A European consensus statement on the use of four-factor prothrombin complex concentrate for cardiac and non-cardiac surgical patients.

Modern four-factor prothrombin complex concentrate was designed originally for rapid targeted replacement of the coagulation factors II, VII, IX and X. Dosing strategies for the approved indication of vitamin K antagonist-related bleeding vary greatly. They include INR and bodyweight-related protocols as well as fixed dose regimens. Particularly in the massively bleeding trauma and cardiac surgery patient, four-factor prothrombin complex concentrate is used increasingly for haemostatic resuscitation. Members of the Transfusion and Haemostasis Subcommittee of the European Association of Cardiothoracic Anaesthesiology performed a systematic literature review on four-factor prothrombin complex concentrate. The available evidence has been summarised for dosing, efficacy, drug safety and monitoring strategies in different scenarios. Whereas there is evidence for the efficacy of four-factor prothrombin concentrate for a variety of bleeding scenarios, convincing safety data are clearly missing. In the massively bleeding patient with coagulopathy, our group recommends the administration of an initial bolus of 25 IU.kg-1 . This applies for: the acute reversal of vitamin K antagonist therapy; haemostatic resuscitation, particularly in trauma; and the reversal of direct oral anticoagulants when no specific antidote is available. In patients with a high risk for thromboembolic complications, e.g. cardiac surgery, the administration of an initial half-dose bolus (12.5 IU.kg-1 ) should be considered. A second bolus may be indicated if coagulopathy and microvascular bleeding persists and other reasons for bleeding are largely ruled out. Tissue-factor-activated, factor VII-dependent and heparin insensitive point-of-care tests may be used for peri-operative monitoring and guiding of prothrombin complex concentrate therapy.

The role of fibrinogen and fibrinogen concentrate in cardiac surgery: an international consensus statement from the Haemostasis and Transfusion Scientific Subcommittee of the European Association of Cardiothoracic Anaesthesiology.

To date, data regarding the efficacy and safety of administering fibrinogen concentrate in cardiac surgery are limited. Studies are limited by their low sample size and large heterogeneity with regard to the patient population, by the timing of fibrinogen concentrate administration, and by the definition of transfusion trigger and target levels. Assessment of fibrinogen activity using viscoelastic point-of-care testing shortly before or after weaning from cardiopulmonary bypass in patients and procedures with a high risk of bleeding appears to be a rational strategy. In contrast, the use of Clauss fibrinogen test for determination of plasma fibrinogen level can no longer be recommended without restrictions due to its long turnaround time, high inter-assay variability and interference with high heparin levels and fibrin degradation products. Administration of fibrinogen concentrate for maintaining physiological fibrinogen activity in the case of microvascular post-cardiopulmonary bypass bleeding appears to be indicated. The available evidence does not suggest aiming for supranormal levels, however. Use of cryoprecipitate as an alternative to fibrinogen concentrate might be considered to increase plasma fibrinogen levels. Although conclusive evidence is lacking, fibrinogen concentrate does not seem to increase adverse outcomes (i.e., thromboembolic events). Large prospective multi-centre studies are needed to better define the optimal perioperative monitoring tool, transfusion trigger and target levels for fibrinogen replacement in cardiac surgery.

Microcirculatory changes in children undergoing cardiac surgery: a prospective observational study.

BACKGROUND: The effects of cardiac surgery on the microcirculation of children are unknown. The aim of this study was to assess the microcirculatory changes in children undergoing surgery for correction of congenital heart disease. METHODS: We used a videomicroscope (Sidestream Dark Field, SDF) in a convenience sample of 24 children

Desmopressin after cardiac surgery in bleeding patients. A multicenter randomized trial.

