Abstract
Purpose
Fibrinogen is widely used in cardiac surgery. Still, reported associations between plasma fibrinogen level and chest tube drainage are weak. The results of trials on fibrinogen supplementation are contradictory. We aimed to investigate how the plasma fibrinogen level relates to severe bleeding and resternotomy for bleeding in patients undergoing on-pump cardiac surgery.
Methods
We conducted an observational post hoc study of 1,386 patients undergoing on-pump cardiac surgery enrolled in the Albumin in Cardiac Surgery (ALBICS) trial. We assessed severe bleeding with the Universal Definition of Perioperative Bleeding classification (UDPB), categorized as “UDPB-low” (classes 0–2) and “UDPB-high” (classes 3–4) and as resternotomy. We measured plasma fibrinogen levels preoperatively and 30 min after protamine administration (“post-cardiopulmonary bypass [CPB]”).
Results
The incidences of UDPB-high and resternotomy were 8.1% (112/1,386) and 3.6% (50/1,386). No patient with preoperative a fibrinogen level > 4.7 g·L−1 (90/1,386; 6.5%) had UDPB-high or resternotomy. After adjustment for hemostatic laboratory values, preoperative fibrinogen predicted UDPB-high (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.60 to 0.98; per standard deviation [SD] [0.9 g·L−1]) and resternotomy (OR, 0.65; 95% CI, 0.43 to 0.98; per SD [0.9 g·L−1]). No patient with a post-CPB fibrinogen level > 3.1 g·L−1 (73/1,386; 5.3%) had UDPB-high or required resternotomy. Post-CPB fibrinogen predicted UDPB-high (OR, 0.51; 95% CI, 0.33 to 0.77; per preoperative SD [0.9 g·L−1]) and resternotomy (OR, 0.31; 95% CI, 0.16 to 0.62; per preoperative SD [0.9 g·L−1]).
Conclusion
The preoperative fibrinogen level had borderline and the post-CPB fibrinogen level had strong associations with severe bleeding and resternotomy in patients undergoing on-pump cardiac surgery. Further research is required to delineate whether the observed association represents a cause-and-effect relationship.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12630-025-03046-7.
Keywords: bleeding, cardiac surgery, cardiopulmonary bypass, fibrinogen
Résumé
Objectif
Le fibrinogène est largement utilisé en chirurgie cardiaque. Pourtant, les associations rapportées entre le taux plasmatique de fibrinogène et les quantités issues du drain thoracique sont faibles. Les résultats des études sur la supplémentation en fibrinogène sont contradictoires. Notre objectif était d’étudier comment le taux plasmatique de fibrinogène est lié aux saignements sévères et à une nouvelle sternotomie pour les saignements chez les individus bénéficiant d’une chirurgie cardiaque sous circulation extracorporelle (CEC).
Méthode
Nous avons réalisé une étude d’observation post hoc de 1386 personnes bénéficiant d’une chirurgie cardiaque sous CEC inscrites à l'étude sur l’albumine en chirurgie cardiaque (ALBICS). Nous avons évalué les saignements graves à l’aide de la classification UDPB, classée comme « UDPB-low » (classes 0 à 2) et « UDPB-high » (classes 3-4) et comme nouvelle sternotomie. Nous avons mesuré les taux plasmatiques de fibrinogène avant l’opération et 30 minutes après l’administration de protamine (« post-CEC »).
Résultats
L’incidence d’UDPB-high et de nouvelle sternotomie était de 8,1 % (112/1386) et de 3,6 % (50/1386). Aucune personne avec un taux de fibrinogène préopératoire > 4,7 grammes· L−1 (90/1386; 6,5 %) n’avait une UDPB-high ou eu une nouvelle sternotomie. Après ajustement pour tenir compte des valeurs de laboratoire hémostatiques, le fibrinogène préopératoire a prédit une UDPB-high (rapport de cotes [RC], 0,77; intervalle de confiance [IC] à 95 %, 0,60 à 0,98; par écart type [ET] [0,9 g· L−1]) et une nouvelle sternotomie (RC, 0,65; IC 95 %, 0,43 à 0,98; par ET [0,9 g· L−1]). Aucune personne avec un taux de fibrinogène post-CEC > 3,1 grammes· L−1 (73/1386; 5,3 %) n’avait une UDPB-high ou une nouvelle sternotomie. Le fibrinogène post-CEC a prédit une UDPB-high (RC, 0,51; IC 95 %, 0,33 à 0,77; par ET préopératoire [0,9 g· L−1]) et la nouvelle sternotomie (RC, 0,31; IC 95 %, 0,16 à 0,62; par ET préopératoire [0,9 g· L−1]).
Conclusion
Le taux de fibrinogène préopératoire affichait une association limite et le taux de fibrinogène post-CEC était fortement associé à des saignements graves et à une nouvelle sternotomie chez les personnes bénéficiant d’une chirurgie cardiaque sous CEC. D’autres recherches sont nécessaires pour déterminer si l’association observée représente une relation de cause à effet.
