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Literature Review

Effect of Fibrinogen Concentrate on Intraoperative Blood Loss Among Patients With Intraoperative Bleeding During High-Risk Cardiac Surgery: A Randomized Clinical Trial

Bilecen S, de Groot JAH, Kalkman CJ, et al. JAMA. 2017;317(7):738-747.

Reviewers: Dean Bowker, MD1; Dalia Banks, MD1

  1. Department of Anesthesiology, UC San Diego School of Medicine, La Jolla, CA
Background

Excessive bleeding is one of the most common complications of cardiac surgery. Although the amount of bleeding is dependent on a multitude of factors, fibrinogen plays a key role in hemostasis and is rapidly depleted during cardiac surgery. Although fibrinogen replacement seems like an attractive option for treating excessive bleeding in these cases, the use of fibrinogen concentrate only has been examined in 2 prior studies,1,2 neither focusing on intraoperative blood loss. This study aimed to determine whether fibrinogen concentrate infusion to target a fibrinogen level of 2.5g/L reduced ongoing intraoperative blood loss in patients undergoing cardiac surgery.

Methods

This was a randomized, prospective, placebo-controlled, double-blinded, single-center trial of fibrinogen vs placebo for the treatment of intraoperative bleeding in high-risk cardiac surgery. High risk was defined as coronary artery bypass grafting and valve, multiple valve, or aortic reconstruction. Exclusion criteria included coagulation disorders, anticoagulant therapy, recent stroke or myocardial infarction (MI), thrombosis, “dry” 5-minute bleed test, post-cardiopulmonary bypass (CPB) fibrinogen >2.5g/L, or major surgical complications.

Following separation from CPB and initial surgical hemostasis, a bleed test was performed in which the chest was packed for 5 minutes. Upon removal of packing and suctioning of the chest, the estimated blood loss (EBL) during this period was categorized as “dry” (<60ml), "intraoperative blood loss” (60-250ml), or "surgical bleeding” (>250ml). Patients with surgical bleeding underwent repeat testing after further surgical hemostasis. Those with intraoperative blood loss were randomized to placebo or fibrinogen concentrate infusion targeted to a plasma level of >2.5g/L.

The primary outcome was EBL between intervention and chest closure. Secondary outcomes included EBL at 1, 3, 6, 12, and 24 hours postoperatively; intraoperative and postoperative blood transfusions; procoagulants and antifibrinolytics administered; and incidence of adverse events. Adverse events included 30-day mortality, MI, stroke, thrombosis, renal injury, allergic reaction, sternal infection, or reoperative thoracotomy.

Results

A total of 120 patients were randomized with 60 in the fibrinogen group and 60 in the placebo group. The mean fibrinogen levels for the two groups were reported at baseline (fibrinogen 2.9g/L, placebo 2.8g/L), immediately postoperatively (fibrinogen 2.3g/L, placebo 1.7g/L), and 24 hours postoperatively (fibrinogen 3.1g/L, placebo 3.3g/L).

For the primary outcome, the median EBL was found to be 50 ml in the fibrinogen group and 70 ml in the placebo group, which was not statistically significant (P=.19). For the secondary outcomes, median cumulative postoperative blood loss at 24 hours in the fibrinogen group (570 ml) was less than in the placebo group (690 ml) according to a post hoc analysis (P=.047). Although not powered to formally assess statistical significance, the study suggests the fibrinogen group may have been associated with fewer transfusions, more procoagulant or antifibrinolytic therapies, and more adverse events.

Discussion

This study did not identify a statistically significant difference in intraoperative blood loss between patients treated with fibrinogen concentrate (median 50 ml) and those receiving placebo (median 70 ml). This is somewhat surprising given that two prior studies looking at the impact of fibrinogen concentrates on blood product administration in cardiac surgery patients both found significant reductions.1,2 The authors acknowledged the brief period during which intraoperative blood loss was assessed and that this may have contributed to the low EBL in both groups, possibly complicating detection of differences between groups. Furthermore, the difficulty of accurate assessment of intraoperative blood loss is well established.

A post hoc analysis of median cumulative 24-hour blood loss did suggest a statistically significant reduction (120 ml) in the fibrinogen group, but this may not be a clinically important difference. The authors noted that 10% of the control group ended up receiving fibrinogen concentrate postoperatively, which may have confounded effects of intraoperative fibrinogen on subsequent outcomes.

Although the study was not designed to assess statistically significant differences in adverse events, there may have been more adverse events in the fibrinogen group. This also differs from the 2 prior studies, which found no differences in safety endpoints. This is an important area for further investigation.

References

  1. Rahe-Meyer N, Solomon C, Hanke A, et al. Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial. Anesthesiology. 2013;118(1):40-50.
  2. Ranucci M, Baryshnikova E, Crapelli GB, et al. Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery. J Am Heart Assoc. 2015;4(6):e002066.

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