BACKGROUND: Previous studies showed that desmopressin decreases post-operative blood loss in patients undergoing cardiac surgery. These studies were small and never studied the effect of desmopressin in patients with active bleeding. Objective of the study was to determine whether desmopressin reduces red blood cells transfusion requirements in patients with active bleeding after cardiac surgery who had been pre-treated with tranexamic acid. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study randomized elective patients with bleeding after cardiac surgery despite pre-treatment with tranexamic acid, to receive placebo (saline solution) or a single administration of desmopressin (0.3 µg/kg in saline solution). The primary endpoint was the number of patients requiring red blood cells transfusion after randomization and during hospital stay. Secondary end points were: blood loss from chest tubes during the first 24 h after study drug administration, hours of mechanical ventilation, intensive care unit stay, and in-hospital mortality. RESULTS: The study was interrupted after inclusion of 67% of the planned patients for futility. The number of patients requiring red blood cells transfusion after randomization was 37/68 (54%) in desmopressin group and 33/67 (49%) in placebo group (P = 0.34) with no difference in blood loss: 575 (interquartile 422-770) ml in desmopressin group and 590 (476-1013) ml in placebo group (P = 0.42), mechanical ventilation, intensive care unit stay or mortality. CONCLUSIONS: This multicenter randomized trial demonstrated that, in patients pre-treated with tranexamic acid, desmopressin should not be expected to improve treatment of patients who experience bleeding after cardiac surgery.

Fibrinogen supplementation after cardiac surgery: insights from the Zero-Plasma trial (ZEPLAST).

BACKGROUND: Fibrinogen supplementation has been proposed both to prevent and treat postoperative bleeding in cardiac surgery. The optimal fibrinogen concentration trigger and target values and the fibrinogen concentrate dose required remain uncertain. This subanalysis of data from the Zero-Plasma Trial (ZEPLAST) assessed target fibrinogen values and the corresponding fibrinogen concentrate dose for supplementation. METHODS: We performed a post hoc analysis of 116 subjects included in the randomized, placebo-controlled ZEPLAST trail. Data considered were fibrin-based thromboelastometry (FIBTEM) maximum clot firmness (MCF) determined by whole-blood thromboelastometry (ROTEM) before and after placebo or fibrinogen concentrate, Clauss fibrinogen concentration after placebo or fibrinogen concentrate, postoperative bleeding and severe bleeding (SB). The association between FIBTEM MCF and Clauss fibrinogen concentration was tested with linear regression analyses. The predictive value for SB of FIBTEM MCF and Clauss fibrinogen concentration was tested with receiver operating characteristic analyses. RESULTS: There was a good association between FIBTEM MCF and Clauss fibrinogen concentration in the baseline study population (r(2) = 0.66), which worsened in fibrinogen-supplemented subjects. Both FIBTEM MCF and Clauss fibrinogen concentration yielded a good discriminative power for SB (area under the curve 0.721 and 0.767, respectively). The negative predictive value for SB was 100% for a Clauss fibrinogen concentration of 287 mg dl(-1) and 98% for an FIBTEM MCF of 14 mm. Based on these newly defined target values, the dose of fibrinogen concentrate needed would be 3 g lower than the dose used in ZEPLAST. CONCLUSIONS: A dose of fibrinogen concentrate rarely exceeding 2 g might be sufficient to prevent bleeding in cardiac surgery.

Moderate-degree acidosis is an independent determinant of postoperative bleeding in cardiac surgery.

BACKGROUND: Acidosis is a well-known factor leading to coagulopathy. It has been widely explored as a risk factor for severe bleeding in trauma patients. However, no information with respect to acidosis as a determinant of postoperative bleeding in cardiac surgery patients exists. The aim of this study was to investigate the role of acidosis and hyperlactatemia (HL) in determining postoperative bleeding and need for surgical revision in cardiac surgery patients. METHODS: We carried out a retrospective analysis on 4521 patients receiving cardiac operations in two institutions. For each patient the preoperative data and operative profile was available. Arterial blood gas analysis data at the arrival in the intensive care unit were analyzed to investigate the association between acidosis (pH<7.35), HL (>4.0 mMol/L) and postoperative bleeding and surgical revision rate. RESULTS: After correction for the potential confounders, both acidosis (P=0.001) and HL (P=0.001) were significantly associated with the amount of postoperative bleeding. HL was an independent risk factor for postoperative bleeding even in absence of acidosis. Overall, surgical revision rate was 5.6% in patients with HL and no acidosis; 7.7% in patients with acidosis and HL, and 7.2% in patients with acidosis and no HL. All these values are significantly (P=0.001) higher than the ones in patients without acidosis/HL (2%). CONCLUSIONS: Even a moderate degree of postoperative acidosis is associated with a greater postoperative bleeding and surgical revision rate in cardiac surgery patients. Correction of acidosis with bicarbonate does not lead to an improvement of the postoperative bleeding asset.

