COMMENTARY

Is Fibrinogen Useful in High-Risk Cardiac Surgery?

Alex Macario, MD, MBA

Disclosures

March 30, 2017

Study Summary

Is fibrinogen concentrate useful for bleeding in high-risk cardiac surgery? In a study conducted in The Netherlands,[1] 647 patients (from 2011 to 2015) scheduled to have high-risk cardiac surgery were deemed eligible. High-risk surgery included (1) combined coronary artery bypass graft surgery and valve repair or replacement surgery; (2) the replacement of multiple valves; (3) aortic root reconstruction; or (4) reconstruction of the ascending aorta or aortic arch. From the outset, 444 of the 647 patients (69%) were excluded, the majority of whom (62%) because they were not willing to participate.

Of the 203 patients enrolled, 83 patients were then excluded because they didn’t qualify as having sufficient bleeding. Bleeding was measured by packing the thoracic cavity with surgical gauze and, after 5 minutes, wringing out the blood. This volume was added to the blood loss captured from suctioning. If total bleeding volume was< 60 mL, then the cases were considered "dry" and classified as having no intraoperative bleeding. Those patients were then excluded from the study.

Patients with > 250 mL blood loss were classified as having sufficient bleeding and were randomly assigned to receive either fibrinogen concentrate or placebo. The dose of fibrinogen was variable; some patients received more than others, and dose was based on measured plasma fibrinogen levels at the end of cardiopulmonary bypass. In other words, patients with lower fibrinogen values received a higher fibrinogen dose, with target plasma fibrinogen concentration of 2.5 g/L for each patient.

Among the 120 patients (mean [SD] age, 71 (10) years; 31% women) included in the study, 72% underwent coronary artery bypass graft surgery combined with a valve repair or replacement. The mean (SD) cardiopulmonary bypass time was 200 (83) minutes.

The primary outcome was blood loss in milliliters between intervention (ie, after removal of cardiopulmonary bypass) and closure of chest. This duration equaled 4.2 minutes (95% confidence interval [CI], 0.4-8.0 minutes) in the fibrinogen group, and 8.7 minutes (95% CI, 5.2-12.1 minutes) in the control group.

Median blood loss in the two groups was not significantly different after controlling for potential confounding variables and equaled 50 mL (interquartile range, 29-100 mL) in the fibrinogen group compared with 70 mL (33-145 mL) in the control group (P = .19).

There were six cases of stroke or transient ischemic attack (four in the fibrinogen group), four myocardial infarctions (three in the fibrinogen group), two deaths (both in the fibrinogen group), five cases with renal insufficiency or failure (three in the fibrinogen group), and nine cases with reoperative thoracotomy (four in the fibrinogen group).

Although fewer blood products were used overall in the fibrinogen group, the study was not adequately powered to formally test these secondary outcomes.

Cumulative blood loss in the first 24 hours after surgery was lower for the fibrinogen group than for the control group with median blood loss of 570 mL (interquartile range [IQR], 390-730 mL) in fibrinogen patients compared with 690 mL (IQR, 400-1090 mL; P = .047) for control patients.

Viewpoint

Bleeding during cardiac surgery is a complex and incompletely understood phenomenon, as the coagulopathy is influenced by patient factors (such as preoperative antiplatelet agents), use of the heparin anticoagulant with subsequent neutralization with protamine, consumption and dilution of clotting factors, the body's inflammatory system, and fibrinolysis. Clinicians in the operating room aim to maintain hemostasis and avoid transfusion because giving blood is associated with poorer patient outcomes.

Unfortunately, the usual coagulation tests that are often sent to the laboratory from the operating room take too long to get a result back to affect decisions during the cardiac surgery case, and often they aren't consistent with the bleeding seen in the operative field. Platelet numbers and fibrinogen level may be measured as normal but may have poor function.

Plasma fibrinogen (factor I) promotes clot formation and may be rapidly depleted during cardiac surgery. Cryoprecipitate can be administered to replace fibrinogen and also contains von Willebrand factor, factor VIII, factor XIII, and fibronectin. The investigators of the current study aimed to specifically study fibrinogen concentrate infusion, and the protocol details illustrate the many confounders and challenges of doing these sorts of studies that will then be generalizable.

After the infusion of the study medication, the blood management regimen included 1 unit of red blood cells if the hemoglobin level went < 8.5 g/dL, and patients received 2 units of fresh frozen plasma if they lost > 1 L of plasma. If ≥ 2 L of plasma were lost, patients received 4 units of fresh frozen plasma. Also, a platelet count of < 80 x 109/L was transfused with platelets. In the ICU, excessive blood loss was treated with 4 units of red blood cells, 4 units fresh frozen plasma, and 1 unit of platelet concentrate.

The study concluded that among patients with intraoperative bleeding, fibrinogen concentrate infusion did not reduce intraoperative blood loss. Of note, plasma fibrinogen concentrations steadily increased postoperatively in both the fibrinogen and control groups, and at 24 hours, plasma fibrinogen levels were nearly equal in the two groups.

Efforts to manage coagulation in the cardiac OR are increasingly focused on using point-of-care tests on whole blood to discern overall clot strength, such as with thromboelastography. If these tests can be made reliably available on site, thereby enabling quick turnaround times, then they can be used with transfusion algorithms to optimally manage bleeding.

Measuring blood loss is an intermediate outcome, as the relevant question is, what is the impact of an intervention on clinical outcomes that patients care about? However, the study was not intended or powered to determine the impact of the fibrinogen replacement on strokes, heart attacks, organ dysfunction, reoperation, or death.

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