Dietmar Fries

Management of severe perioperative bleeding Guidelines from the European Society of Anaesthesiology

The aims of severe perioperative bleeding management are three-fold. First, preoperative identification by anamesis and laboratory testing of those patients for whom the perioperative bleeding risk may be increased. Second, implementation of strategies for correcting preoperative anaemia and stabilisation of the macro- and microcirculations in order to optimise the patients tolerance to bleeding. Third, targeted procoagulant interventions to reduce the amount of bleeding, morbidity, mortality and costs. The purpose of these guidelines is to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists throughout Europe to integrate this knowledge into daily patient care wherever possible. The Guidelines Committee of the European Society of Anaesthesiology (ESA) formed a task force with members of scientific subcommittees and individual expert members of the ESA. Electronic databases were searched without language restrictions from the year 2000 until 2012. These searches produced 20 664 abstracts. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. At the suggestion of the ESA Guideline Committee, the Scottish Intercollegiate Guidelines Network (SIGN) grading system was initially used to assess the level of evidence and to grade recommendations. During the process of guideline development, the official position of the ESA changed to favour the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. This report includes general recommendations as well as specific recommendations in various fields of surgical interventions. The final draft guideline was posted on the ESA website for four weeks and the link was sent to all ESA members. Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines.

Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration.

BACKGROUND:To explore whether disturbed fibrin polymerization is the main problem underlying dilutional coagulopathy and can be reversed by fibrinogen administration, we conducted a prospective study using modified thrombelastography (ROTEM®). METHODS:Sixty-six orthopedic patients randomly received modified gelatin solution, hydroxyethyl starch 130/0.4, or exclusively Ringer lactate solution. ROTEM® analysis was performed, concentrations of coagulation factors and markers of thrombin generation were measured. Fibrinogen concentrate (Hemocomplettan®) was administered (30 mg/kg) when thrombelastographically measured fibrinogen polymerization was critically decreased. RESULTS:The α angle, clot firmness, and fibrinogen polymerization (median [min to max]) significantly decreased in the patients receiving hydroxyethyl starch (area under the curve minus baseline (−5 [−9 to −2]), followed by gelatin solution (−3 [−8 to 0]), with the least reductions seen for Ringer lactate solution (−2 [− 4 to 1]) (colloids versus Ringer lactate P < 0.0001). Thirteen patients in the colloid groups but none in the Ringer lactate group needed fibrinogen concentrate to maintain borderline clot firmness. Activity of FVII, FVIII, FIX, and von Willebrand ristocetin activity decreased significantly with colloids. Thrombelastographically measured coagulation time, molecular markers of thrombin generation, and activity of all other coagulation factors were comparable in all groups. CONCLUSION:Disturbance of fibrinogen/fibrin polymerization is the primary problem triggering dilutional coagulopathy during major orthopedic surgery. The magnitude of clot firmness reduction is determined by the type of fluid used, with hydroxyethyl starch showing the most pronounced effects. These undesirable effects of intravascular volume therapy can be reversed by increasing fibrinogen concentration by administering fibrinogen concentrate, even during continuing blood loss and intravascular volume replacement.

Risk for postoperative infection after transfusion of white blood cell-filtered allogeneic or autologous blood components in orthopedic patients undergoing primary arthroplasty.

BACKGROUND:  This study was designed to obtain data on the incidence of postoperative infection in patients undergoing elective orthopedic surgery and receiving white blood cell (WBC)‐filtered blood components prepared according to current standards.

The Effect of Fibrinogen Substitution on Reversal of Dilutional Coagulopathy: An In Vitro Model

Colloids and crystalloids are usually administered as treatment for hypovolemia in severely injured patients. However, dilution of clotting factors and platelets together with impaired fibrinogen polymerization are associated with fluid therapy and may aggravate hemorrhage, thus worsening final outcome of these patients. We investigated, in an in vitro model, whether the addition of fibrinogen to diluted blood samples can reverse dilutional coagulopathy. Blood from 5 healthy male volunteers was diluted by 60% using lactated Ringers solution, 4% modified gelatin solution, or 6% hydroxyethyl starch 130/0.4, as well as the combination of lactated Ringers solution with either of the 2 colloid solutions. Thereafter, aliquots of diluted blood samples were incubated with 3 different concentrations of fibrinogen (0.75, 1.5, and 3.0 mg/mL). Measurements were performed by modified thrombelastography (ROTEM®; Pentapharm, Munich, Germany). After 60% dilution, clotting times increased, whereas clot firmness and fibrin polymerization decreased significantly. After administration of fibrinogen, clotting times decreased and clot firmness, as well as fibrin polymerization, increased in all diluted blood samples. The effect of in vitro fibrinogen substitution on ROTEM® variables was dependent on the fibrinogen dosage and the type of solution used to dilute the blood samples.

