Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: First update 2016.

: The management of perioperative bleeding involves multiple assessments and strategies to ensure appropriate patient care. Initially, it is important to identify those patients with an increased risk of perioperative bleeding. Next, strategies should be employed to correct preoperative anaemia and to stabilise macrocirculation and microcirculation to optimise the patient's tolerance to bleeding. Finally, targeted interventions should be used to reduce intraoperative and postoperative bleeding, and so prevent subsequent morbidity and mortality. The objective of these updated guidelines is to provide healthcare professionals with an overview of the most recent evidence to help ensure improved clinical management of patients. For this update, electronic databases were searched without language restrictions from 2011 or 2012 (depending on the search) until 2015. These searches produced 18 334 articles. All articles were assessed and the existing 2013 guidelines were revised to take account of new evidence. This update includes revisions to existing recommendations with respect to the wording, or changes in the grade of recommendation, and also the addition of new recommendations. The final draft guideline was posted on the European Society of Anaesthesiology website for four weeks for review. All comments were collated and the guidelines were amended as appropriate. This publication reflects the output of this work.

Fluids and coagulation.

PURPOSE OF REVIEW: Infusion therapy is essential in intravascular hypovolaemia and extravascular fluid deficits. Crystalloidal fluids and colloidal volume replacement affect blood coagulation when infused intravenously. The question remains if this side-effect of infusion therapy is clinically relevant in patients with and without bleeding manifestations, and if fluid-induced coagulopathy is a risk factor for anaemia, blood transfusion, and mortality, and a driver for resource use and costs. RECENT FINDINGS: Pathomechanisms of dilutional coagulopathy and evidence for its clinical relevance in perioperative and critically ill patients are reviewed. Furthermore, the article discusses medicolegal aspects. SUMMARY: The dose-dependent risk of dilutional coagulopathy differs between colloids (dextran > hetastarch > pentastarch > tetrastarch, gelatins > albumin). Risk awareness includes monitoring for early signs of side-effects. With rotational thromboelastometry/thrombelastography, the deterioration not only in clot strength but also in clot formation and in platelet interaction can be assessed. Fibrinogen concentrate administration may be considered in severe bleeding as well as relevant dilutional coagulopathy. Targeted doses of gelatins and tetrastarches seem to have no proven adverse effect on anaemia and allogeneic blood transfusions. Further studies are needed.

Intravenous fluids: should we go with the flow?

Sensitive monitoring should be used when prescribing intravenous fluids for volume resuscitation. The extent and duration of tissue hypoperfusion determine the severity of cellular damage, which should be kept to a minimum with timely volume substitution. Optimizing the filling status to normovolaemia may boost the resuscitation success. Macrocirculatory pressure values are not sensitive in this indication. While the Surviving Sepsis Campaign guidelines focus on these conventional pressure parameters, the guidelines from the European Society of Anaesthesiology (ESA) on perioperative bleeding management recommend individualized care by monitoring the actual volume status and correcting hypovolaemia promptly if present. The motto is: 'give what is missing'. The credo of the ESA guidelines is to use management algorithms with predefined intervention triggers. Stop signals should help in avoiding hyper-resuscitation. The high-quality evidence-based S3 guidelines on volume therapy in adults have recently been prepared by 14 German scientific societies. Statements include, for example, repeated clinical inspection including turgor of the skin and mucosa. Adjunctive laboratory parameters such as central venous oxygen saturation, lactate, base excess and haematocrit should be considered. The S3 guidelines propose the use of flow-based and/or dynamic preload parameters for guiding volume therapy. Fluid challenges and/or the leg-raising test (autotransfusion) should be performed. The statement from the Co-ordination group for Mutual Recognition and Decentralized Procedures-Human informs healthcare professionals to consider applying individualized medicine and using sensitive monitoring to assess hypovolaemia. The authorities encourage a personalized goal-directed volume resuscitation technique.

Coagulation and transfusion in the postoperative bleeding patient.

PURPOSE OF REVIEW: Bleeding can be minimal, severe, life-threatening, or organ-threatening. Depending on the compensatory capacity of the patient, most bleeding events going beyond 20% blood volume may represent an emergency as well as a risk factor for anemia, transfusion, coagulopathy, and tissue hypoperfusion. All these factors are independent predictors for survival in postoperative critical care and are drivers for resource use and costs. RECENT FINDINGS: A systematic literature search behind the guidelines from the European Society of Anesthesiology on the management of severe perioperative bleeding gives an up-to-date evidence-based summary of strategies intended to correct hemostasis, control bleeding, and increase patient safety. The current review discusses information, recommendations, and suggestions in the European Society of Anesthesiology guidelines, which appear applicable to the bleeding patient after the end of surgery. SUMMARY: Individualized coagulation management guided by viscoelastic tests and restrictive transfusion behavior are encouraged in clinical practice of critical care. Potential fields of research are multifold, for example, thromboembolic adverse effects of hemostatic interventions in the isochronic postoperative acute-phase response, transfusion restrictions by increasing postoperative tolerance to anemia and erythropoiesis, and implementation of guidelines and institutional algorithms.

