualized and continuous adaption to clinical requirements. Therefore, we developed a demonstrator with an integrated control algorithm to keep continuously measured peripheral oxygen saturation and partial pressure of carbon dioxide constant by automatically adjusting extracorporeal blood and gas flow. The "SmartECLA" system was tested in six animal experiments with increasing pulmonary hypoventilation and hypoxic inspiratory gas mixture to simulate progressive acute respiratory failure. During a cumulative evaluation time of 32 h for all experiments, automatic ECLA control resulted in a peripheral oxygen saturation ≥90% for 98% of the time with the lowest value of 82% for 15 s. Partial pressure of venous carbon dioxide was between 40 and 49 mm Hg for 97% of the time with no value 49 mm Hg. With decreasing inspiratory oxygen concentration, extracorporeal oxygen uptake increased from 68 ± 25 to 154 ± 34 mL/min (P

SummaryClinical use of non-vitamin K antagonist oral anticoagulants is increasingly well established. However, specific agents for reversal of these drugs are not currently available. It was to objective of this study to investigate the impact of activated prothrombin complex concentrate (aPCC) on the anticoagulant effects of dabigatran in a randomised, controlled, porcine trauma model. Twenty-one pigs received oral and intravenous dabigatran, resulting in supratherapeutic plasma concentrations. Twelve minutes after injury (standardised bilateral femur fractures and blunt liver injury), animals (n=7/group) received 25 or 50 U/kg aPCC (aPCC25 and aPCC50) or placebo (control) and were followed for 5 hours. The primary endpoint was total volume of blood loss (BL). Haemodynamic and coagulation variables (prothrombin time [PT], activated partial thromboplastin time, diluted thrombin time, thrombin–antithrombin complexes, thromboelastometry, thrombin generation and D-dimers) were measured. Twelve minutes post-injury, BL was similar between groups. Compared with control (total BL: 3807 ± 570 ml) and aPCC25 (3690 ± 454 ml; p=0.77 vs control), a significant reduction in total BL (1639 ± 276 ml; p< 0.0001) and improved survival (p< 0.05) was observed with aPCC50. Dabigatran’s anticoagulant effects were effectively treated in the aPCC50 group, as measured by several parameters including EXTEM clotting time (CT) and PT. In contrast, with aPCC25, laboratory values were initially corrected but subsequently deteriorated due to ongoing blood loss. Thromboembolic or bleeding effects were not detected. In conclusion, blood loss following trauma in dabigatran-anticoagulated pigs was successfully reduced by 50 U/kg aPCC. Optimal methodology for measuring amelioration of dabigatran anticoagulation by aPCC is yet to be determined.

Background In the event of trauma, emergency reversal of anticoagulation therapy may be required. However, no specific reversal agents are routinely available for the direct oral anticoagulants such as dabigatran. The authors investigated four-factor prothrombin complex concentrate (PCC) for treating dabigatran-induced anticoagulation in a porcine polytrauma model. Methods Dabigatran etexilate was given orally for 3 days and intravenously on day 4 to 32 pigs. Animals were randomized 1:1:1:1 to PCC (25, 50, or 100 U/kg) or saline. Study medication was administered 12 min after bilateral femur fractures and blunt liver injury. The primary endpoint was blood loss at 300 min. Results The mean plasma concentration of dabigatran was 487 ± 161 ng/ml after intravenous administration. Blood loss was 3,855 ± 258 ml in controls and 3,588 ± 241 ml in the PCC25 group. In the PCC50 and PCC100 groups, blood loss was significantly lower: 1,749 ± 47 ml and 1,692 ± 97 ml, respectively. PCC50 and PCC100 effectively reduced dabigatran’s effects on coagulation parameters, whereas control and (to a lesser extent) PCC25 animals developed severe coagulopathy. Sustained increases in endogenous thrombin potential occurred with PCC50 and PCC100. Conclusion Four-factor PCC (50 or 100 U/kg) is effective in reducing blood loss in dabigatran-anticoagulated pigs, but higher doses may induce a procoagulant state.