Role of fibrinogen in trauma-induced coagulopathy

Coagulation defects related to severe trauma, trauma-induced coagulopathy (TIC), have a number of causal factors including: major blood loss with consumption of clotting factors and platelets, and dilutional coagulopathy after administration of crystalloids and colloids to maintain blood pressure. In addition, activation of the fibrinolytic system or hyperfibrinolysis, hypothermia, acidosis, and metabolic changes can also affect the coagulation system. All of these directly affect fibrinogen polymerization and metabolism. Other bleeding-related deficiencies usually develop later in massive bleeding related to severe multiple trauma. In major blood loss, fibrinogen reaches a critical value earlier than other procoagulatory factors, or platelets. The question of the critical threshold value is presently the subject of heated debate. A threshold of 100 mg dl(-1) has been recommended, but recent clinical data have shown that at a fibrinogen level of <150-200 mg dl(-1), there is already an increased tendency to peri- and postoperative bleeding. A high fibrinogen count exerts a protective effect with regard to the amount of blood loss. In multiple trauma patients, priority must be given to early and effective correction of impaired fibrin polymerization by administering fibrinogen concentrate.

The effect of the combined administration of colloids and lactated Ringer's solution on the coagulation system: an in vitro study using thrombelastograph coagulation analysis (ROTEG.

Gelatin solutions are often given in clinical practice once the maximal dose of a median-weight hydroxyethyl starch (HES) has been reached. Colloids are usually combined with lactated Ringer’s solution (RL). Whether the combined administration of colloids and/or crystalloids affects blood coagulation is not known. We diluted blood by 20%, 40%, and 60% with RL, gelatin (Gelofusin®), 6% HES 130/0.4 (Voluven®), and 6% HES 200/0.5 (Iso-Hes®), as well as with combinations of these solutions at a ratio of 1:1 (gelatin/RL, 6% HES 130/0.4:RL, 6% HES 200/0.5:RL, 6% HES 130/0.4:gelatin, 6% HES 200/0.5:gelatin). Thereafter, blood was analyzed by using modified thrombelastograph® coagulation analysis (ROTEG®) and clotting time, clot formation time, and maximal clot firmness were determined. RL had the least effect on hemostasis. Gelatin administered alone impaired the coagulation system significantly less than each median-weight HES administered alone. We conclude that gelatin combined with 6% HES 200/0.5 or 6% HES 130/0.4 decreases hemostasis <6% HES 200/0.5 or 6% HES 130/0.4 administered alone.

Reduction of Fresh Frozen Plasma Requirements by Perioperative Point-of-Care Coagulation Management with Early Calculated Goal-Directed Therapy

Background: Massive bleeding and transfusion of packed red blood cells (PRBC), fresh frozen plasma (FFP) and platelets are associated with increased morbidity, mortality and costs. Patients and Methods: We analysed the transfusion requirements after implementation of point-of-care (POC) coagulation management algorithms based on early, calculated, goal-directed therapy with fibrinogen concentrate and prothrombin complex concentrate (PCC) in different perioperative settings (trauma surgery, visceral and transplant surgery (VTS), cardiovascular surgery (CVS) and general and surgical intensive care medicine) at 3 different hospitals (AUVA Trauma Centre Salzburg, University Hospital Innsbruck and University Hospital Essen) in 2 different countries (Austria and Germany). Results: In all institutions, the implementation of POC coagulation management algorithms was associated with a reduction in the transfusion requirements for FFP by about 90% (Salzburg 94%, Innsbruck 88% and Essen 93%). Furthermore, PRBC transfusion was reduced by 8.4–62%. The incidence of intraoperative massive transfusion (≧10 U PRBC) could be more than halved in VTS and CVS (2.56 vs. 0.88%; p < 0.0001 and 2.50 vs. 1.06%; p = 0.0007, respectively). Platelet transfusion could be reduced by 21–72%, except in CVS where it increased by 115% due to a 5-fold increase in patients with dual antiplatelet therapy (2.7 vs. 13.7%; p < 0.0001). Conclusions: The implementation of perioperative POC coagulation management algorithms based on early, calculated, goaldirected therapy with fibrinogen concentrate and PCC is associated with a reduction in the transfusion requirements for FFP, PRBC and platelets as well as with a reduced incidence of massive transfusion. Thus, the limited blood resources can be used more efficiently.

