Emergency care of patients receiving non-vitamin K antagonist oral anticoagulants.

Non-vitamin K antagonist oral anticoagulants (NOACs), which inhibit thrombin (dabigatran) and factor Xa (rivaroxaban, apixaban, edoxaban) have been introduced in several clinical indications. Although NOACs have a favourable benefit-risk profile and can be used without routine laboratory monitoring, they are associated-as any anticoagulant-with a risk of bleeding. In addition, treatment may need to be interrupted in patients who need surgery or other procedures. The objective of this article, developed by a multidisciplinary panel of experts in thrombosis and haemostasis, is to provide an update on the management of NOAC-treated patients who experience a bleeding episode or require an urgent procedure. Recent advances in the development of targeted reversal agents are expected to help streamline the management of NOAC-treated patients in whom rapid reversal of anticoagulation is required.

Evaluation of clinical practice in perioperative patient blood management.

BACKGROUND: Several guidelines have been published to facilitate implementation of patient blood management (PBM). This study was performed to evaluate clinical practices in PBM. METHODS: An online survey based on the guidelines for the management of severe perioperative bleeding from the European Society of Anaesthesiology (ESA) was conducted among ESA members. We assessed characteristic data of participating physicians, preoperative assessment of bleeding risk and anaemia, intraoperative transfusion practices, specific pharmacologic treatment of significant bleeding, and clinical use of PBM algorithms. Data distributions for five European regions and the workplace and experience of physicians were analysed using a χ2 test. RESULTS: We received 706 fully completed surveys from physicians in 57 countries. Most (99%) respondents were anaesthetists or intensive care physicians, and 68% worked at university or university-affiliated hospitals. A standardised bleeding history before surgery is routinely obtained by 48% of physicians. When bleeding history is negative, 55% of physicians routinely order preoperative coagulation testing. Only 24% of physicians timely assess patients at risk of bleeding during surgery for anaemia before elective surgery. When anaemia is diagnosed, 38% of physicians routinely investigate its cause. The rate of routinely performed targeted haemostatic interventions with fibrinogen, vitamin K or prothrombin complex, and tranexamic acid was 60%, 52%, and 54%, respectively. Algorithms to guide PBM are used by 62% of physicians. Results varied between geographic regions. CONCLUSIONS: Major deficits exist in the use of recommended PBM among anaesthetists, indicating an opportunity to improve clinical standards.

Clinical efficacy of fresh frozen plasma compared with coagulation factor concentrates for treating coagulopathy in patients with massive bleeding / Eficacia clínica del plasma fresco congelado frente a concentrado de factores de coagulación en el tratamiento de la coagulopatía de pacientes con hemorragia masiva

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Intraoperative transfusion practices in Europe.

BACKGROUND: Transfusion of allogeneic blood influences outcome after surgery. Despite widespread availability of transfusion guidelines, transfusion practices might vary among physicians, departments, hospitals and countries. Our aim was to determine the amount of packed red blood cells (pRBC) and blood products transfused intraoperatively, and to describe factors determining transfusion throughout Europe. METHODS: We did a prospective observational cohort study enrolling 5803 patients in 126 European centres that received at least one pRBC unit intraoperatively, during a continuous three month period in 2013. RESULTS: The overall intraoperative transfusion rate was 1.8%; 59% of transfusions were at least partially initiated as a result of a physiological transfusion trigger- mostly because of hypotension (55.4%) and/or tachycardia (30.7%). Haemoglobin (Hb)- based transfusion trigger alone initiated only 8.5% of transfusions. The Hb concentration [mean (sd)] just before transfusion was 8.1 (1.7) g dl(-1) and increased to 9.8 (1.8) g dl(-1) after transfusion. The mean number of intraoperatively transfused pRBC units was 2.5 (2.7) units (median 2). CONCLUSION: Although European Society of Anaesthesiology transfusion guidelines are moderately implemented in Europe with respect to Hb threshold for transfusion (7-9 g dl(-1)), there is still an urgent need for further educational efforts that focus on the number of pRBC units to be transfused at this threshold. CLINICAL TRIAL REGISTRATION: NCT 01604083.