Fibrinogen is the most abundant coagulation factor in plasma, with a crucial role in coagulation. Although fibrinogen supplementation is widely used in cardiac surgery, the evidence behind its current practice is surprisingly limited. Since patient-related factors affect red blood cell (RBC) transfusions, RBC transfusion is a poor estimate for bleeding. Indeed, both low and high preoperative plasma fibrinogen levels have been associated with an increased need for RBC transfusions in cardiac surgery.1–3 Most observational studies on fibrinogen in cardiac surgery have small patient numbers.4 To our knowledge, there are 6 larger observational studies that investigated the association of plasma fibrinogen levels with bleeding, assessed either with chest tube drainage1,3,5–7 or with the Universal Definition of Perioperative Bleeding (UDPB) classification.8 In these studies, chest tube drainage was only weakly associated with plasma fibrinogen levels.1,3,5–7 Furthermore, only 3 out of the 7 published clinical trials on fibrinogen supplementation in cardiac surgery favored fibrinogen supplementation.9–15 Thus, there is insufficient evidence to support or refute the benefit of prophylactic administration of fibrinogen to patients undergoing cardiac surgery.16
Chest tube drainage as an outcome measure does not cover all manifestations of perioperative bleeding in cardiac surgery. The UDPB classification was developed to tackle this issue.17 The UDPB classification categorizes perioperative bleeding into five classes on the basis of postoperative chest tube drainage and interventions used to treat and control bleeding, i.e., blood product transfusions, coagulation factor administration, and surgical interventions. The only study on plasma fibrinogen levels in cardiac surgery using UDPB class as the outcome variable showed a U-shaped association, indicating that both low and high plasma fibrinogen concentrations were associated with severe bleeding.8
The recent Albumin in Cardiac Surgery (ALBICS) trial, with 1,386 adult patients who underwent cardiac surgery, compared 4% albumin and Ringer’s acetate in cardiopulmonary bypass (CPB) priming and perioperative volume replacement therapy.18 The use of 4% albumin increased the risk of clinically significant bleeding and resternotomy for bleeding.19 Since the UDPB class is a better estimate for bleeding in cardiac surgery than chest tube drainage or RBC transfusion, in the ALBICS trial, data for assessment of the UDPB class were collected prospectively. In the current post hoc study of the ALBICS trial cohort, we aimed to characterize the role of the plasma fibrinogen level, measured both preoperatively and after weaning from CPB, in severe perioperative bleeding in cardiac surgery.
Methods
Patients
The present study is an observational post hoc study arising from the recent ALBICS trial. The ALBICS trial (ClinicalTrials.gov: NCT02560519) was a single-centre (Helsinki University Hospital, Helsinki, Finland), randomized, double-blind trial comparing 4% albumin (intervention group) and Ringer’s acetate (control group) as CPB priming solutions and intra- and postoperative volume replacement solutions in 1,386 adult patients undergoing on-pump cardiac surgery. The randomization was blinded to patients, study groups, study nurses, and personnel taking care of patients. Our previous publications have described the methodology in detail, including the inclusion and exclusion criteria, recruitment periods, follow-up, and data collection.18,20 The ALBICS trial was conducted according to the principles of the Declaration of Helsinki and was approved by the ethics committee of the Hospital District of Helsinki and Uusimaa, Helsinki, Finland (HUS/2917/2016 14.12.16/6.2.17/14.6.2017) and the Finnish Medicines Agency (Fimea; 136/2015, 25.11.2016 & 30.01.2017, EudraCT 2015-002556-27). We obtained written informed consent from the patients before surgery. This manuscript adheres to the applicable Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. A data analysis and statistical plan for the present post hoc study were written after the data for the main ALBICS study were accessed.
Trial intervention and patient care
The trial intervention comprised two phases conducted in a blinded fashion: 1) CPB priming (1,500 mL) and 2) intravenous volume replacement therapy (up to 3,200 mL) intraoperatively and during the first 24 postoperative hr. The Ringer’s group received Ringer’s acetate solution (RingerAcetat Baxter Viaflo®, Baxter Oy, Helsinki, Finland) in both phases. For CPB priming, the albumin group received a mixture of 20% albumin solution (Albuman® 200 mg·mL−1, Prothya Biosolutions, Amsterdam, Netherlands) and Ringer’s acetate solution, adjusted to a final albumin concentration of 4%. For intravenous volume replacement, the albumin group received 4% albumin solution (Albuman 40 mg·mL−1). Ringer’s acetate solution was administered in an unblinded fashion in both study groups if more than 3,200 mL of volume replacement was needed. Otherwise, patient care followed the standard clinical practice of the study site.
We performed CPB using a nonpulsatile pump and membrane oxygenator at mild hypothermia. The use of blood products, coagulation factor concentrates, and antifibrinolytics was based on clinical judgement. Tranexamic acid 1 g iv was typically given during anesthesia induction, and a second dose of 1 g iv at initiation of CPB. Clinical judgement guided the additional doses of tranexamic acid after CPB. The initial heparin dose was typically 300 IU·kg–1 iv. We administered additional heparin boluses to maintain activated clotting time over 480 sec. After CPB, 1 mg of protamine per 100 IU of heparin was typically administered iv. The anesthesiologist retransfused the residual volume of the CPB circuit into the patient after CPB.
According to institutional practice, management of postoperative bleeding after cardiac surgery in the intensive care unit necessitated RBC transfusion for hematocrit < 30%, administration of platelets for platelet count < 100 × 109·L−1, and administration of fibrinogen concentrate for a plasma fibrinogen level < 1.5 g·L−1.
