British Journal of Anaesthesia, 117 (S2): ii85–ii94 (2016) doi: 10.1093/bja/aew270 Review Article

Management of bleeding in vascular surgery Y. E. Chee*, S. E. Liu and M. G. Irwin Department of Anesthesia, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong *Corresponding author. E-mail: [email protected]

Abstract Management of acute coagulopathy and blood loss during major vascular procedures poses a significant haemostatic challenge to anaesthetists. The acute coagulopathy is multifactorial in origin with tissue injury and hypotension as the precipitating factors, followed by dilution, hypothermia, acidemia, hyperfibrinolysis and systemic inflammatory response, all acting as a self-perpetuating spiral of events. The problem is confounded by the high prevalence of antithrombotic agent use in these patients and intraoperative heparin administration. Trials specifically examining bleeding management in vascular surgery are lacking, and much of the literature and guidelines are derived from studies on patients with trauma. In general, it is recommended to adopt permissive hypotension with a restrictive fluid strategy, using a combination of crystalloid and colloid solutions up to one litre during the initial resuscitation, after which blood products should be administered. A restrictive transfusion trigger for red cells remains the mainstay of treatment except for the high-risk patients, where the trigger should be individualized. Transfusion of blood components should be initiated by clinical evidence of coagulopathy such as diffuse microvascular bleeding, and then guided by either laboratory or point-of-care coagulation testing. Prophylactic antifibrinolytic use is recommended for all surgery where excessive bleeding is anticipated. Fibrinogen and prothrombin complex concentrates administration are recommended during massive transfusion, whereas rFVIIa should be reserved until all means have failed. While debates over the ideal resuscitative strategy continue, the approach to vascular haemostasis should be scientific, rational, and structured. As far as possible, therapy should be monitored and goal directed. Key words: acute coagulopathy; bleeding management; vascular surgery

Editor’s key points • Much of the evidence on the management of major bleeding comes from studies conducted in trauma patients. • Blood and FFP and platelets should be administered early in major bleeding. • The use of fibrinogen concentrate is recommended in major bleeding where low circulating concentrations of fibrinogen have been demonstrated or are suspected. • Data from the IMPROVE trial suggest that aggressive permissive hypotension (SAP75 yr of age (10.8% vs 4.1%, P=0.02). Interestingly there was no difference in the rates of venous thromboembolic events.87 88 A Cochrane review on the use of rFVIIa in patients without thrombophilia or coagulation factor deficiency found that, when given as a prophylaxis, compared with placebo, there was no mortality benefit (RR 1.04; 95% CI 0.55–1.97) but a trend in favour of rFVIIa in reducing the number of patients receiving RBC transfusion (RR 0.85; 95% CI 0.72–1.01).89 A trend against rFVIIa use with respect to adverse thromboembolic events (RR 1.35; 95% CI 0.82–2.25) was seen. The use of rFVIIa should, therefore, be considered only for bleeding that cannot be stopped by

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conventional, surgical or interventional radiological means and when comprehensive coagulation therapy has failed.

Antifibrinolytics Fibrinolysis is a process in which plasminogen removes excess fibrin deposition at the site of vascular injury, which acts to improve localization of the fibrin clot and promote wound healing. Hyperfibrinolysis can be significant in acute coagulopathy. Fibrinolytic agents include tranaxemic acid, aprotinin and ε-aminocaproic acid. Aprotinin is a non-specific serine protease inhibitor. In an observational study and a RCT,90 91 aprotinin was shown to be associated with a higher risk of renal, cardio- and cerebrovascular events when compared with tranaxemic acid and ε-aminocaproic acid in patients undergoing myocardial revascularization. The BART trial (Blood Conservation Using Antifibrinolytics in a Randomised Trial) randomized high-risk cardiac patients to receive prophylactic aprotinin, ε-aminocaproic acid or tranexamic acid. The mortality was increased in patients who received aprotinin compared with the combined rate for the two other antifibrinolytics (RR 1.53, 95% CI 1.06–2.22). Aprotinin was withdrawn from the market in 2008. Tranexamic acid and ε-aminocaproic acid are synthetic lysine-analogues and act by reversibly blocking the lysine binding sites of plasminogen, thus preventing its activation to plasmin. The use of high doses of tranexamic acid, however, is associated with an increased risk of postoperative seizures. It is proposed that this is as a result of its competitive antagonistic action on the inhibitory glycine receptor.92 93 In the Clinical Randomization of Antifibrinolytics in Significant Haemorrhage 2 (CRASH-2) trial,94 early use of tranexamic acid, compared with placebo, reduced all-cause mortality at 28 days (14.5% vs 16%; RR 0.91 (95% CI 0.85–0.99; P=0.0035) and bleeding related deaths (4.9% vs 5.7%; RR 0.85% (95% CI 0.76–0.96; P=0.008). Vascular occlusive events did not differ significantly between the two groups. In a Cochrane review largely based on CRASH 2 trial data and trauma patients, the use of tranexamic acid reduced the chance of receiving a blood transfusion by 30%.95 Tranexamic acid reduces mortality from bleeding and transfusion requirement with little evidence of adverse effects. It should be administered in a dose of 20–25 mg kg−1 in the management of major perioperative bleeding.