Idarucizumab (IDA) is approved for emergency reversal of dabigatran; prothrombin complex concentrates (PCCs) are recommended in the absence of specific antidote. The combined effects of IDA and PCC in trauma-related bleeding are unknown. The efficacy and safety of combined IDA + PCC were assessed in a lethal porcine model of double trauma under dabigatran anticoagulation.Male pigs (n = 28) received oral dabigatran etexilate (30 mg/kg bid) for 3 days; a non-dabigatran control group (n = 7) received placebo. On Day 4, dabigatran-treated animals were randomized 1:1:1:1 to receive placebo + placebo (dabigatran-treated control), IDA + PCC (60 mg/kg + 50 IU/kg), PCC + IDA, or IDA + IDA. Trauma was induced at t = 0 (bilateral femur fractures and blunt liver injury) and t = 60 minutes (second blunt liver injury). Study treatment was administered 15 minutes after each trauma. Animals were monitored for 5 hours or until death.Total blood loss in IDA + PCC, PCC + IDA, and IDA + IDA was 1673 ± 370, 1981 ± 361, and 1417 ± 135 mL, respectively, with 100% survival at 5 hours. Blood loss in dabigatran-treated controls was 4427 ± 162 mL with 100% mortality. With IDA + IDA, plasma coagulation parameters and thrombin generation were similar to non-dabigatran control group levels after the second dose and remained stable over time. In the IDA + PCC and PCC + IDA groups, thrombin generation and d-dimer levels after the second dose were higher than with IDA + IDA. No thromboembolic complications were found.IDA and PCC are effective in treating trauma-related bleeding with dabigatran anticoagulation. IDA is preferable for emergency reversal of dabigatran, but PCC may be valuable when the anticoagulant is unknown.

Scientific reports 8(1), 8031 (2018). doi:10.1038/s41598-018-25977-6, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Clinical nutrition 38(6), 2756-2762 (2019). doi:10.1016/j.clnu.2018.11.033, Published by Elsevier, Amsterdam [u.a.]

Clinical and applied thrombosis, hemostasis 24(5), 724-733 (2018). doi:10.1177/1076029618755947, Published by Sage, Thousand Oaks, Calif.

Background Traumatic brain injury (TBI) is the leading cause of death among trauma patients. Patients under antithrombotic therapy (ATT) carry an increased risk for intracranial haematoma (ICH) formation. There is a paucity of data about the role of direct oral anticoagulants (DOACs) among TBI patients. Methods In this retrospective study, we investigated all TBI patients ≥60-years-old who were admitted to the intensive care unit (ICU) from January 2014 until May 2017. Patients were grouped into those receiving vitamin K antagonists (VKA), platelet inhibitors (PI), DOACs and no antithrombotic therapy (no-ATT). Results One-hundred-eighty-six, predominantly male (52.7%) TBI patients with a median age of 79 years (range: 70–85 years) were enrolled in the study. Glasgow Coma Scale and S-100β were not different among the groups. Patients on VKA and DOACs had a higher Charlson Comorbidity Index compared to the PI group and no-ATT group (p = 0.0021). The VKA group received reversal agents significantly more often than the other groups (p

There is increasing interest in prothrombin complex concentrates as therapy for perioperative and trauma-related bleeding. A suitable point-of-care test is needed to guide such therapy, and randomized controlled trials are needed for robust, evidence-based recommendations.

Purpose of review To provide an overview of acquired coagulopathies that can occur in various perioperative clinical settings. Also described are coagulation disturbances linked to antithrombotic medications and currently available strategies to reverse their antithrombotic effects in situations of severe hemorrhage. Recent findings Recent studies highlight the link between low fibrinogen and decreased fibrin polymerization in the development of acquired coagulopathy. Particularly, fibrin(ogen) deficits are observable after cardiopulmonary bypass in cardiac surgery, on arrival at the emergency room in trauma patients, and with ongoing bleeding after child birth. Regarding antithrombotic therapy, although new oral anticoagulants offer the possibility of efficacy and relative safety compared with vitamin K antagonists, reversal of their anticoagulant effect with nonspecific agents, including prothrombin complex concentrate, has provided conflicting results. Specific antidotes, currently being developed, are not yet licensed for clinical use, but initial results are promising. Summary Targeted hemostatic therapy aims to correct coagulopathies in specific clinical settings, and reduce the need for allogeneic transfusions, thus preventing massive transfusion and its deleterious outcomes. Although there are specific guidelines for reversing anticoagulation in patients treated with antiplatelet agents or warfarin, there is currently little evidence to advocate comprehensive recommendations to treat drug-induced coagulopathy associated with new oral anticoagulants.