Blood samples and laboratory analyses
The study nurse collected arterial blood samples into tubes containing 3.2% sodium citrate (BD Vacutainer Citrate, Becton Dickinson Finland, Vantaa, Finland) before anesthesia induction (“preoperative”) and 30 min after protamine administration (“post-CPB”). Plasma was separated in the hospital laboratory at 2,500 × g for 15 min and stored at −80 °C until analyzed. We used preoperative plasma samples for the analysis of plasma fibrinogen levels and post-CPB plasma samples for the analyses of plasma fibrinogen levels, activated partial thromboplastin time (aPTT), and international normalized ratio (INR). Preoperative hematocrit, platelet count, aPTT, and INR were analyzed as part of the clinical routine at the preoperative anesthesia screening. The plasma fibrinogen level was analyzed with the Clauss method (normal range, 2.0–4.0 g·L−1), platelet count with impedance and flow cytometry particle count (normal range, 150–360 × 109·L−1), and aPTT with direct coagulation time measurement (normal range, 28–37 sec). INR was calculated from prothrombin time (PT) measured with the Owren method (normal range, 0.7–1.2) in the hospital laboratory. All coagulation parameters were measured with ACL TOP 500 (Instrumentation Laboratory, Werfen, Barcelona, Spain). Perioperative hematocrit was analyzed with an arterial blood gas analyzer (ABL90 Flex Plus, Radiometer, Turku, Finland).
Preoperatively, 1,336 plasma fibrinogen concentration, 1,382 platelet count, 1,268 aPTT, and 1,385 INR analyses were performed. The corresponding numbers for post-CPB analyses were 1,319 for plasma fibrinogen concentration, 1,317 for aPTT, and 1,319 for INR. Blood samples were collected consistently from all patients, but a small number of plasma samples were lost during storage.
Universal Definition of Perioperative Bleeding classification
To define severe perioperative bleeding, we used two dichotomous outcome measures based on the UDPB classification.17 First, we classified patients as UDPB-high (classes 3 and 4) vs UDPB-low (classes 0–2). Second, we divided patients according to resternotomy for bleeding, as defined in the UDPB classification. According to the classification, all patients with resternotomy were included in the category of UDPB-high. Blood products, coagulation factor concentrates, and resternotomy were accounted for from the cessation of CPB to the first 24 hr postoperatively. We accounted for chest tube drainage for the first 12 hr postoperatively.17
Statistical analysis
The study nurses or the study-specific IT application prospectively collected all data of this post hoc study of the ALBICS trial. The amount of missing data was low and random in nature. We did not impute missing data. We tested differences in continuous variables between two groups with Student’s t test and correlations between continuous variables with Pearson’s test. Fisher’s exact test was used to test for associations between two categorical variables. In multivariable logistic regression, we used variance inflation factor analysis to check for multicollinearity. We constructed two multivariable models for UDPB-high and resternotomy: 1) plasma fibrinogen level and standard hemostatic laboratory parameters (INR, aPTT, hematocrit, and platelet count), to study the predictive power of plasma fibrinogen levels in relation to other commonly used hemostatic laboratory parameters and 2) plasma fibrinogen levels and clinical risk factors of perioperative bleeding, detected previously in the multivariable analysis of the ALBICS cohort (age, body mass index, preoperative use of acetylsalicylic acid, ALBICS study group allocation, complex surgery, and urgent surgery),19 to study whether plasma fibrinogen levels carry an independent risk beyond preoperative risk factors for bleeding. We also constructed analogous multivariable models, including CPB time in addition to the variables mentioned above. We included all variables in the multivariable analysis irrespective of the significance levels in the univariable regression analyses.
We present results as mean and standard deviation (SD), frequency and proportion, or odds ratio (OR) and 95% confidence interval (CI). Odds ratios for continuous variables are expressed as per SD. For comparability between preoperative and postoperative laboratory measurements, preoperative SDs were also used for postoperative ORs. We considered a two-sided P value of < 0.05 statistically significant. We conducted statistical analyses with IBM SPSS Statistics version 28 software (IBM Corp., Armonk, NY, USA).
Results
Patient and surgical characteristics and bleeding outcomes
Table 1 presents the baseline patient and surgical characteristics. Cardiopulmonary bypass time was 109 (42) min. The ORs of CPB time were 1.53 (95% CI, 1.30 to 1.79; P < 0.001; per SD [42 min]) for UDPB-high and 1.33 (95% CI, 1.06 to 1.68; P = 0.02; per SD [42 min]) for resternotomy. In the entire patient cohort of 1,386 patients, according to UDPB classification, bleeding was insignificant in 786 (56.7%), mild in 167 (12.0%), moderate in 321 (23.2%), severe in 102 (7.4%), and massive in 10 (0.7%) patients. Consequently, 1,274 (91.9%) patients were classified into the category of UDPB-low (i.e., insignificant, mild, or moderate bleeding) and 112 (8.1%) patients into the category of UDPB-high (i.e., severe or massive bleeding). Fifty (3.6%) patients underwent resternotomy for bleeding. In 17 (34%) of these patients, a surgical bleeding site was identified.
Table 1.