Coagulopathy induced by acidosis, hypothermia and hypocalcaemia in severe bleeding.

Acidosis, hypothermia and hypocalcaemia are determinants for morbidity and mortality during massive hemorrhages. However, precise pathological mechanisms of these environmental factors and their potential additive or synergistic anticoagulant and/or antiplatelet effects are not fully elucidated and are at least in part controversial. Best available evidences from experimental trials indicate that acidosis and hypothermia progressively impair platelet aggregability and clot formation. Considering the cell-based model of coagulation physiology, hypothermia predominantly prolongs the initiation phase, while acidosis prolongs the propagation phase of thrombin generation. Acidosis increases fibrinogen breakdown while hypothermia impairs its synthesis. Acidosis and hypothermia have additive effects. The effect of hypocalcaemia on coagulopathy is less investigated but it appears that below the cut-off of 0.9 mmol/L, several enzymatic steps in the plasmatic coagulation system are blocked while above that cut-off effects remain without clinical sequalae. The impact of environmental factor on hemostasis is underestimated in clinical practice due to our current practice of using routine coagulation laboratory tests such as partial thromboplastin time or prothrombin time, which are performed at standardized test temperature, after pH correction, and upon recalcification. Temperature-adjustments are feasible in viscoelastic point-of-care tests such as thrombelastography and thromboelastometry which may permit quantification of hypothermia-induced coagulopathy. Rewarming hypothermic bleeding patients is highly recommended because it improves patient outcome. Despite the absence of high-quality evidence, calcium supplementation is clinical routine in bleeding management. Buffer administration may not reverse acidosis-induced coagulopathy but may be essential for the efficacy of coagulation factor concentrates such as recombinant activated factor VII.

Fibrinogen but not factor XIII deficiency is associated with bleeding after craniotomy.

BACKGROUND: Postoperative haemorrhage in neurosurgery is associated with significant morbidity and mortality. There is controversy whether or not factor XIII (FXIII) deficiency leads to bleeding complications after craniotomy. Decreased fibrinogen levels have been associated with an increased incidence of bleeding complications in cardiac and orthopaedic surgery. The aim of this study was to assess perioperative fibrinogen and FXIII levels in patients undergoing elective intracranial surgery with and without severe bleeding events. METHODS: Perioperative FXIII and fibrinogen levels were prospectively assessed in 290 patients undergoing elective craniotomy. Patients were divided into two groups according to the presence or absence of severe bleeding requiring surgical revision. Coagulation test results of these groups were compared using Student's t-test. RESULTS: The incidence of postoperative severe bleeding was 2.4%. No differences in FXIII levels were observed, but postoperative fibrinogen levels were significantly lower in patients suffering from postoperative haematoma compared with those without postoperative intracranial bleeding complications [237 mg dl(-1) (standard deviation, SD 86) vs 170 mg dl(-1) (SD 35), P=0.03]. The odds ratio for postoperative haematoma in patients with a postoperative fibrinogen level below 200 mg dl(-1) was 10.02 (confidence interval: 1.19-84.40, P=0.03). CONCLUSIONS: This study emphasizes the role of fibrinogen as potentially modifiable risk factor for perioperative bleeding in intracranial surgery. Future randomized controlled trials will be essential to identify patients who might benefit from fibrinogen substitution during neurosurgical procedures.

Monitoring of unfractionated heparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent (PiCT®).