Perioperative management issues of direct oral anticoagulants.

The treatment repertoire of oral anticoagulation has changed dramatically over the past few years from one class of vitamin K1 antagonists to an increasing number of direct oral anticoagulants (DOACs). Clinicians are confronted with the problem of managing patients on novel agents in the critical setting before, during, and after surgery, where the risk of bleeding and thrombosis are increased simultaneously. Randomized clinical data are insufficient to date, but clinical exposure enlarges the body of experience. The following review considers perioperative management issues in various categories, including minor elective surgery, major elective surgery, and acute surgery. This review is a credo to personalized medicine where the patient's underlying thromboembolic risk status, the potential bleeding risk, or actual hemorrhagic manifestation determine the selection of multi-modal targeted management strategies.

Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology.

The aims of severe perioperative bleeding management are three-fold. First, preoperative identification by anamesis and laboratory testing of those patients for whom the perioperative bleeding risk may be increased. Second, implementation of strategies for correcting preoperative anaemia and stabilisation of the macro- and microcirculations in order to optimise the patient's tolerance to bleeding. Third, targeted procoagulant interventions to reduce the amount of bleeding, morbidity, mortality and costs. The purpose of these guidelines is to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists throughout Europe to integrate this knowledge into daily patient care wherever possible. The Guidelines Committee of the European Society of Anaesthesiology (ESA) formed a task force with members of scientific subcommittees and individual expert members of the ESA. Electronic databases were searched without language restrictions from the year 2000 until 2012. These searches produced 20 664 abstracts. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. At the suggestion of the ESA Guideline Committee, the Scottish Intercollegiate Guidelines Network (SIGN) grading system was initially used to assess the level of evidence and to grade recommendations. During the process of guideline development, the official position of the ESA changed to favour the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. This report includes general recommendations as well as specific recommendations in various fields of surgical interventions. The final draft guideline was posted on the ESA website for four weeks and the link was sent to all ESA members. Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines.

Results of a consensus meeting on the use of argatroban in patients with heparin-induced thrombocytopenia requiring antithrombotic therapy - a European Perspective.

Argatroban has been introduced as an alternative parenteral anticoagulant for HIT-patients in several European countries in 2005. In 2009 a panel of experts discussed their clinical experience with argatroban balancing risks and benefits of argatroban treatment in managing the highly procoagulant status of HIT-patients. This article summarizes the main conclusions of this round table discussion. An ongoing issue is the appropriate dosing of argatroban in special patient groups. Therefore, dosing recommendations for different HIT-patient groups (ICU patients; non-ICU patients, paediatric patients, and for patients undergoing renal replacement therapies) are summarized in this consensus statement. Because of the strong correlation between argatroban dosing requirements and scores used to characterize the severity of illness (APACHE; SAPS, SOFA) suitable dosing nomograms are given. This consensus statement contributes to clinically relevant information on the appropriate use and monitoring of argatroban based on the current literature, and provides additional information from clinical experience. As the two other approved drugs for HIT, danaparoid and lepirudin are either currently not available due to manufacturing problems (danaparoid) or will be withdrawn from the market in 2012 (lepirudin), this report should guide physicians who have limited experience with argatroban how to use this drug safely in patients with HIT.

New anticoagulants: perioperative considerations.

During preoperative patient evaluation, anaesthesiologists assess the patient's bleeding history and risks for thrombosis and initiate individualized coagulation management. New potent anticoagulants may increase blood loss and the risk for spinal haematoma in patients scheduled for neuraxial anaesthesia. Postoperative start of thromboprophylaxis and recommendations on the timing of invasive interventions help in controlling these risks. Before widespread use for cardiological indications open questions need to be answered e.g. oral drug administration in postoperative vomiting and potential interactions with postoperative pain therapy.

Perioperative coagulation monitoring.

Perioperative coagulation monitoring is the rational diagnostic basis for pro- and anti-thrombotic interventions in patients undergoing emergency and elective surgery. The main goal of perioperative monitoring of haemostasis is to increase safety of patients undergoing surgical procedures. Currently, there is a change in paradigm with (1) increasing implementation of evidence-based approach to preoperative patient evaluation with laboratory coagulation testing secondary to the results of the standardised bleeding history and (2) awareness of the limitations of routine coagulation tests to guide coagulation management in massive bleeding. Alternatively, visco-elastic point-of-care monitoring is increasingly used worldwide. This innovative methodology triggers a trend towards an 'early goal-directed coagulation management' focussing on potent coagulation factor concentrates. Practicability, cost-effectiveness, safety and--above all--growing scientific evidence support this concept, and lively discussions among anaesthesiologists and various medical disciplines may help to refine it. The present review focusses on the following key issues of perioperative coagulation monitoring: standardised bleeding history, routine coagulation testing, visco-elastic point-of-care coagulation testing, heparin monitoring, and platelet function testing.