Background Although idarucizumab is the preferred treatment for urgent dabigatran reversal, it is not always available. Prothrombin complex concentrate (PCC) may be an alternative and, with bleeding in trauma, additional hemostatic therapy may be required. The authors investigated multimodal treatment in a preclinical polytrauma model. Methods Dabigatran etexilate (30 mg/kg twice daily) was given orally to 45 male pigs for 3 days. On day 4, animals received a dabigatran infusion before blunt liver injury and bilateral femur fractures. After injury, animals were randomized 1:1:1:1:1 to receive placebo (control), tranexamic acid (TXA; 20 mg/kg) plus human fibrinogen concentrate (FCH; 80 mg/kg) (TXA–FCH group), PCC (25 U/kg or 50 U/kg) plus TXA plus FCH (PCC25 and PCC50 groups), or 60 mg/kg idarucizumab (IDA) plus TXA plus FCH (IDA group). Animals were monitored for 240 min after trauma, or until death. Results The degree of injury was similar in all animals before intervention. Control and TXA–FCH animals had the highest total postinjury blood loss (3,652 ± 601 and 3,497 ± 418 ml) and 100% mortality (mean survival time 96 and 109 min). Blood loss was significantly lower in the PCC50 (1,367 ± 273 ml) and IDA (986 ± 144 ml) groups, with 100% survival. Thrombin–antithrombin levels and thrombin generation were significantly elevated in the PCC50 group. Conclusions Idarucizumab may be considered the optimal treatment for emergency reversal of dabigatran anticoagulation. However, this study suggests that PCC may be similarly effective as idarucizumab and could therefore be valuable when idarucizumab is unavailable. (Anesthesiology 2017; 127:852-61)

Plasma products, including fresh frozen plasma, are administered extensively in a variety of settings from massive transfusion to vitamin K antagonist reversal. Despite the widespread use of plasma as a hemostatic agent in bleeding patients, its effect in comparison with other available choices of hemostatic therapies is unclear. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed Central, and databases of ongoing trials for randomized controlled trials that assessed the efficacy and/or safety of therapeutic plasma as an intervention to treat bleeding patients compared with other interventions or placebo. Of 1243 unique publications retrieved in our initial search, no randomized controlled trials were identified. Four nonrandomized studies described the effect of therapeutic plasma in bleeding patients; however, data gathered from these studies did not allow for comparison with other therapeutic interventions primarily as a result of the low number of patients and the use of different (or lack of) comparators. We identified two ongoing trials investigating the efficacy and safety of therapeutic plasma, respectively; however, no data have been released as yet. Although plasma is used extensively in the treatment of bleeding patients, evidence from randomized controlled trials comparing its effect with those of other therapeutic interventions is currently lacking.

Supplemental Digital Content is available in the text. Published ahead of print August 24, 2017., Prothrombin complex concentrates (PCCs) have been associated with a possible risk of thromboembolic complications, potentially attributable to an increased ratio of the plasma concentration of factor II (FII) to antithrombin (AT). We developed a mathematical model to examine the relationship between amounts of PCC or therapeutic plasma administered, and plasma levels of FII and AT. The model showed that PCC produces substantial increases in plasma levels of FII but only small changes in AT, increasing the FII:AT ratio. Therapeutic plasma was shown to have only modest effects on levels of FII or AT, unless high doses are used.

Supplemental Digital Content is available in the text, Several direct oral anticoagulants (DOACs), including direct thrombin and factor Xa inhibitors, have been approved as alternatives to vitamin K antagonist anticoagulants. As with any anticoagulant, DOAC use carries a risk of bleeding. In patients with major bleeding or needing urgent surgery, reversal of DOAC anticoagulation may be required, presenting a clinical challenge. The optimal strategy for DOAC reversal is being refined, and may include use of hemostatic agents such as prothrombin complex concentrates (PCCs; a source of concentrated clotting factors), or DOAC-specific antidotes (which bind their target DOAC to abrogate its activity). Though promising, most specific antidotes are still in development. Preclinical animal research is the key to establishing the efficacy and safety of potential reversal agents. Here, we summarize published preclinical animal studies on reversal of DOAC anticoagulation. These studies (n = 26) were identified via a PubMed search, and used rodent, rabbit, pig, and non-human primate models. The larger of these animals have the advantages of similar blood volume/hemodynamics to humans, and can be used to model polytrauma. We find that in addition to varied species being used, there is variability in the models and assays used between studies; we suggest that blood loss (bleeding volume) is the most clinically relevant measure of DOAC anticoagulation-related bleeding and its reversal. The studies covered indicate that both PCCs and specific reversal agents have the potential to be used as part of a clinical strategy for DOAC reversal. For the future, we advocate the development and use of standardized, clinically, and pharmacologically relevant animal models to study novel DOAC reversal strategies.

