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ESA guidelines on the management of severe perioperative bleeding: Comments on behalf of the Subcommittee on Transfusion and Haemostasis of the European Association of Cardiothoracic Anaesthesiologists

Dietrich, Wulf; Faraoni, David; von Heymann, Christian; Bolliger, Daniel; Ranucci, Marco; Sander, Michael; Rosseel, Peter

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European Journal of Anaesthesiology: April 2014 - Volume 31 - Issue 4 - p 239-241
doi: 10.1097/EJA.0000000000000033

Editor,

We read with interest the recent guidelines of the European Society of Anaesthesiology published in the June 2013 issue of the European Journal of Anaesthesiology.1 We congratulate the authors for putting their efforts together with the common aim to review the current literature and to write these recommendations. Indeed, more than 18 general and specific clinical settings were reviewed, leading to about 200 recommendations. However, we believe that for the specific setting of cardiac surgery, some important remarks should be made.

The GRADE system used by the authors should be detailed and considered before guidelines can be applied in clinical practice. Indeed, only GRADE 1A and 1B are based on randomised trials in which benefit appears to outweigh risk. GRADE 1C relates to observational or low-quality randomised controlled trials. On the contrary, trials in which the benefit was closely balanced with risk are classified as GRADE 2. Considering this scoring system, all recommendations with GRADE >1B should be interpreted with caution and should not be considered as strong and clinically relevant until further evidence from sufficiently powered studies has been provided. Figure 1 summarises grades of recommendation drawn from the ESA guidelines. We found that the vast majority of the recommendations consisted of low-grade recommendations and therefore should be interpreted with caution.

Fig. 1
Fig. 1:
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For example, the authors recommended the application of transfusion algorithms incorporating predefined intervention triggers to guide haemostatic therapy during intraoperative bleeding (GRADE 1C). We agree that an algorithm-based approach improves perioperative management of bleeding. However, it is not clear whether this benefit is due to the application of the algorithm itself or to the use of point-of-care monitoring (1C). Thus, an algorithm-based approach should be recommended, but further studies are needed to better define the benefit of using point-of-care devices, especially platelet function testing (2C).

The authors recommend the administration of fibrinogen concentrates in different clinical settings. Rahe-Meyer et al.2 recently published the only randomised controlled trial that tested a well designed algorithm in cardiac surgery. Even if the results of this study argue that fibrinogen concentrates should be used as a first-line therapy, this study only included 29 patients who were treated with fibrinogen. Furthermore, in the Guidelines, the target fibrinogen level after cardiac surgery is recommended to be a maximum clot firmness of 22 mm in the FIBTEM tracing (p. 288). This target value has been investigated in two small nonrandomised studies including a total of 16 patients in whom a maximum clot firmness of 22 mm was targeted. In the fibrinogen concentrate supplemented patients, reduced blood loss and less transfusion requirements were observed.3,4 Furthermore, the suggested fibrinogen dose is a matter of concern. The authors recommend (2C) the administration of 25 to 50 mg kg−1 fibrinogen. However, this arbitrary target level of 22 mm at FIBTEM was only reached in one study,4 with a median fibrinogen dose of 7.8 ± 2.7 g (range, 5 to 13 g). Such high doses require support from sufficiently powered studies.

In addition, the recommendation of a prophylactic preoperative infusion of 2 g fibrinogen concentrate in patients with fibrinogen concentration less than 3.8 g l−1 comes from a retrospective analysis (N = 98, CABG patients) by Blome et al.5 but could not be confirmed in a larger prospective study (N = 170).6 Preoperative fibrinogen levels between transfused and nontransfused patient were not different, but postoperative fibrinogen levels were associated with blood loss, although this correlation was rather weak (r = −0.53). This is too little evidence to support preoperative fibrinogen supplementation.

