Fibrinogen Concentrate Corrects Dilutional Coagulopathy: A Prospective, Randomized Placebo Controlled Clinical Trial.

Introduction: Infusion of artificial colloids such as hydroxyethyl starch (HES) induces a coagulopathy, beyond simple dilution. Laboratory and animal studies have suggested that the coagulopathy could be corrected by substitution with a fibrinogen concentrate.

Aims and Hypotheses: The present prospective randomized placebo controlled trial aimed to:

• verify the development of a coagulopathy following in vivo infusion of HES, and

• investigate the haemostatic effect of a fibrinogen concentrate patients experiencing sudden excessive bleeding during elective cystectomy.

We hypothesized that HES induces a coagulopathy characterized by dysfunctional fibrin polymerization and thereby compromised maximum clot firmness (MCF). Furthermore, we hypothesized that fibrinogen corrects the coagulopathy caused by HES and reduce blood product transfusion requirements.

Materials and Methods: Based on sample size calculation a total of twenty patients undergoing cystectomy were included in the study. Approval was granted by the Danish Medicines Agency, Human Ethics Committee, and the Danish Data Protection Agency. Monitoring of the study was performed by the GCP-Unit at Aarhus University Hospital. During the cystectomy operation persisting bleeding was substituted 1:1 with hydroxyethyl starch 130/0.4. At a level of dilution of 30% patients were randomly assigned for intra-operative administration of a fibrinogen concentrate (45 mg/kg) (Haemocomplettan^® CSL Behring, Germany) or placebo. The primary endpoint was MCF as assessed by whole blood thromboelastometry. Other pre-specified secondary endpoints blood loss and transfusion requirements as well as other thrombelastometry parameters, platelet function, and thrombin generation. Data were parametric and paired analysis was performed using student’s t-test and ANOVA. Data are presented as mean (95%CI), p<0.05 was considered statistical significant.

Results: Whole blood MCF was significantly reduced from 59.2 (SD; 5.8) mm to 50.6 (SD; 4.7) mm following in vivo 30% dilution with HES. Placebo resulted in a further decline of the MCF of −1.2 (SD; 1.4) mm, whereas randomized administration of fibrinogen significantly increased the MCF with +3.1 (SD; 1.7) mm (p<0.001). Furthermore, patients randomized to fibrinogen substitution only needed postoperative red blood cells transfusions in 2 out or 10 cases, as compared with 8 out of 10 in the placebo group (p=0.023). Both platelet function and thrombin generation was reduced following in vivo 30 % haemodilution and fibrinogen administration induced no significant changes.

Discussion/Conclusion: Fluid resuscitation with hydroxyethyl starch 130/0.4 as a result of sudden excessive bleeding during cystectomy induces a coagulopathy characterized by reduced whole blood maximum clot firmness. Randomized administration of fibrinogen concentrate significantly improved maximum clot firmness and reduced postoperative transfusion requirements.