SummaryIdarucizumab is licensed for emergency reversal of dabigatran. A single 5 g dose is usually sufficient, but higher doses may sometimes be required and optimum dosing has not been defined. It was the aim of this study to investigate the effect of idarucizumab, given once or as a split dose, after double trauma in pigs anticoagulated with dabigatran. Dabigatran etexilate (30 mg/kg bid) was given to 18 male pigs orally for 3 days. On day 4, animals were randomised 1:1:1 to receive idarucizumab 60+0, 60+60 or 120+0 mg/kg. Doses were administered 15 and 75 minutes after initial liver trauma. At 60 minutes, a second liver injury was undertaken. Animals were monitored for 5 hours after initial trauma or until death. Blood loss during the first hour was 990 ± 109 ml, 988 ± 84 ml and 964 ± 75 ml in the 60+0, 60+60 and 120+0 groups, respectively. In the 120+0 and 60+60 groups, total blood loss was 1659 ± 346 and 1426 ± 106 ml, respectively, and survival at 5 hours was 100 %. However, in the 60+0 group, total blood loss was 3561 ± 770 ml and survival was 50 %. Analysis of dabigatran plasma concentrations showed that equimolar concentrations of idarucizumab are necessary to bind all dabigatran and achieve sufficient thrombin generation. At sufficient doses, idarucizumab rapidly reduced blood loss and improved survival in this lethal porcine model of double trauma with dabigatran anticoagulation. In clinical practice, should bleeding continue after initial treatment with the approved 5 g dose of idarucizumab, a second dose may potentially be effective to control bleeding caused by redistribution of unbound dabigatran.Supplementary Material to this article is available online at www.thrombosis-online.com.

Purpose The expression pattern of angiogenetic factors and acquired von Willebrand syndrome (AvWS) play a key role in the high incidence of nonsurgical bleeding in left ventricular assist device (LVAD) patients. In this study, we aimed to prospectively compare the perioperative time-course of angiopoietin-1 (Ang1), angiopoietin-2 (Ang2) and von Willebrand Factor (vWF) between HeartMate II (HMII) and HeartMate 3 (HM3) patients in correlation with postoperative complications. Methods Blood samples of 11 HMII and 14 HM3 patients were prospectively collected at 7 different time points pre-, peri- and early post-operatively and analysed by ELISA for Ang2 and Ang1 as well as vWF antigen (vWF:Ag) and collagen binding activity (vWF:CBA). Postoperative hemocompatibility-related adverse events (HRAE) were collected within 90 days follow-up period. Results Time-course of Ang1 and Ang2 did not differ between HMII and HM3 patients, but within each group the Ang2/Ang1 ratio increased significantly at 24h postoperatively compared to the baseline values (p=0.002 in HMII and p Conclusion Ang2/Ang1 increased immediately post HMII as well as HM3 implantation, and despite our small cohort study, we could detect a correlation between Ang1 and Ang2 with the incidence of HS. vWF ratios did not differ between groups and did not correlate with non-surgical bleeding events. Larger studies will further proof, if LVAD patients can benefit from early monitoring of Ang1 and Ang2.

Shear stress from left ventricular assist devices induces von Willebrand factor degradation and platelet dysfunction, leading to nonsurgical bleeding. We characterized the hemostatic changes induced by 2 centrifugal left ventricular assist devices, the HeartMate 3 (Abbott Inc, Chicago, Ill) and the EVAHEART (Evaheart Inc, Houston, Tex), for comparison.Whole blood from 8 healthy volunteers was used ex vivo. Blood from the same donor was used for 6 hours of circulation in a miniature mock-loop system consisting of 2 identical extracorporeal circuits to compare the following experimental settings: (1) optimal revolutions per minute (rpm) for the HeartMate 3 (n = 4; 5000 rpm) and the EVAHEART (n = 4; 2500 rpm) and (2) equal rpm (3000 rpm for the HeartMate 3 and EVAHEART, n = 4 vs n = 4). For both settings, blood flow was adjusted to 1 mock-loop filling volume per minute (HeartMate 3 = 82 mL/min, EVAHEART = 100 mL/min). A panel of coagulation markers was analyzed to investigate hemostatic changes.The free plasma hemoglobin concentration was significantly lower in the EVAHEART compared with the HeartMate 3 after 6 hours of mock-loop circulation under both settings (optimal: 37 ± 31 vs 503 ± 173 mg/dL, P .0001; equal: 27 ± 4 vs 139 ± 135 mg/dL, P = .024). Loss of von Willebrand factor high-molecular-weight multimers occurred in both left ventricular assist devices and settings, but the von Willebrand factor:activity/von Willebrand factor:antigen ratio after 6 hours was significantly lower in optimal settings for the HeartMate 3 (P = .009). The thrombin-antithrombin complex level was significantly lower with the EVAHEART for both settings (P .0001).The EVAHEART left ventricular assist device caused less hemolysis, resulted in lower coagulation activation, and provided better preservation of von Willebrand factor functional activity compared with the HeartMate 3 device. These findings prove that left ventricular assist device design plays a major role in minimizing blood damage during left ventricular assist device support.