PURPOSE: To achieve sufficient and safe anticoagulation with unfractionated heparin (UFH) a close and reliable drug monitoring is necessary. In general, the activated partial thromboplastin time (APTT) is used for this purpose. In acute phase response, however, the APTT test procedure might be unreliable e.g. with false low results in the presence of elevated factor VIII. In this so called heparin resistance, measurement of anti-Xa activity is recommended over APTT to avoid potentially harmful dose escalation. A combination of anti-Xa measurement and global hemostatic testing with ROTEM® employing the anti-Xa sensitive PiCT® reagent showed high correlation with enoxaparin levels. This test modification could also be suitable for monitoring UFH. Aim of the study was to evaluate the correlation between PiCT®-ROTEM® and levels of UFH. METHODS: In this in-vitro study blood samples from healthy volunteers were spiked with UFH and subjected to different ROTEM® tests. RESULTS: There was a linear correlation between UFH level and clotting time (CT) in the PiCT®-ROTEM® test with an excellent correlation coefficient of 0.92. Additional endpoints showed similar results (PiCT®-ROTEM® MaxVel r = -0.85 and PiCT®-ROTEM® t_MaxVel r = 0.88). CONCLUSIONS: As a point-of-care applicable tool ROTEM® is immediately at hand. If further clinical studies confirm sensitivity in heparin resistance, PiCT®-ROTEM® could permit rapid UFH dose adjustments especially required in critical illness with acute phase response.

Effect of the carrier solution for hydroxyethyl starch on platelet aggregation and clot formation.

BACKGROUND: Hydroxyethyl starch (HES) solutions alter blood coagulation, mainly platelet function and fibrinogen polymerization. Haemostasis can also be impaired by dilutional-hyperchloraemic acidosis induced by the HES carrier solution. We hypothesized that a saline-based tetrastarch carrier solution impairs parameters of blood coagulation more than a balanced carrier solution. METHODS: The study was designed as a prospective, double-blinded, randomized, cross-over trial in healthy male volunteers. At intervals of at least 10 days, 13 subjects received 20 ml kg(-1) of balanced or saline-based tetrastarch over 2 h. Blood was subjected to blood gas analysis, assessment of platelet function [with multiple electrode aggregometry (MEA)], and clot formation (with rotational thrombelastometry). RESULTS: Maximum aggregation in response to adenosine diphosphate (ADP) decreased after saline-based HES infusion, but not after balanced solution-based HES infusion. ADP-induced platelet aggregation was significantly lower after saline-based HES compared with baseline (21%; P<0.025) and compared with balanced solution-based HES (17%; P<0.025). There were no significant changes in platelet aggregation induced by thrombin receptor-activating peptide and in any parameter of rotational thrombelastometry. Chloride concentrations were significantly higher after saline-based HES compared with balanced solution-based HES. CONCLUSIONS: The carrier solution for HES up to 20 ml kg(-1) had little impact on platelet aggregation or clot formation as assessed by MEA and rotational thrombelastometry, respectively. Further clinical studies are required to verify this finding in patients and to correlate results of whole blood aggregometry and rotational thrombelastometry with perioperative bleeding and transfusion requirements.

Perioperative treatment algorithm for bleeding burn patients reduces allogeneic blood product requirements.

BACKGROUND: Surgical excision of burn wounds is often associated with severe bleeding. Timely and targeted correction of coagulopathy reduces transfusion requirements and improves survival in trauma victims. We hypothesized that rapid correction of coagulopathy after a treatment algorithm based on point-of-care viscoelastic coagulation testing would decrease allogeneic blood product transfusions during surgical excision of burn wounds. METHODS: Thirty consecutive patients undergoing surgical excision of burn wounds were enrolled into this prospective, randomized, controlled, single-centre study. In the control group, coagulation management was performed according to the clinicians' discretion. For the algorithm group, we standardized treatment based on the Austrian recommendation for the management of trauma-induced coagulopathy using point-of-care rotational thromboelastometry (ROTEM(®)). The main outcome parameter was the cumulative number of allogeneic blood units transfused on the day of surgery. RESULTS: The difference between the groups regarding the cumulative use of allogeneic blood products was highly significant with 3.0 (1.3-5.5) blood products in the algorithm group compared with 9.0 (6.0-12.3) in the control group [median (inter-quartile range); P=0.002]. No plasma was administered in the algorithm group compared with 5.0 (1.5-7.5) units overall in the control group (P<0.001). Fibrinogen concentrate administration was not significantly different between the groups (P=0.89). Tranexamic acid was not administered. CONCLUSIONS: The significant reduction in allogeneic blood product requirements during surgical burn wound excision is a prospective proof of concept that a bleeding management algorithm based on thromboelastometry is efficacious. Hypofibrinogenaemia and hyperfibrinolysis are not significant pathomechanisms of bleeding in this setting and ROTEM(®) helps to avoid unnecessary interventions.