Patient and surgical characteristics
| Albumin group | Ringer’s group | P value | |
|---|---|---|---|
| N = 693 | N = 693 | ||
| Male, n (%) | 549 (79.2%) | 542 (78.2%) | 0.69 |
| Age (yr), mean (SD) | 65 (10) | 65 (10) | 0.99 |
| BMI (kg·m−2), mean (SD) | 28.1 (4.8) | 27.7 (4.7) | 0.15 |
| Preoperative use of ASA, n/total N (%) | 386 (55.7%) | 370 (53.4%) | 0.42 |
| Preoperative albumin (g·L−1), mean (SD) | 38.7 (4.5) | 38.3 (5.0) | 0.17 |
| Preoperative GFR (CKD-EPI, mL·min–1·1.73 m−2), mean (SD) | 80 (17) | 80 (17) | 0.54 |
| Preoperative hemoglobin (g·L−1), mean (SD) | 141 (13) | 141 (13) | 0.78 |
| Preoperative hematocrit (%), mean (SD) | 42.3 (3.8) | 42.2 (3.8) | 0.86 |
| Preoperative plasma fibrinogen level (g·L−1), mean (SD) | 3.3 (0.9) | 3.3 (0.9) | 0.87 |
| Preoperative platelet count (109·L−1), mean (SD) | 231 (67) | 230 (64) | 0.83 |
| Preoperative INR, mean (SD) | 1.1 (0.3) | 1.1 (0.3) | 0.90 |
| Preoperative aPTT (sec), mean (SD) | 32 (7) | 32 (7) | 0.18 |
| Post-CPB hematocrit (%), mean (SD) | 28.3 (2.9*) | 31.0 (3.1*) | < 0.01 |
| Post-CPB plasma fibrinogen level (g·L−1), mean (SD) | 2.0 (0.5*) | 2.3 (0.6*) | < 0.001 |
| Post-CPB INR, mean (SD) | 1.4 (0.2*) | 1.3 (0.2*) | < 0.001 |
| Post-CPB aPTT (sec), mean (SD) | 32.0 (7.3) | 31.9 (7.2) | 0.82 |
| CPB time (min), mean (SD) | 109 (40) | 110 (44) | 0.54 |
| Aortic cross-clamp time (min), mean (SD) | 81 (33) | 82 (34) | 0.83 |
| Urgent surgery†, n (%) | 197 (28.4%) | 185 (26.7%) | 0.51 |
| Complex surgery‡, n (%) | 209 (30.2%) | 230 (33.2%) | 0.25 |
| EuroSCORE II (%), mean (SD) | 2.6 (2.9) | 2.6 (3.5) | 0.80 |
| CABG procedure, n (%) | 413 (59.6%) | 409 (59.0%) | 0.87 |
| CABG-only procedure, n (%) | 322 (46.6%) | 304 (43.9%) | 0.36 |
| Aortic valve replacement or repair procedure, n (%) | 89 (12.8%) | 95 (13.7%) | 0.64 |
| Mitral valve replacement or repair procedure, n (%) | 72 (10.4%) | 63 (9.1%) | 0.47 |
| Ascending aortic or aortic root procedure, n (%) | 23 (3.3%) | 29 (4.2%) | 0.48 |
| Other/multiple procedures, n (%) | 128 (18.5%) | 131 (18.9%) | 0.89 |
Continuous variables are expressed as mean (SD) and categorical as numbers and proportions in percentages. “Post-CPB” refers to 30 min after the administration of protamine in the operating room.
*Preoperative vs post-CPB, P < 0.001; Student’s t test
†Urgent surgery, all nonelective procedures, as defined in EuroSCORE II
‡Complex surgery, other than CABG only or a single-valve operation
aPTT = activated partial thromboplastin time; ASA = acetylsalicylic acid; BMI = body mass index; CABG = coronary artery bypass grafting; CPB = cardiopulmonary bypass; EuroSCORE = European System for Cardiac Operative Risk Evaluation; GFR = glomerular filtration rate; INR = international normalized ratio
Preoperative plasma fibrinogen level
Preoperative plasma fibrinogen levels had only a weak inverse correlation with 12 hr postoperative chest tube drainage (Fig. 1A). Ninety out of 1,336 (6.7%) patients had a preoperative plasma fibrinogen level > 4.7 g·L−1. None of these patients were classified as UDPB-high or underwent resternotomy for bleeding (Fig. 2A, B). Since the number of patients classified into the UDPB-high category or those requiring resternotomy was low, a comparison of distributions of preoperative plasma fibrinogen level between patients with and without these outcomes is difficult. Therefore, we divided patients into four quartiles. The proportion of patients classified as UDPB-high did not differ between the preoperative plasma fibrinogen quartiles (Fig. 2C). Patients in the highest quartile underwent resternotomy less often than patients in the other quartiles (Fig. 2D). The mean (SD) preoperative plasma fibrinogen level was 2.8 (0.6) g·L−1 in the patients with a surgical bleeding site in resternotomy and 3.0 (0.6) g·L−1 in the rest of the patients who underwent resternotomy (P = 0.45).
Fig. 1.
Correlation of preoperative (A) and post-CPB (B) plasma fibrinogen levels with postoperative 12-hr chest tube drainage. Horizontal grey line indicates UDPB class 1 or higher, i.e., 12-hr chest tube drainage of > 600 mL. Post-CPB refers to 30 min after the administration of protamine in the operating room.
UDPB = Universal Definition of Perioperative Bleeding
Fig. 2.
Preoperative plasma fibrinogen and UDPB-high (n = 112) vs UDPB-low (n = 1,274) (A), preoperative plasma fibrinogen and resternotomy (n = 50) vs no resternotomy (n = 1,336) (B), preoperative plasma fibrinogen in quartiles and incidence of UDPB-high (C), and preoperative plasma fibrinogen in quartiles and incidence of resternotomy (D)
*P < 0.05
**P < 0.01 (UDPB-high vs UDPB-low or resternotomy vs no resternotomy)
UDPB-high = Universal Definition of Perioperative Bleeding class 3 or 4; UDPB-low = Universal Definition of Perioperative Bleeding classes 0–2
In multivariable analyses, among hemostatic laboratory values, preoperative plasma fibrinogen, and INR levels were the strongest predictors for UDPB-high and resternotomy (Tables 2 and 3). When we added the preoperative plasma fibrinogen level to a multivariable logistic regression model together with clinical risk factors of bleeding,19 the preoperative plasma fibrinogen level was an independent predictor of UDPB-high (Table 4) and resternotomy for bleeding (Table 5).