Direct thrombin inhibitors: pharmacology and application in intensive care medicine.

PURPOSE: Anticoagulation is part of the daily routine of intensive care physicians. As the possibilities of pharmacological anticoagulation are becoming more numerous and diverse, intensive care physicians have to be familiar with indications, contraindications, dosing, and reversal of many different substances. This paper presents an overview of the substance group of direct thrombin inhibitors (DTI) indicated for alternative anticoagulation in intensive care medicine. METHODS: The review is a synopsis of scientific evidence, expert opinion, open forum commentary, and clinical feasibility data. RESULTS AND CONCLUSIONS: Due to their antithrombotic potential without direct activation of platelets, DTI could offer potential advantages over heparins and vitamin K antagonists in critically ill patients, especially regarding heparin-induced thrombocytopenia. Because of multiple organ dysfunction, organ failure, and comedications, simple extrapolation of results of medical to critically ill patients is not permissible. The fine line between thrombosis and bleeding in intensive care patients requires cautious dosing and close drug monitoring. Studies dealing with DTI in the intensive care setting are of utmost clinical interest.

Influence of fluid therapy on the haemostatic system of intensive care patients.

Haemostatic alterations associated with the use of fluids are related to non-specific dilutional effects and colloid-specific effects, such as acquired von Willebrand syndrome, inhibition of platelet function and fibrin polymerization. Judging by currently available evidence, dextran, hetastarch and pentastarch have a more pronounced impact than tetrastarch, gelatin and albumin. In patients with hypocoagulability, tetrastarch appears to be a suitable volume expander due to its high safety index and volume efficacy. Gelatins have lower inhibitory effects on clot strength compared with tetrastarch, but their volume efficacy is also lower. Dextrans are potent anticoagulants with a high risk for adverse reactions. Albumin has negligible effects on haemostasis, but low volume efficacy and costs limit the use of a blood product as a routine volume replacement fluid. To avoid potential acidosis-induced changes in haemostasis, plasma-adapted carrier solutions may be used instead of saline-based solutions.

The effect of ex vivo anticoagulants on whole blood platelet aggregation.

Pre- and intraoperative platelet function monitoring is increasingly recommended in order to detect risk factors for bleeding and to target coagulation management. The ideal anticoagulant for accurate platelet aggregometry remains controversial. The aim of this experimental trial was to compare platelet aggregability in whole blood stored in citrate, heparin and direct thrombin inhibitors. Whole blood was drawn from 11 healthy adult volunteers who had not taken any medication in the previous 14 days. Blood was stored in trisodium citrate, unfractionated heparin, melagatran, lepirudin and argatroban. Platelet aggregation was performed using the impedance aggregometer Multiplate (Dynabyte, Munich, Germany) with adenosine diphosphate (ADP), thrombin receptor activating peptide (TRAP), collagen, arachidonic acid and ristocetin as agonists. Samples were analysed immediately after blood sampling (baseline), as well as 30 and 120 min afterwards. At baseline there were no significant differences in aggregability between samples containing direct thrombin inhibitors and heparin. In contrast, aggregation in response to all agonists except for ristocetin was significantly impaired in citrated blood. During storage the response to arachidonic acid and collagen was maintained by direct thrombin inhibitors and heparin, whereas ADP-, TRAP- and ristocetin-induced aggregation varied considerably over time in all ex vivo anticoagulants tested. Pre-analytical procedures should be standardized because storage duration and anticoagulants significantly affect platelet aggregability in whole blood. For point-of-care monitoring with immediate analysis after blood withdrawal all tested direct thrombin inhibitors as well as unfractionated heparin can be used as anticoagulants whereas citrate is not recommended.

The effects of hydroxyethyl starch 130/0.4 (6%) on blood loss and use of blood products in major surgery: a pooled analysis of randomized clinical trials.