Background: Prompt reversal of factor Xa (FXa) anticoagulation is essential in clinical situations with major bleeding or urgent surgery. Andexanet alfa (Andexxa, AnXa) is approved in the US for reversal of rivaroxaban or apixaban anticoagulation when necessary due to life-threatening or uncontrolled bleeding. In ANNEXA-4 interim report, ~85% of patients had good or excellent hemostasis after AnXa treatment (bolus + 2-h infusion). However, the minimum extent and duration of anticoagulation reversal required for a clinically relevant reduction in bleeding in humans have not been fully characterized. Purpose: The impact of escalating doses of AnXa on reversing bleeding in a porcine polytrauma model with apixaban anticoagulation was investigated. Method: After ethical approval, 40 anesthetized male pigs underwent a standardized polytrauma by blunt liver injury and bilateral femur fractures following 3-day apixaban administration (20 mg/day). 12 min post-trauma, animals were randomized (n=8 per group) to 5 groups: 250 mg bolus (AnXa 250 B), 500 mg bolus (AnXa 500 B), 250 bolus + 300 mg 2-h infusion (AnXa 250 B+), 500 mg bolus + 600 mg 2-h infusion (AnXa 500 B+), or vehicle (control). Blood loss (BL), hemodynamics and coagulation profiles were monitored over 5 h or until death; the primary outcome was total BL. Coagulation profiles consisted of apixabananti-FXa activity, global coagulation assays (PT, aPTT), rotational thromboelastometry (ROTEM) and thromboelastography (TEG). For differentiated risk assessment, thrombin generation, thrombin-antithrombin (TAT) and D-Dimer levels were measured. Data were analyzed by two-way ANOVA and log-rank tests (mean ± SD). Results: Before the polytrauma, anti-FXa levels were 178.2 ± 52.7 ng/mL (similar among 5 groups). Trauma led to comparable BL at 12 min after injury (814 ± 79 mL). Compared with control (3464 ± 719 mL) and AnXa 250 B (3155 ± 364 mL; p=0.99 vs control), a significant reduction in total BL was observed in AnXa 250 B+ (2113 ± 297 mL; p Conclusion: Dose-dependent reversal of apixaban by AnXa in this animal model was associated with decreased BL and mortality. The results indicate that AnXa regimens that decreased anti-FXa activity below a certain level (approx. 50 ng/mL), whether temporarily or sustained, was sufficient to prevent exsanguination in this animal model. This remaining low level of anticoagulation after apixaban reversal does not prevent activation of coagulation, allowing for sufficient hemostasis. Our results warrant further investigation of the extent and duration of reversal of FXa inhibition required to achieve adequate hemostasis in humans. Figure 1: Anti-FXa activity in control, AnXa 250 B and AnXa 250 B+ groups (A). Anti-FXa activity in control, AnXa 500 B and AnXa 500 B+ groups (B). Initially n=8 per group. *P Disclosures Grottke: Pfizer: Honoraria; Sanofi: Honoraria; Octapharma: Consultancy, Research Funding; Portola: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding. Conley:Portola: Employment. Rossaint:CSL Behring: Honoraria; Boehringer Ingelheim: Honoraria.

