Description of the condition
Liver resection is the treatment of choice for many benign and malignant liver tumours (Jarnagin 2002). Despite the considerable development in surgical technique since the late nineteenth century (Langenbuch 1888; Warvi 1945) and the improved understanding of segmental liver anatomy (Couinaud 1999), liver resection can still be associated with significant intraoperative bleeding (Berrevoet 2007). The intrinsic capacity of the liver to bleed is due to both its abundant venous vascular network and its inability to vasoconstrict in response to injury (Clark 1970). In addition, this can be complicated by coagulation disorders related to the underlying disease.
Operative mortality following liver resection is reported to range from 3% in non-cirrhotic patients (Jarnagin 2002) to 25% in the presence of liver cirrhosis (Mullin 2005). Intraoperative bleeding is the major cause of morbidity and mortality in liver resection (Jarnagin 2002; Ibrahim 2006). Allogeneic blood transfusion also increases morbidity and mortality through transfusion reactions, transmission of blood-borne infective agents, and potentially through immunosuppressive effects of donor-derived leukocytes (Shinozuka 2000).
Description of the intervention
Various surgical, anaesthetic, and pharmacological techniques have been applied to minimise blood loss and achieve haemostasis in liver surgery (Table 1). The evidence behind the effectiveness of various vascular occlusion techniques, parenchymal transection techniques, cardiopulmonary manoeuvres, and antifibrinolytics in reducing blood loss in liver resections has been examined in Cochrane reviews (Gurusamy 2009a; Gurusamy 2009b; Gurusamy 2009c; Gurusamy 2009d).
|Anaesthetic techniques||Surgical techniques||Surgical instruments|
|Lowering venous pressure||Anatomical dissection||CUSA1|
|Autologous transfusion||Hepatic inflow occlusion||RFA2 needle dissection|
|Antifibrinolytic agents||Ischaemic preconditioning||Monopolar Dissecting Sealer3|
|Total vascular exclusion||Water jet dissection4|
|In situ hypothermic perfusion||Argon beam coagulation|
Fibrin-based haemostatic agents are bioabsorbable topical haemostatic agents used in liver resection to enhance haemostasis and reduce blood loss. These products contain clotting factors and act by mimicking the final stages of the coagulation cascade ending in the formation of fibrin, thus promoting the process of coagulation and wound healing. The main components of commercially available fibrin-based haemostatic agents are thrombin and fibrinogen, derived from human plasma and typically purified from cryoprecipitate.
How the intervention might work
The two components, thrombin and fibrinogen, are usually delivered to the site of bleeding via a dual-syringe or aerosol applicator. In some products, the clotting factors are coated on a collagen sheet and applied as a surgical patch. Non-commercial preparations of fibrin-based haemostatic agents utilise autologous or allogenic blood products as a source of fibrinogen which is then combined with topical bovine thrombin (Mintz 2001). The relative concentrations of fibrinogen and thrombin within these preparations affect the haemostatic process. Higher concentrations of thrombin tend to accelerate clot formation and increase clot adhesion, whereas higher concentrations of fibrinogen produce stronger clots. Fibrinogen concentrations are usually higher and more consistent in commercial fibrin-based haemostatic agents than non-commercial preparations (Albala 2003). Other additives, including factor XIII and antifibrinolytic agents, such as aprotinin or tranexamic acid, can also be included in these preparations in order to improve clot stability (Table 2).
|Product name||Fibrinogen concentration (mg/mL)||Thrombin concentration (IU/mL)||Factor XIII concentration (U/mL)||Antifibrinolytic agent|
|Beriplast®P (CSL Behring, Germany)||90||500||60||Bovine aprotinin: 1000 KIU/mL|
|Biocol® (LFB, France)||127||558||11||Bovine aprotinin: 3000 KIU/mL|
|Bolheal® (Kaketsuken Pharmaceutical, Japan)||80||250||75||Bovine aprotinin: 1000 KIU/mL|
|Evicel® - formerly Crosseal® (Omrix Biopharmaceuticals, Israel)||70||1000||None||None|
|Quixil® (Omrix Biopharmaceuticals, Israel)||50||1000||None||Tranexamic acid: 85 to 105 mg/mL|
|Tachosil® (Nycomed, Switzerland)||5.5*||2.0**||None||None|
|Tisseel® (Baxter, Austria)||90||500||30||Bovine aprotinin: 3000 KIU/mL|
In addition to their effect on haemostasis, fibrin-based haemostatic agents are also thought to have a sealant effect, preventing the leakage of bile and reducing the incidence of other complications of liver resection such as intra-abdominal fluid collection (Berrevoet 2007).
However, the use of these products is not without its risks. Fibrin-based haemostatic agents that contain plasma-derived or bovine products carry the risk of transmitting viral and prion infections (Spotnitz 2005). Those that contain bovine thrombin, upon repeated exposure, can also lead to immunologically induced coagulopathies (Rapaport 1992; Banninger 1993) and anaphylactic reactions (Mitsuhata 1994).
Why it is important to do this review
Various topical haemostatic agents have been employed to reduce resection surface bleeding during liver resection. Although fibrin-based haemostatic agents have been advocated as most favourable sealants (Berrevoet 2007), two recent meta-analyses have failed to show clinical improvements in outcomes from using these products in liver surgery (Sanjay 2013; Ding 2013). Nevertheless, fibrin-based haemostatic agents are frequently used in liver surgery with the aim of reducing blood loss and biliary leakage (Boonstra 2009; Nakajima 2002). The evidence for the benefits of these agents in liver resection (and indeed their superiority over other haemostatic adjuncts) is yet to be examined in a Cochrane review. It is, therefore, important to evaluate the literature critically and systematically for the benefits and risks of using fibrin-based haemostatic agents compared with no (or other) haemostatic adjuncts in these procedures.