Coagulation Day 2010: an Austrian survey on the routine of thromboprophylaxis in intensive care.

PURPOSE: Venous thromboembolism (VTE) is a common but often overlooked life-threatening complication of critical illness. The aim of this cross-sectional survey was to assess current practice of thromboprophylaxis as well as adherence to international guidelines. METHODS: After ethics committee approval, all intensive care units in Austrian hospitals treating adult patients were invited to participate in this web-based survey. Anonymized data on each patient treated at the participating intensive care units on Coagulation Day 2010 were collected using an electronic case report form. Risk assessment, choice and monitoring of anticoagulants, means of mechanical prophylaxis, and demographic data were recorded. RESULTS: Data from 325 critically ill patients were collected. Patients had a median of four risk factors for thrombosis and 6 % suffered from VTE. Of the 325 patients, 80 % received low molecular weight heparins subcutaneously, 10 % received unfractionated heparin intravenously, 1 % received alternative anticoagulants and 9 % received no pharmacological prophylaxis. Mechanical prophylaxis was used in 49 % with a predominant use of graduated compression stockings. In 39 % a combination of pharmacological and mechanical prophylaxis was applied and 5 % received no prophylaxis at all. Overall guideline adherence was 40 % on Coagulation Day 2010. CONCLUSION: Current practice of thromboprophylaxis is predominantly based on the administration of low molecular weight heparins prescribed at rather arbitrary doses without a discernible relationship to drug monitoring, thromboembolic risk factors, vasopressor use or fluid balance. The use of mechanical prophylaxis, evaluation of risk scores and overall guideline adherence must be further encouraged by education, training and communication.

Point-of-care assessment of platelet aggregation in paediatric open heart surgery.

BACKGROUND: Congenital heart disease (CHD) is associated with complex coagulation abnormalities. Platelet aggregability has not been investigated in detail in children with acyanotic and cyanotic malformations undergoing open heart surgery. The method of whole-blood multiple electrode aggregometry (MEA) appears suitable for rapid platelet analysis in children, for example, because of small sample volumes. We investigated perioperative evolution of platelet aggregation by means of MEA in children with CHD. METHODS: Fifty children with acyanotic or cyanotic malformations were included in a prospective observational study. Laboratory testing was assessed before anaesthesia, and during and after surgery until the fifth postoperative day. MEA was performed in hirudin-anticoagulated blood using adenosine diphosphate (ADP), arachidonic acid, and thrombin receptor-activating peptide for platelet activation. Surgical variables, bleeding volumes, and transfusion requirements were documented during hospital stay. RESULTS: Mean platelet count was within the normal range in all patients with no intergroup differences. Before surgery, aggregation to all agonists was within the age-adjusted normal range in cyanotic children and was statistically significantly higher compared with acyanotic children. Platelet aggregation decreased significantly during surgery in both groups followed by a slow recovery not reaching baseline levels. Bleeding and platelet transfusions were higher in the cyanotic group. Transfusion requirements correlated with ADP-induced platelet aggregation. CONCLUSIONS: These results indicate higher blood loss, despite better platelet aggregation in cyanotic patients compared with acyanotic patients. MEA alone might not be suitable for predicting increased perioperative blood loss.

Mild and moderate hypothermia increases platelet aggregation induced by various agonists: a whole blood in vitro study.