Background Andexanet alfa (AnXa; Andexxa) was developed as a specific antidote for direct and indirect factor Xa (FXa) inhibitors. It has been approved in the US for the reversal of apixaban and rivaroxaban anticoagulation when necessary due to life-threatening or uncontrolled bleeding. Generation 2 manufacturing process of AnXa is promising for providing adequate global supply of AnXa and awaits comprehensive regulatory evaluation for comparability to the current commercial process. Purpose: In this ongoing porcine polytrauma study, we investigated and compared efficacy and safety of the first and second generation AnXa product for the reversal of apixaban anticoagulation. Method: In 35 anesthetized male pigs, a polytrauma consisting of bilateral femur fractures and a standardized blunt liver injury was inflicted after 3 days of apixaban intake (20 mg/day). 12 min after the polytrauma, pigs were randomly allocated to receive (n=7 per group) either 1000 mg bolus of 2nd generation AnXa followed by 2-hour (h) infusion of normal saline (2nd G AnXa B) or 1000 mg bolus immediately followed by infusion of 1200 mg 2nd generation AnXa in 2 h (2nd G AnXa B+). These two groups that received 2nd generation AnXa were compared with the cohorts from our previous study following precisely the same protocol with bolus and 2 h infusion of normal saline (Control group), 1000 mg bolus of 1st generation AnXa followed by 2 h infusion of normal saline (1st G AnXa B), and 1000 mg bolus immediately followed by 2 h 1200 mg infusion of 1st generation AnXa (1st G AnXa B+). Animals were then observed for 5 h or until death. The blood loss (BL) was the primary outcome. Hemodynamics and coagulation profile comprised apixaban (anti FXa activity and rotational thromboelastometry (ROTEM). Further D-dimer levels and thrombin generation (TG) were measured. Right after the premature death or at the end of the observation period, internal organs were obtained and examined for the occurrence of thromboembolic incidents. Two-way ANOVA (mean ± SD) and log-rank tests were performed to analyze the data, and the statistical significance was set at p Results: Three days of oral apixaban administration resulted in comparable anti-FXa activity levels before the trauma (195.4 ± 90.9 ng/mL, Figure 1). The increased anti-FXa activity also prolonged the clotting time (CT) on extrinsically activated ROTEM channel EXTEM (43.6 ± 5.5 to 110.1 ± 28.2 sec). BL at 12 min after the trauma was similar among the study groups (856 ± 118 mL). Anticoagulation with apixaban in control group resulted in a total BL of 3403 ± 766 mL (p Conclusion: This animal polytrauma model is the first to show that 2nd generation AnXa is as effective and well tolerated as the 1st generation in reducing blood loss and improving survival in apixaban anticoagulated pigs with massive hemorrhage. Disclosures Grottke: Boehringer Ingelheim: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Portola: Consultancy, Research Funding; Octapharma: Consultancy, Research Funding; Sanofi: Honoraria; Pfizer: Honoraria. Conley:Portola: Employment. Rossaint:CSL Behring: Honoraria; Boehringer Ingelheim: Honoraria.

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.

Die massive Blutung mit hamorrhagischem Schock und begleitender Koagulopathie stellt ein lebensbedrohliches Krankheitsbild dar. Die Verhinderung der Exsanguination fulminant blutender Patienten erfordert die optimale, standardisierte und patientenorientierte Behandlung sowie eine enge interdisziplinare Zusammenarbeit. Dabei konnen insbesondere die Einfuhrung standardisierter Massivtransfusionsprotokolle und ein zielgerichtetes Gerinnungsmanagement zur Reduzierung sekundarer Folgeschaden beitragen. In der Helsinki-Deklaration zur Patientensicherheit der Europaischen Gesellschaft fur Anasthesiologie (ESA, European Society of Anaesthesiology) wird die Einfuhrung eines klinikspezifischen Protokolls zur Behandlung einer Massivblutung bereits ausdrucklich gefordert. Daher wurde mit der vorliegenden Handlungsempfehlung im Konsens mit der Deutschen Gesellschaft fur Anasthesiologie und Intensivmedizin (DGAI) ein Algorithmus zur Behandlung von Patienten mit lebensbedrohlichen Blutungen erstellt, der an lokale Gegebenheiten und Ressourcen im Detail angepasst werden muss.

Trauma-induced coagulopathy is a frequent complication in severely injured patients. To correct coagulopathy and restore haemostasis, these patients have traditionally been treated with fresh frozen plasma, but in the last decade, there has been a shift from empirical therapy to targeted therapy with coagulation factor concentrates and other haemostatic agents. This review highlights emerging therapeutic options and controversial topics.Early administration of the antifibrinolytic medication tranexamic acid was shown in the multicentre CRASH-2 trial to be an effective and inexpensive means of decreasing blood loss. Numerous retrospective and experimental studies have shown that the use of coagulation factor concentrates decreases blood loss and may be useful in reducing the need for transfusion of allogeneic blood products. In particular, early use of fibrinogen concentrate and thrombin generators has a positive impact on haemostasis. However, the use of prothrombin complex concentrate to correct trauma-induced coagulopathy has also been associated with a potential risk of serious adverse events.Current evidence in trauma resuscitation indicates a potential role for coagulation factor concentrates and other haemostatic agents in correcting trauma-induced coagulopathy. Despite a shift towards such transfusion strategy, there remains a shortage of data to support this approach.