BACKGROUND: The effects of different types of hydroxylethyl starch (HES) on blood coagulation closely depend on their physicochemical properties. HES with lower molar substitution and a lower in vivo molecular weight interferes relatively little with hemostasis and therefore results in lower perioperative blood losses and red blood cell (RBC) transfusion. To test this hypothesis, we analyzed pooled data from all available studies in major surgery comparing 6% HES 130/0.4 and 6% HES 200/0.5 from waxy maize starch. METHODS: Estimated blood loss, drainage loss, calculated blood loss, transfused blood product volumes, and coagulation variables were examined for 24 h after the start of surgery. Groups were compared using analysis of variance, evaluating several covariates. RESULTS: Four-hundred-forty-nine patients from seven clinical trials were analyzed, 228 received HES 130/0.4, and 221 received HES 200/0.5. For HES 130/0.4 patients, when compared to HES 200/0.5 patients, the estimated blood loss was reduced by 404 mL [P = 0.006], drainage loss was 272 mL less [P = 0.009], and calculated RBC loss was 149 mL less [P = 0.003]. RBC transfusion volumes were also lower for HES 130/0.4 by 137 mL [P = 0.004]. In the early postoperative phase, HES 130/0.4 was found to exert significantly less effect on measures of coagulation, especially activated partial thromboplastin time and von Willebrand factor (antigen and ristocetin cofactor), than HES 200/0.5. CONCLUSIONS: Blood loss and transfusion requirements can be significantly reduced in major surgery when using third generation HES 130/0.4 (Voluven) compared to second generation waxy maize starch HES 200/0.5. Since HES 130/0.4 and HES 200/0.5 were found similar regarding volume efficacy in other studies, HES 130/0.4 is recommended in this clinical setting.

Median effective local anesthetic doses of plain bupivacaine and ropivacaine for spinal anesthesia administered via a spinal catheter for brachytherapy of the lower abdomen.

BACKGROUND AND OBJECTIVES: Continuous spinal anesthesia via a spinal catheter allows adjusting the duration and extent of anesthesia to surgical needs, maintenance of hemodynamic stability, and good postoperative analgesia. This study was designed to determine the median effective local anesthetic dose of plain ropivacaine and bupivacaine administered intrathecally for interstitial brachytherapy of the lower abdomen using the Dixon up-and-down method. METHODS: Forty patients were randomly allocated to receive either intrathecal bupivacaine 5 mg per mL or ropivacaine 10 mg per mL via a 24-gauge spinal catheter at the L3-4 interspace. The initial dose was 10 mg of bupivacaine or 20 mg of ropivacaine; the dosing intervals were 1 mg and 2 mg, respectively. Doses for subsequent patients were determined by the response of the previous patient in that group. Successful anesthesia was defined as a loss of sensation to a cold stimulus at the T6 level and full motor blockade within 20 minutes after administration of the local anesthetic. RESULTS: The median effective local anesthetic dose for intrathecal bupivacaine was 11.2 mg (95% confidence interval [CI], 10.3-12.1) and 22.6 mg for ropivacaine (95% CI, 20.5-24.6). A relative analgesic potency ratio of 0.50 (95% CI, 0.44-0.56) was calculated between the median effective local anesthetic dose of intrathecal bupivacaine and ropivacaine. CONCLUSIONS: Bupivacaine and ropivacaine are appropriate for continuous spinal anesthesia for interstitial radiation therapy procedures of the lower abdomen. In the dose-ranges investigated, intrathecal ropivacaine is approximately half as potent as bupivacaine.

Garlic at dietary doses does not impair platelet function.

BACKGROUND: In vitro studies suggest that various bioactive constituents of Allium sativum (garlic) inhibit platelet function. The extent, however, to which dietary doses of garlic influence platelet function remains unknown. Therefore, we tested the effect of raw garlic on platelet function using point-of-care monitoring devices sensitive for cyclooxygenase I-inhibition and platelet adhesion. METHODS: Whole blood from 18 healthy volunteers was investigated before and 5 h after ingestion of the study medication consisting of Greek tsatsiki with 4.2 g raw garlic (verum), or Greek tsatsiki without garlic (placebo), in a randomized, crossover, observer-blinded, placebo-controlled study. The potential long-term effects of garlic were investigated in five volunteers after daily ingestion of 4.2 g of raw garlic over 1 wk. Platelet function was assessed with the Platelet Function Analyzer (PFA-100), impedance aggregometry (Multiplate), and thrombelastographic Platelet Mappingtrade mark. In vitro experiments were performed to prove the sensitivity of the assays to garlic-induced platelet inhibition. RESULTS: Baseline values of platelet function were within normal range in all volunteers. Platelet function was not impaired by single and repeated oral consumption of Greek tsatsiki containing raw garlic in any point-of-care monitoring test used. CONCLUSIONS: Platelet function is not impaired by single and repeated oral consumption of a dietary dose of garlic in healthy volunteers. Dishes containing socially acceptable doses of raw garlic are unlikely to increase the risk of perioperative bleeding. Further studies are warranted to determine the potential additive effects of platelet-inhibiting drugs combined with garlic and other herbs.