Pre-operative fibrinogen supplementation in cardiac surgery patients: an evaluation of different trigger values.

BACKGROUND: Pre-operative fibrinogen levels are negatively associated with postoperative bleeding in cardiac surgery patients. The guidelines of the European Society of Anaesthesiology consider the possibility of a prophylactic pre-operative supplementation in patients with fibrinogen levels<`3.8 g/l. The present study is a reanalysis of published data aimed to define the diagnostic accuracy of different values of pre-operative fibrinogen levels in predicting severe post-operative bleeding. METHODS: Data were retrieved for 2154 patients in four different studies. Severe bleeding (SB) was defined as a post-operative chest drain output>1 l/12 h. Diagnostic accuracy for prediction of SB was tested at three cutoff values of pre-operative fibrinogen (2.5 g/l, 3.0 g/l, and 3.8 g/l). RESULTS: At all the three cutoff values, pre-operative fibrinogen levels had an excellent negative predictive value, ranging from 86% to 100%. Conversely, the positive predictive value was poor at all the cutoff levels: 12% (3.8 g/l), 14% (3.0 g/l), and 19% (2.5 g/l). Overall, the accuracy of pre-operative fibrinogen levels for the prediction of SB was poor. A strategy based on pre-operative fibrinogen supplementation would lead to inappropriate treatment in > 80% of the treated patients. Overall, a trigger value of 3.8 g/l would result in an inappropriate treatment in 52% of the patients, of 3.0 g/l in 20% of the patients, and of 2.5 g/l in 4% of the patients. CONCLUSION: Correction of pre-operative fibrinogen levels below 3.8 g/l would lead to an excessive rate of inappropriate interventions. Values below 2.5 g/l could be considered.

Effect of preoperative P2Y12 and thrombin platelet receptor inhibition on bleeding after cardiac surgery.

BACKGROUND: Drugs that act on the platelet P2Y12 receptor are responsible for postoperative bleeding in cardiac surgery. However, protease-activated receptor (PAR) that reacts to thrombin stimulation might still be active in patients treated with P2Y12 inhibitors. Preoperative platelet function testing could possibly guide the timing of surgery. We investigated the association between P2Y12 receptor and PAR inhibition and bleeding after cardiac surgery. METHODS: A retrospective cohort study of 361 patients undergoing cardiac surgery and treated with P2Y12 anti-platelet agents was undertaken. All patients received a preoperative multiplate electrode aggregometry testing of platelet P2Y12 receptor activity (ADPtest) and PAR reactivity with thrombin receptor-activating peptide (TRAP) stimulation. ADPtest and TRAPtest data measured before surgery were analysed for association with postoperative bleeding (ml per 12 h) and severe postoperative bleeding. RESULTS: Both the ADPtest and the TRAPtest were significantly (P=0.001) associated with postoperative bleeding. A threshold of 22 U for the ADPtest yielded a negative predictive value (NPV) of 94% and a positive predictive value (PPV) of 20%, and a threshold of 75 U for the TRAPtest yielded an NPV of 95% and a PPV of 23%. In the subgroup of patients with ADPtest <22 U, TRAPtest ≥75 U was not associated with severe bleeding (NPV of 100% and PPV of 37%). CONCLUSIONS: In patients taking P2Y12 receptor inhibitors, residual platelet reactivity to thrombin stimulation limits the risk of severe postoperative bleeding.