Objectives For patients with a severe acute respiratory distress syndrome (ARDS), extracorporeal membrane oxygenation (ECMO) represents a life-saving measure. Frequently, patients with severe ARDS also show signs of severe sepsis. As blood contact with the membrane oxygenator surface leads to adverse effects due to insufficient biocompatibility partly caused by activation of platelets, coagulation factors and leucocytes, we hypothesized that these adverse effects would be amplified if septic blood in a preactivated state came into contact with the membrane oxygenator. Methods In a previously established in vitro 12-h ECMO test system (mock loop), we used septic or healthy domestic pig blood to analyse coagulation and inflammatory parameters. Sepsis was induced by a caecal ligation and puncture model in pigs. Results At the beginning of the mock loop experiments, the septic blood showed significantly increased thrombin-antithrombin complexes (76.9 vs 27.7 µg/l), D-dimers (1.2 vs 0.3 mg/l) and fibrinogen concentration (1.8 vs 1.5 g/l), as well as elevated extrinsic coagulation activity (shorter EXTEM-CT: 44.2 vs 57 s) and higher lactate (3.4 vs 1.5 mmol/l) and cytokine levels (interleukin-6: 827 vs 31 pg/ml) when compared with the blood from healthy animals. Despite the preactivated status of the septic blood, no further increase of coagulation activity, inflammatory response or increased oxygenator resistance was observed in comparison to the control experiments. Conclusion Septic porcine blood was not further activated due to the contact with an oxygenator, and no increased clot formation or biocompatibility problems were observed.

Dabigatran is effective in decreasing the risk of ischaemic stroke in patients with atrial fibrillation. However, like all anticoagulants, it is associated with a risk of bleeding. In cases of trauma or emergency surgery, emergency reversal of dabigatran-induced anticoagulation may be required. A specific reversal agent for dabigatran, idarucizumab, has been approved by the US Food and Drug Administration. Alternative reversal agents are available, such as prothrombin complex concentrates (PCCs) and activated PCCs (aPCCs). In this review we evaluate the role of PCCs and aPCCs in the reversal of dabigatran anticoagulation and consider which tests are appropriate for monitoring coagulation in this setting. Pre-clinical studies, small clinical studies and case reports indicate that PCCs and aPCCs may be able to reverse dabigatran-induced anticoagulation in a dose-dependent manner. However, dosing based on coagulation parameters can be difficult because available assays may not provide adequate sensitivity and specificity for measuring anticoagulation induced by dabigatran or the countering effects of PCCs/aPCCs. In addition, PCCs or aPCCs can potentially provoke thromboembolic complications. Despite these limitations and the fact that PCCs and aPCCs are not yet licensed for dabigatran reversal, their use appears to be warranted in patients with life-threatening haemorrhage if idarucizumab is not available.

Veno-venous extracorporeal lung assist (ECLA) can provide sufficient gas exchange even in most severe cases of acute respiratory distress syndrome. Commercially available systems are manually controlled, although an automatically controlled ECLA could allow individualized and continuous adaption to clinical requirements. Therefore, we developed a demonstrator with an integrated control algorithm to keep continuously measured peripheral oxygen saturation and partial pressure of carbon dioxide constant by automatically adjusting extracorporeal blood and gas flow. The "SmartECLA" system was tested in six animal experiments with increasing pulmonary hypoventilation and hypoxic inspiratory gas mixture to simulate progressive acute respiratory failure. During a cumulative evaluation time of 32 h for all experiments, automatic ECLA control resulted in a peripheral oxygen saturation ≥90% for 98% of the time with the lowest value of 82% for 15 s. Partial pressure of venous carbon dioxide was between 40 and 49 mm Hg for 97% of the time with no value 35 mm Hg or 49 mm Hg. With decreasing inspiratory oxygen concentration, extracorporeal oxygen uptake increased from 68 ± 25 to 154 ± 34 mL/min (P 0.05), and reducing respiratory rate resulted in increasing extracorporeal carbon dioxide elimination from 71 ± 37 to 92 ± 37 mL/min (P 0.05). The "SmartECLA" demonstrator allowed reliable automatic control of the extracorporeal circuit. Proof of concept could be demonstrated for this novel automatically controlled veno-venous ECLA circuit.

Rekombinanter aktivierter Faktor VII (rFVIIa) ist ein Gerinnungsenzym, das nach hochdosierter intravenoser Gabe eine massive Thrombinbildung (Thrombinburst) induziert und dadurch hamostyptisch wirkt. Fur diese Wirkung essentiell sind ausreichend hohe Plasmaspiegel der Gerinnungsfaktoren X, V und II sowie von Fibrinogen und eine ausreichend hohe Thrombozytenzahl. Eine Hypothermie und eine azidotische Stoffwechsellage sind weitere Faktoren, die zu einer Einschrankung der rFVIIa-Wirkung fuhren konnen. Vor der Gabe von rFVIIa sollten deswegen entsprechende Korrekturmasnahmen eingeleitet werden.