Table 2.
Univariable and multivariable logistic regression of hemostatic laboratory variables in the prediction of Universal Definition of Perioperative Bleeding-high (n = 112)
| Platelet count (109·L−1) 231 (65)* |
Plasma fibrinogen (g·L−1) 3.3 (0.9)* |
INR 1.1 (0.3)* |
aPTT (sec) 32.0 (7.2)* |
Hematocrit (%) 42.2 (3.8)* |
|||
|---|---|---|---|---|---|---|---|
| Preoperative | Univariable | OR (95% CI) | 0.93 (0.76 to 1.13) | 0.76 (0.60 to 0.95) | 1.24 (1.06 to 1.45) | 1.04 (0.90 to 1.19) | 1.07 (0.88 to 1.31) |
| P value | 0.45 | 0.01 | 0.001 | 0.61 | 0.49 | ||
| Multivariable | OR (95% CI) | 1.07 (0.86 to 1.31) | 0.77 (0.60 to 0.98) | 1.25 (1.05 to 1.49) | 1.03 (0.84 to 1.26) | 0.99 (0.80 to 1.22) | |
| P value | 0.56 | 0.04 | 0.01 | 0.79 | 0.90 | ||
| Post-CPB | Univariable | OR (95% CI) | 0.43 (0.29 to 0.66) | 1.67 (1.25 to 2.22) | 1.25 (1.11 to 1.40) | 0.71 (0.57 to 0.90) | |
| P value | < 0.001 | < 0.001 | < 0.001 | 0.005 | |||
| Multivariable | OR (95% CI) | 0.51 (0.33 to 0.77) | 1.36 (0.97 to 1.90) | 1.22 (1.08 to 1.38) | 0.78 (0.60 to 0.99) | ||
| P value | < 0.001 | 0.07 | 0.002 | 0.04 |
For comparability, both preoperative and post-CPB ORs are calculated per preoperative SDs. All variables used in univariable analyses were included in the multivariable regression analysis. “Post-CPB” refers to 30 min after the administration of protamine in the operating room.
*The levels of the parameters are expressed as preoperative mean (SD)
aPTT = activated partial thromboplastin time; CI = confidence interval; INR = international normalized ratio; OR = odds ratio; SD = standard deviation
Table 3.
Univariable and multivariable logistic regression of hemostatic laboratory variables in the prediction of resternotomy (n = 50)
| Platelet count (109·L−1) 231 (65)* |
Plasma fibrinogen (g·L−1) 3.3 (0.9)* |
INR 1.1 (0.3)* |
aPTT (sec) 32.0 (7.2)* |
Hematocrit (%) 42.2 (3.8)* |
|||
|---|---|---|---|---|---|---|---|
| Preoperative | Univariable | OR (95% CI) | 0.65 (0.46 to 0.91) | 0.59 (0.41 to 0.86) | 1.30 (1.07 to 1.59) | 0.99 (0.77 to 1.28) | 0.89 (0.77 to 1.36) |
| P value | 0.01 | 0.006 | 0.009 | 0.97 | 0.89 | ||
| Multivariable | OR (95% CI) | 0.83(0.58 to 1.20) | 0.65 (0.43 to 0.98) | 1.32(1.02 to 1.70) | 0.91 (0.59 to 1.41) | 0.93 (0.68 to 1.28) | |
| P value | 0.32 | 0.04 | 0.03 | 0.68 | 0.65 | ||
| Post-CPB | Univariable | OR (95% CI) | 0.24 (0.12 to 0.49) | 1.82 (1.25 to 2.64) | 1.19 (1.01 to 1.41) | 0.58 (0.41 to 0.82) | |
| P value | < 0.001 | 0.002 | 0.04 | 0.002 | |||
| Multivariable | OR (95% CI) | 0.31 (0.16 to 0.62) | 1.51 (0.96 to 2.37) | 1.15 (0.96 to 1.37) | 0.70 (0.49 to 1.01) | ||
| P value | < 0.001 | 0.07 | 0.13 | 0.06 |
For comparability, both preoperative and post-CPB ORs are calculated per preoperative SDs. All variables used in univariable analyses were included in the multivariable regression analysis. “Post-CPB” refers to 30 min after the administration of protamine in the operating room.
*The levels of the parameters are expressed as preoperative mean (SD)
aPTT = activated partial thromboplastin time; CI = confidence interval; CPB = cardiopulmonary bypass; INR = international normalized ratio; OR = odds ratio; SD = standard deviation
Table 4.