Fibrinogen in Craniosynostosis Surgery

BACKGROUND: During craniosynostosis repair, massive blood loss, consumption and dilution of clotting factors often result in coagulopathy, for which cryoprecipitate, fresh frozen plasma (FFP), and platelets are recommended for treatment. However, cryoprecipitate is not available in most European countries, and the efficacy of FFP in correcting fibrinogen deficiency is limited. We report our experience with human fibrinogen concentrate (Hemocomplettan®) used to improve impaired fibrinogen polymerization in children. METHODS: Results of routine coagulation tests, thrombelastometry (ROTEM®), transfusion requirements, administration of fibrinogen concentrate, and data on the postoperative course of nine consecutive children undergoing major craniofacial surgery were retrospectively collected from anesthesia protocols, medical charts, laboratory and ROTEM® databases. RESULTS: The nine children aged 12 (8, 22) mo (median [25th, 75th percentile]), weighing 9.5 (9, 10) kg had a calculated blood loss of 80 (49, 92)% of calculated blood volume during the surgery lasting 6.4 (4.5, 7.2) h. Impaired fibrinogen polymerization detected by ROTEM® was the main problem underlying dilutional coagulopathy. In all cases, sufficient hemostasis was achieved without adverse effects by administering (if necessary), repeated doses of fibrinogen concentrates (each single dose 30 mg/kg) without FFP or platelet transfusions. All children were successfully weaned from mechanical ventilation within a few hours and were able to be discharged early from the Intensive Care Unit. CONCLUSIONS: Administration of fibrinogen concentrate effectively improves fibrinogen polymerization and total clot strength, which were the main underlying problems of dilutional coagulopathy in children undergoing craniosynostosis surgery.

Time for changing coagulation management in trauma-related massive bleeding.

Purpose of review New insights into the pathophysiology of trauma-induced coagulopathy, the increasing availability of point-of-care devices and awareness of side effects of intravenous fluids and traditional fresh frozen plasma therapy has encouraged new concepts for managing massive blood loss. Recent findings Trauma-induced coagulopathy primarily results from blood loss, hypovolemia-induced activation of the protein C system and consequent increase of the fibrinolytic potential, whereas hemodilution, localized consumption of clotting factors and platelets, hypothermia, acidosis, anemia and hypocalcemia further decrease the hemostatic potential. The widespread use of viscoelastic devices highlighted the importance of the contribution of fibrinogen to clot firmness, a precondition for cessation of bleeding. The evidence is growing that targeted therapy using coagulation factor concentrates guided by viscoelastic measurements enables effective correction of severe coagulopathy. Summary During massive blood loss, viscoelastic measurements should guide aggressive treatment of deficiency or hyperfibrinolysis or both. In addition, the impact of contributing factors should be considered and as far as possible corrected. New data underscore the importance of avoiding hypoperfusion, and the use of coagulation factor concentrates should enable more effective correction of coagulopathy.

Hemostasis and Hemodilution: A Quantitative Mathematical Guide for Clinical Practice

Quantitative changes of hemostasis during hemodilution remain unclear. With the increasing popularity of artificial blood substitutes (ABS), which solely provide oxygen-transport capacity, this issue becomes even more complex. We developed a mathematical model to quantitatively analyze hemostasis during hemodilution and validated it by recalculating patient data. We calculated and compared maximal allowable blood losses (MABL) related to minimal acceptable hematocrit, platelet concentration, and plasma fibrinogen concentration. MABL is the maximal blood loss that can be tolerated without any additional blood products. The variable with the smallest MABL thus limits hemodilution foremost. Hemodilution included isovolemic replacement of blood loss with colloid or acute normovolemic hemodilution (ANH) followed by isovolemic replacement of blood loss with colloid and ABS. We also related our findings to preoperative patient data (n = 204). The decline in platelet concentrations rarely (<2% of all patients) limits hemodilution. By contrast, critical plasma fibrinogen (≤100 mg/dL) concentrations can often (≤20% of all patients) limit hemodilution if their initial concentrations are within the lower normal range (<300 mg/dL). These findings become more frequent if ANH is combined with ABS. Under those circumstances ANH blood products are solely required for stabilization of hemostasis, thereby defeating the original purpose of combining ANH with ABS.