Die Akutbehandlung polytraumatisierter Patienten mit Massenblutungen stellt trotz verbesserter chirurgischer und konventioneller Therapien eine besondere interdisziplinare Herausforderung dar. Die epidemiologische Bedeutung dieses komplexen Krankheitsbilds ergibt sich aus der hohen Zahl von 5 Mio. Menschen, die weltweit jahrlich an den Folgen eines Traumas sterben. Da traumaassoziierte Massenblutungen auf dem Boden einer Koagulopathie potenziell vermeidbar und behandelbar sind, gilt die Exsanguination als die haufigste vermeidbare Komplikation, die zum fruhen Versterben nach Trauma fuhrt. Mit dem Ziel, Behandlungsalgorithmen nach dem aktuellen Stand der Wissenschaft fur die Versorgung schwer verletzter Patienten mit Gerinnungsstorungen zu entwickeln, wurde die „Task Force for Advanced Bleeding Care in Trauma“ 2005 gegrundet. Die Erstveroffentlichung aus dem Jahr 2007 wurde entsprechend den Grundsatzen der „evidence-based medicine“ unter Berucksichtigung neuer klinischer Studien in uberarbeiteter Form publiziert. Der vorliegende Beitrag gibt einen Uberblick uber die einzelnen Empfehlungen unter besonderer Berucksichtigung wesentlicher Neuerungen.

SummaryAlthough prothrombin complex concentrate (PCC) is increasingly used for the treatment of trauma-induced coagulopathy, few studies have investigated the impact and safety of PCC for this indication. The present study was performed to assess PCC for treatment of coagulopathy after blunt liver injury under severe hypothermia. Coagulopathy in 14 anaesthetised pigs was induced by haemodilution. Subsequently, standardised blunt liver injury was induced under severe hypothermia (32.8–33.2°C). Animals were randomised to receive either PCC (35 IU kg-1) or saline (control). Coagulation was assessed over the following 2 hours by thromboelastometry and thrombin generation. Internal organs were examined to determine presence of emboli. The administration of PCC showed a significant reduction in blood loss (p=0.002 vs. controls) and a significant increase in the rate of survival (p=0.022 vs. controls). Plasma thrombin generation in the PCC group increased considerably above baseline levels, with significant increases in peak thrombin levels and endogenous thrombin potential versus controls throughout the follow-up period. In addition, PT decreased significantly in the PCC group versus the control group. However, only slight improvements in thromboelastometry variables were observed. Histology showed an equal degree of liver injury in both groups, and no thromboembolism. In severely hypothermic pigs, the application of PCC corrected trauma-induced coagulopathy and reduced blood loss. Thus, the infusion of PCC might be a reasonable approach to reduce the need for blood cell transfusion in trauma. Furthermore, the impact and safety of PCC application can be monitored through thrombin generation and thromboelastometry under hypothermia.Note: This study was performed at the RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074 Aachen, Germany.

Background and objective In the elderly, monitoring depth of anaesthesia seems to be of particular importance. We evaluated the bispectral index (BIS) for monitoring depth of anaesthesia during clinically guided balanced xenon or sevoflurane anaesthesia in aged patients. Methods In this randomized controlled clinical trial, 40 patients (65–75 years) undergoing elective noncardiac surgery were randomly assigned to balanced anaesthesia with either 53.2 ± 0.8% xenon (n = 19) or 1.6 ± 0.1% sevoflurane (n = 20) in minimum 30% oxygen and remifentanil titrated to clinical needs. Depth of anaesthesia was guided by end-tidal gas concentrations and clinical signs. The attending anaesthesiologist was blinded to the BIS values, which were recorded at 1 min rates during induction, at 5 min rates during maintenance and at 20 s rates during emergence. Emergence from anaesthesia was assessed by the times to open eyes, react on demand, extubation and orientation. Results During induction and maintenance of anaesthesia, BIS values in the xenon group were comparable to sevoflurane and at the lower limit of the recommended range for deep anaesthesia. Emergence to full orientation was significantly faster from xenon than from sevoflurane. BIS values were significantly lower during emergence from xenon anaesthesia. Conclusion During xenon and sevoflurane anaesthesia in the elderly, BIS-values show sufficient concordance with clinical signs of anaesthetic depth. Since during clinically guided anaesthesia values were at the lower recommended limit, additional BIS monitoring may help reduce anaesthetic consumption and costs.