Univariable and multivariable logistic regression analyses of preoperative and postcardiopulmonary bypass plasma fibrinogen levels and clinical risk factors of severe bleeding in the prediction of the Universal Definition of Perioperative Bleeding-high
| Urgent surgery* (n = 382) | Complex surgery† (n = 439) | Albumin study group (n = 693) | Preoperative use of ASA (n = 756) | BMI (kg·m−2) 27.9 (4.8)‡ | Age (yr) 65.4 (9.9)‡ | Post-CPB plasma fibrinogen (g·L−1) 2.1 (0.6)‡ | Preoperative plasma fibrinogen (g·L−1) 3.3 (0.9)‡ | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Univariable | OR (95% CI) | 1.45 (0.96 to 2.18) | 2.07 (1.40 to 3.05) | 2.70 (1.76 to 4.12) | 1.49 (0.99 to 2.22) | 0.73 (0.59 to 0.90) | 1.06 (0.87 to 1.29) | 0.43 (0.29 to 0.66 | 0.76 (0.60 to 0.95) | |
| P value | 0.07 | < 0.001 | < 0.001 | 0.05 | 0.004 | 0.59 | < 0.001 | 0.01 | ||
| Multivariable | Preoperative | OR (95% CI) | 1.76 (1.10 to 2.84) | 2.98 (1.90 to 4.67) | 2.81 (1.82 to 4.36) | 2.36 (1.46 to 3.81) | 0.76 (0.60 to 0.96) | 0.96 (0.78 to 1.18) | 0.73 (0.57 to 0.94) | |
| P value | 0.02 | < 0.001 | < 0.001 | < 0.001 | 0.02 | 0.71 | 0.01 | |||
| Post-CPB | OR (95% CI) | 1.84 (1.14 to 2.98) | 2.87 (1.82 to 4.53) | 2.44 (1.53 to 3.89) | 2.29 (1.40 to 3.73) | 0.78 (0.61 to 0.99) | 0.96 (0.78 to 1.19) | 0.54 (0.35 to 0.85) | ||
| P value | 0.01 | < 0.001 | < 0.001 | < 0.001 | 0.05 | 0.71 | 0.01 |
All variables used in univariable analyses were included in the multivariable regression analysis. ORs for continuous variables are calculated per SD. For comparability, ORs for both preoperative and post-CPB plasma fibrinogen were calculated using preoperative SD. “Post-CPB” refers to 30 min after the administration of protamine in the operating room.
*Urgent surgery: all nonelective procedures, as defined in EuroSCORE II
†Complex surgery: all procedures other than isolated CABG or valve procedure
‡The levels of the continuous parameters are expressed as mean (SD)
ASA = acetylsalicylic acid; BMI = body mass index; CABG: coronary artery bypass grafting; CPB = cardiopulmonary bypass; CI = confidence interval; EuroSCORE = European System for Cardiac Operative Risk Evaluation; OR = odds ratio; SD = standard deviation
Table 5.
Univariable and multivariable logistic regression analyses of preoperative and postcardiopulmonary bypass plasma fibrinogen levels and clinical risk factors of severe bleeding in the prediction of resternotomy for bleeding
| Urgent surgery* (n = 382) | Complex surgery† (n = 439) | Albumin study group (n = 693) | Preoperative use of ASA (n = 756) | BMI (kg·m−2) 27.9 (4.8)‡ | Age (yr) 65.4 (9.9)‡ | Post-CPB plasma fibrinogen (g·L−1) 2.1 (0.6)‡ | Preoperative plasma fibrinogen (g·L−1) 3.3 (0.9)‡ | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Univariable |
OR (95% CI) |
1.13 (0.61 to 2.10) |
1.88 (1.07 to 3.33) |
2.95 (1.56 to 5.60) |
1.50 (0.84 to 2.7) |
0.68 (0.49 to 0.94) |
1.08 (0.81 to 1.45) |
0.24 (0.12 to 0.49) |
0.59 (0.41 to 0.86) |
|
| P value | 0.69 | 0.03 | < 0.001 | 0.17 | 0.02 | 0.59 | < 0.001 | 0.006 | ||
| Multivariable | Preoperative |
OR (95% CI) |
1.33 (0.66 to 2.70) |
2.34 (1.23 to 4.46) |
2.88 (1.49 to 5.56) |
2.52 (1.25 to 5.10) |
0.72 (0.51 to 1.03) |
1.03 (0.76 to 1.40) |
0.60 (0.40 to 0.90) |
|
| P value | 0.43 | 0.01 | 0.002 | 0.01 | 0.08 | 0.84 | 0.01 | |||
| Post-CPB |
OR (95% CI) |
1.34 (0.66 to 2.69) |
2.04 (1.08 to 3.87) |
2.45 (1.22 to 4.91) |
2.07 (1.04 to 4.11) |
0.78 (0.55 to 1.12) |
1.10 (0.80 to 1.51) |
0.34 (0.16 to 0.72) |
||
| P value | 0.42 | 0.03 | 0.01 | 0.04 | 0.19 | 0.55 | 0.005 |
All variables used in univariable analyses were included in the multivariable regression analysis. ORs for continuous variables are calculated per SD. For comparability, ORs for both preoperative and post-CPB plasma fibrinogen were calculated using preoperative SD. “Post-CPB” refers to 30 min after the administration of protamine in the operating room.
*Urgent surgery: all nonelective procedures, as defined in EuroSCORE II
†Complex surgery: all procedures other than isolated CABG or valve procedure
‡The levels of the continuous parameters are expressed as mean (SD)
ASA = acetylsalicylic acid; BMI = body mass index; CABG = coronary artery bypass grafting; CPB = cardiopulmonary bypass; CI = confidence interval; EuroSCORE = European System for Cardiac Operative Risk Evaluation; OR = odds ratio; SD = standard deviation
The corresponding multivariable analyses including CPB time are presented in Electronic Supplementary Material (ESM) eTables 1–4.