The mechanisms causing temperature-dependent bleeding, especially in hypothermic patients, warrant clarification. Therefore the aim of this study was to investigate platelet aggregation at the clinically important temperature range of 30-34 degrees C. After obtaining informed consent citrated whole blood was drawn from 12 healthy adult male volunteers, who had not taken any medication in the previous 14 days. After venipuncture blood samples were incubated at 37 degrees C until platelet testing. Platelet aggregation was performed in whole blood using the impedance aggregometer Multiplate at five different test temperatures between 30 degrees C and 34 degrees C. Aggregation responses at 37 degrees C served as controls. At temperatures of mild and moderate hypothermia (30-34 degrees C), overall platelet aggregation was increased compared to 37 degrees C. Increases were recorded in response to collagen, thrombin receptor activating peptide and ristocetin between 31 degrees C and 34 degrees C and in response to adenosine diphosphate between 30 degrees C and 34 degrees C. Overall platelet aggregation is increased at mild and moderate hypothermia down to 30 degrees C. These results indicate that bleeding complications reported in mildly hypothermic patients are not due to hypothermia-induced platelet inhibition. The pathomechanism of the overall increased platelet aggregation between 30 degrees C and 34 degrees C requires further detailed study.

Evaluation of the Platelet Mapping Assay on rotational thromboelastometry ROTEM.

Rotational thromboelastometry ROTEM is available as point-of-care coagulation monitoring in an increasing number of European operating theatres and emergency rooms. The Platelet Mapping Assay has been described as a platelet aggregation assay for thromboelastography TEG. The aim of this experimental trial was to evaluate feasibility of the Platelet Mapping Assay on the ROTEM test system. Whole blood was drawn from 22 adult volunteers and patients with and without antiplatelet medication. Platelet aggregability was determined in three whole blood assays: the Platelet Mapping Assay using both activators arachidonic acid (AA) and adenosine diphosphate (ADP) on TEG, its adapted version on ROTEM, and the multiple electrode impedance aggregometer Multiplate. Percent aggregation inhibition results were plotted in a linear regression analysis and correlation was estimated. Sensitivity and specificity for detecting antiplatelet medication were determined. Overall correlations were statistically significant with an r(2) = 0.83 in AA-activated and an r(2) = 0.82 in ADP-activated Platelet Mapping Assay. AA-activated tests and the Multiplate analysis identified aspirin-inhibition in 86% and 100%, respectively. ADP-activated tests and the Multiplate analysis identified clopidogrel-inhibition in 67% and 89%, respectively. Specificity was low both in ROTEM and TEG. Differences in frequency distribution between the results obtained in ROTEM and TEG were not statistically significant. The Platelet Mapping Assay can be performed on the ROTEM. For the perioperative scenario, however, longer test duration and higher costs have to be considered compared to Multiplate analyses.

Withdrawal forces of lumbar spinal catheters: no dependence on body position.

BACKGROUND: Spinal catheters, because of their smaller diameter, have lower tensile strength than epidural catheters. This study was designed to measure the withdrawal forces needed to remove lumbar spinal catheters and to determine whether patient position affects withdrawal forces. METHODS: Eighty-two patients with a 24-gauge spinal catheter placed midline at the lumbar L3/4 or L4/5 level were randomly assigned to catheter removal either in flexed lateral or sitting position. Withdrawal forces were measured using a tension spring balance. RESULTS: Mean withdrawal force was 0.91 N (95% CI: 0.73, 1.09) with extremes up to 5 N. Withdrawal force in the flexed lateral position was 1.04 N (95% CI: 0.73, 1.34) or in the sitting position was 0.78 N (95% CI: 0.59, 0.97). The 95% CI for the difference of the means was -0.62 N, 0.10 N. Thus, the absolute mean difference between the positions can be assumed to be smaller than 0.62 N. Neither the length of the spinal catheter under the skin or in the subarachnoid space, nor BMI influenced withdrawal force. CONCLUSION: Withdrawal force of spinal catheters is not influenced by body position during catheter removal, length of catheter under skin, or BMI.