Role of point of care coagulation testing Traditional coagulation tests such as PT, INR and aPTT provide a quantitative measure of plasma clotting factors, monitor the first 4% of thrombin production and the initiation phase of the coagulation cascade.96 These tests do not reflect the complex interplay of haemostatic components in vivo and are poor predictors of bleeding.97 98 In addition, laboratory testing results, on average, take 30–60 min to be available, which is too slow to support clinical decision making during vascular surgery in acute and profuse bleeding. The activation of coagulation factors and platelet function are temperature-sensitive yet most laboratory assays are performed in an artificial milieu of 37°C instead of the patient’s actual body temperature. These limitations render conventional coagulation tests time-insensitive, with low predictive values for bleeding, and restrict their usefulness in the intraoperative management of bleeding. As such, point-ofcare diagnostic tools (POCT) have gained growing interest as more promising alternatives.

Viscoelastic methods are among the many POCTs that have been developed to provide rapid assessment of coagulation status. Johansson and collagues99 reported a before-and-after study design (n=832) that implemented a TEG-guided early haemostatic resuscitation regime, and showed improved outcomes. A retrospective study on 3865 patients who underwent cardiovascular surgery, demonstrated that using combined thromboelastometry and portable coagulometry to guide intraoperative transfusion resulted in a reduction in blood product use and thromboembolic events, but not mortality.100 Furthermore, parameters measured by viscoelastic testing have been shown to be good predictors for the need for massive transfusion, incidence of thromboembolic events and mortality in surgical and trauma patients.101–107 Two commercially available viscoelastic-based products dominate the market, TEG 5000 (Haemonetics Corporation, Braintree, MA) and ROTEM (TEM International GmbH, Munich, Germany). Both devices consist of a pin suspended in a cup of native whole blood. As the pin and cup rotate relative to each other in controlled, repetitive, low shear movements, the formation and eventual dissolution of clot are captured as changes in torque that are transduced and displayed graphically. Both devices provide whole blood clotting tests that evaluate different aspects of haemostatic status including platelet function, fibrinogen and fibrinolysis.108 Although the mechanical principles underlying the two devices are similar, the different hardware and activators used have resulted in different output values and reference ranges that are not interchangeable. The principles and reference ranges of both devices have been extensively reviewed.109–111 A large body of literature has demonstrated the effectiveness of TEG® 5000 and ROTEM in guiding transfusion therapy, leading to a reduction in the need for and the volumes of blood and plasma transfusion.109–116 Despite the popularity of viscoelastic-based POCTs, their usefulness has been questioned. A recent systematic review found insufficient evidence to support the diagnostic accuracy of thromboelastometry, and hence, was unable to offer advice on its use as a global measure of haemostatic function in trauma patients.117 Another systematic review concluded that viscoelastic POCT predicts the need for blood product transfusion but does not alter mortality or other important outcomes in trauma patients.118 Several other limitations have also been described, including the inability of TEG to discriminate between dilutional coagulopathy and coagulopathy secondary to thrombocytopenia,119 the lack of sensitivity to detect and monitor platelet dysfunction as a result of antiplatelet drugs,120 121 and the need for trained personnel to guarantee quality of test performance.114 Evidence on POCT-guided transfusion is largely derived from trauma or cardiac surgery. The latest edition of the ‘European Guidelines on Management of Major Bleeding and Coagulopathy Following Trauma’38 has recommended institution of early and repeated coagulation monitoring in managing trauma induced coagulopathy (TIC), using conventional laboratory assays (Grade 1A) and/or viscoelastic methods (Grade 1C). On the contrary, the consensus statement on viscoelastic POCT-based guided transfusion that was published in 2015122 prompted clinicians to take ‘practical advantages’ into consideration when deciding the mode of coagulation testing during bleeding management. The practical advantages include rapid results to guide clinical decisions, a logistic advantage with less laboratory travels, treatment efficiency by obtaining crucial information on fibrinogen and fibrinolysis, and cost saving from avoidance of transfusion.

Management of bleeding in vascular surgery

Conclusion Although there has been improved understanding on the management of perioperative bleeding through laboratory and clinical research, it remains the single most important adverse prognostic factor for mortality and continues to pose a major challenge. The optimal management of perioperative bleeding is likely to evolve into real-time monitoring and goal directed transfusion protocols, especially in regards to component therapy.

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Authors’ contributions Review design: MGI. Review conduct: EYC., MGI., SEL. Writing paper: all authors Revising paper: all authors

Declaration of interest

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None declared.

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