Postcardiopulmonary bypass plasma fibrinogen level
The post-CPB plasma fibrinogen level had only a weak inverse correlation with 12-hr postoperative chest tube drainage (Fig. 1B). Of the 1,319 patients, 73 (5.5%) had a post-CPB plasma fibrinogen level > 3.1 g·L−1. None of these patients were classified as UDPB-high or underwent resternotomy for bleeding (Fig. 3A, B). We divided patients into four quartiles based on post-CPB plasma fibrinogen level. The proportion of patients classified as UDPB-high, and the proportion of patients who underwent resternotomy decreased steadily from the lowest quartile of postoperative plasma fibrinogen towards the highest (Fig. 3C, D). In multivariable analysis, among hemostatic laboratory values, the plasma fibrinogen level was the strongest predictor for UDPB-high and resternotomy (Tables 2 and 3). When we added the post-CPB plasma fibrinogen level to a multivariable logistic regression model together with clinical risk factors of bleeding,19 post-CPB plasma fibrinogen level was an independent predictor of UDPB-high (Table 4) and resternotomy for bleeding (Table 5). The mean (SD) post-CPB plasma fibrinogen level was 1.8 (0.4) g·L−1 in the patients with a surgical bleeding site in resternotomy and 1.8 (0.4) g·L−1 in the rest of the patients with resternotomy (P = 0.86).
Fig. 3.
Post-CPB plasma fibrinogen and UDPB-high (n = 112) vs UDPB-low (n = 1,274) (A), post-CPB plasma fibrinogen and resternotomy (n = 50) vs no resternotomy (n = 1,336) (B), post-CPB plasma fibrinogen in quartiles and incidence of UDPB-high (C), and post-CPB plasma fibrinogen in quartiles and incidence of resternotomy (D). “Post-CPB” refers to 30 min after the administration of protamine in the operating room.
***P < 0.001 (UDPB-high vs UDPB-low or resternotomy vs no resternotomy)
UDPB-high = Universal Definition of Perioperative Bleeding class 3 or 4; UDPB-low = Universal Definition of Perioperative Bleeding classes 0–2
The corresponding multivariable analyses including CPB time are presented in ESM eTables 5–8.
Administration of fibrinogen concentrate in the operating room
Altogether, 39 patients (2.8%) received fibrinogen concentrate in the operating room after weaning from CPB. Of these, 14 were classified as UDPB-high and 25 as UDPB-low. Eight patients classified as UDPB-high underwent resternotomy before and one patient after the transfer to the intensive care unit. When we excluded the patients who had received fibrinogen concentrate post-CPB, post-CPB hematocrit did not independently predict the UDPB-high class in the multivariable model including the post-CPB plasma fibrinogen level and post-CPB standard hemostatic parameters. Otherwise, all results concerning post-CPB plasma fibrinogen levels remained the same (data not shown).
Discussion
The current post hoc analysis of the recent ALBICS trial of 1,386 patients who underwent on-pump cardiac surgery is based on prospectively collected blood samples and prospectively collected data for the UDPB classification. The main finding was a clinically meaningful association of plasma fibrinogen level measured after weaning from CPB (post-CPB) with severe bleeding (UDPB classes 3 and 4) and resternotomy for bleeding.
Although fibrinogen supplementation is widely used in cardiac surgery, the relationship between plasma fibrinogen level and perioperative bleeding is thus far inadequately understood. In all observational studies with a larger sample size (over 200 patients), plasma fibrinogen levels were associated only weakly with chest tube drainage.1,3,5–7 Furthermore, not only hypofibrinogenemia but also hyperfibrinogenemia associated with a need for RBC transfusions,1–3 incidence of resternotomy for bleeding,1 and severe bleeding according to the UDPB classification.8 Finally, only 3 out of the 7 published clinical trials on fibrinogen supplementation in cardiac surgery favored fibrinogen supplementation.9–15
In agreement with previous findings,1,3,5–7 we observed only weak associations of either preoperative (R = −0.10) or postoperative (R = −0.21) plasma fibrinogen levels with chest tube drainage. In the current study, we also assessed bleeding with the UDPB classification and further divided this into low (classes 0–2) vs high (classes 3 and 4) bleeding.8 Preoperative plasma fibrinogen levels had a moderate association with severe bleeding, reflected by adjusted ORs per SD of 0.77 for UDPB-high and 0.65 for resternotomy. Since the number of patients classified into the UDPB-high category or requiring resternotomy was low, a comparison of distributions of plasma fibrinogen levels between patients with and without these outcomes is difficult. Therefore, we divided patients into four plasma fibrinogen quartiles, from lowest to highest concentrations. We found no differences in the proportion of patients in the UDPB-high category between the quartiles of preoperative plasma fibrinogen, suggesting no difference in preoperative plasma fibrinogen distribution between patients who were UDPB-high and UDPB-low. Resternotomy rate was significantly lower only in the highest preoperative plasma fibrinogen quartile. Taken together, the association of the preoperative plasma fibrinogen level with severe bleeding was weak. In contrast, for the post-CPB plasma fibrinogen level, the proportion of patients in the UDPB-high category and the incidence of resternotomy decreased steadily with every increasing plasma fibrinogen quartile. This was reflected as low adjusted ORs per SD of 0.51 for UDPB-high and 0.31 for resternotomy. These associations can be regarded as strong.
The current study has clinical implications. First, a preoperatively measured plasma fibrinogen level does not substitute for measuring the post-CPB plasma fibrinogen level in patients bleeding after weaning from CPB. Second, most of the patients who had a low preoperative plasma fibrinogen level did not experience severe bleeding. Therefore, we suggest that fibrinogen should not be administered prophylactically,16 and fibrinogen supplementation should not be based solely on the measurement of preoperative plasma fibrinogen levels.
Previously, a high plasma fibrinogen level has been associated with increased RBC transfusions in on-pump cardiac surgery.1,2,21 Nevertheless, this association disappeared when confounding factors, such as older age, preoperative anemia, the urgency of operation, long CPB time, and P2Y12 inhibitor use, were included.21 Hyperfibrinogenemia was also associated with increased incidences of both resternotomy for bleeding and UDPB classes 3 and 4, but these findings were not confirmed in multivariable analysis.1,8 In comparison, in the ALBICS trial cohort, the associations of preoperative and postoperative plasma fibrinogen levels with UDPB-high and resternotomy persisted, even after adjusting for clinical risk factors of bleeding.19 We conclude that a high plasma fibrinogen level improves hemostasis in cardiac surgery. Previous opposite findings of increased risk for resternotomy or UDPB classes 3 and 4 in patients with a high plasma fibrinogen level might be secondary to risk factors associated with both bleeding and increased plasma fibrinogen levels, such as older age.1,22
To our knowledge, 7 placebo-controlled randomized trials have studied the use of fibrinogen concentrates for preventing perioperative bleeding in cardiac surgery.9–15 Only 3 reported a positive effect,9,10,13 which is surprising in the context of the established use of fibrinogen supplementation in cardiac surgery but perhaps reflects difficulties in designing fibrinogen trials. We propose the following implications for future fibrinogen trials based on the findings of the current study. First, we suggest that fibrinogen doses in trial interventions be high enough to raise plasma levels near to the upper margin of the normal reference range. Fibrinogen doses have varied in published trials, with 4 using a fixed or mean dose between 1 g and 3.1 g,11,13–15 which raises the plasma fibrinogen level only approximately 1.0–1.5 g·L−1.23 Second, in our study, only 8.1% of patients with normal preoperative plasma fibrinogen levels were subsequently classified as UDPB-high. To prevent low-incidence complications, such as severe postoperative bleeding or resternotomy, with prophylactic fibrinogen supplementation in unselected cardiac surgical populations, studies would require considerably higher patient numbers to gain sufficient statistical power. We suggest that future trials recruit only patients objectively bleeding after weaning from CPB. Although this strategy was beneficial in a single-centre pilot trial,9 objective measurement of bleeding proved challenging in a multicenter trial.12,24
This study has limitations. First, while preoperative platelet count was analyzed, we did not measure platelet count or function assays after CPB. Therefore, we could not define the predictive value of postoperative platelet count or function on bleeding. Second, since we measured the post-CPB fibrinogen level 30 min after protamine administration, fibrinogen supplementation for bleeding after heparin reversal but before blood sampling may have affected our results. Nevertheless, the number of patients receiving fibrinogen concentrate in the operating room was low;19 their exclusion did not change the results. Third, rather than a predefined transfusion algorithm, transfusions followed hospital guidelines. Fourth, as the ALBICS study consisted of patients with low risk, the findings of the current study may not be generalizable to patients with high risk undergoing cardiac surgery. Fifth, the results of the current study may not be generalizable to operations with extended CPB times. As a strength, a large data set including all components of the UDPB classification was prospectively collected in detail by study personnel with an IT application to ensure validity. Also, UDPB classification and resternotomy are clinically meaningful and highly relevant outcome measures for bleeding, although as a limitation, the UDPB classification does not separately identify resternotomies performed for a surgical bleeding site.
In conclusion, in the ALBICS trial cohort, low plasma fibrinogen levels after weaning from CPB were associated to a clinically meaningful extent with severe bleeding. A preoperatively measured plasma fibrinogen level, owing to only weak association with severe bleeding, does not substitute for measuring the plasma fibrinogen level after weaning from CPB. These findings may also have implications for the study design of future randomized controlled trials on fibrinogen supplementation in on-pump cardiac surgery.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
Author contributions
Akseli Talvasto contributed to laboratory analyses, statistical analyses, data interpretation, and manuscript writing. Peter Raivio contributed to study design, data acquisition, data interpretation, and manuscript revision. Minna Ilmakunnas contributed to study design, data interpretation, and manuscript revision. Erika Wilkman, Hanna Vlasov, Raili Suojaranta, Seppo Hiippala, and Tatu Juvonen contributed to study design, data acquisition, and manuscript revision. Liisa Petäjä contributed to data acquisition and manuscript revision. Otto Helve contributed to laboratory analyses and manuscript revision. Eero Pesonen contributed to financing, study design, data interpretation, and manuscript revision. All authors approved the publishing of the manuscript.
Acknowledgements
The present study was supported by the Helsinki University Hospital Research Fund and Finnish Foundation for Cardiovascular Research.
Disclosures
Prothya Biosolutions (the manufacturer of Albuman; formerly Sanquin Plasma Products; Amsterdam, Netherlands) supported the ALBICS trial.
Funding statement
Open Access funding provided by University of Helsinki (including Helsinki University Central Hospital).
Generative AI tools use
None.
Editorial responsibility
This submission was handled by Dr. Philip M. Jones, Deputy Editor-in-Chief, Canadian Journal of Anesthesia/Journal canadien d’anesthésie.
Footnotes
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