Finally, we think that the Guidelines should have mentioned that, despite no clear safety concerns about thromboembolic complications of fibrinogen supplementation, the existing body of literature is not large enough to clearly exclude this potential risk.

In conclusion, our committee agrees that the administration of fibrinogen concentrate may be associated with reduced blood loss and transfusion requirements in the perioperative period in patients undergoing cardiac surgery, but the dosing scheme, the fibrinogen level to be targeted and outcomes should be better studied in further large, well designed trials. There are at least four randomised trials on fibrinogen supplementation in cardiac surgery currently registered in clinicaltrials.gov, and we suggest waiting for the results of these studies before sound recommendations are made.

Almost the same concerns could be applied to the use of prothrombin complex concentrate. No prospective trial has compared the efficacy of prothrombin complex concentrate alone with other therapies in the perioperative period of cardiovascular surgery. Well designed, randomised controlled trials are needed before prothrombin complex concentrate may be recommended. The authors state that ‘goal-directed therapy with coagulation factor concentrates (fibrinogen and/or prothrombin complex concentrate) may reduce transfusion-associated costs in trauma, cardiac surgery and liver transplantation (B)’. Similar to the use of fibrinogen concentrate, EACTA's Subcommittee of Transfusion and Haemostasis recommends considering these recommendations in clinical practice with extreme caution owing to the small amount of data that are available supporting the use of prothrombin complex concentrate in cardiac surgery.

Apart from coagulation, these Guidelines have also addressed perioperative anaemia management. The Guidelines recommend (p. 217) ‘if iron deficiency has been ruled out, we suggest treating anaemic patients with erythropoietin-stimulating agents 2A’. The authors have clearly pointed out that a large body of prospective trials (N = 18), systematic reviews, meta-analyses (N = 3) and guidelines (N = 1) has demonstrated the efficacy of human recombinant erythropoietin. With regard to the clinical benefit outweighing the risks of erythropoietin treatment, there has been only one study so far that has shown an increased risk of thromboembolism in spinal surgery.7 In this study, thromboprophylaxis was not performed routinely as recommended. According to the GRADE system, the recommendation to treat anaemia should not be 2A, but at least 1B.

In general conclusion, the Subcommittee on Transfusion and Haemostasis of EACTA would like to congratulate the European Society of Anaesthesiology for publishing this large review of the literature. However, we would like to draw attention to the fact that some recommendations in these Guidelines are only supported by small, and not always randomised studies. In particularly with respect to the use of coagulation factor concentrates, further prospective trials are needed before high-level recommendations can be made.

Acknowledgements relating to this article

Assistance with the letter: none.

Financial support and sponsorship: none.

Conflicts of interest: WD: Formerly, consultant for Bayer Corp., Leverkusen, Germany, Consultant for The Medicines Company, Munich-Leipzig, Germany, Consultant for Nordic Pharma SAS, Paris, France. Formerly, study support from CSL Behring, Marburg, Germany. DF: no conflicts of interest. CvH: Within the last 3 years, CvH received speaker and/or consultancy honoraria from Bayer Healthcare, Boehringer Ingelheim, Pfizer GmbH, BMS, NovoNordisk Pharma, Nordic Pharma, The Medicines Company, Vifor Pharma and Janssen-Cilag as well as research support by CSL Behring, TEM International, Bayer Healthcare, Boehringer Ingelheim and Baxter. DB: received speaker honorarium from TEM International, Munich, Germany, and an unrestricted research grant from CSL Behring, Berne, Switzerland. MR: Within the last 3 years, MR received speaker and/or consultancy honoraria from NovoNordisk Pharma, The Medicines Company, CSL Behring, Grifols, Roche, Medtronic. DB received speaker honorarium from TEM International, Munich, Germany, and an unrestricted research grant from CSL Behring, Berne, Switzerland. MS: within the last 3 years, MS received research support from The Medicines Company and NovoNordisk Pharma. PR: no conflicts of interest.

References

1. Kozek-Langenecker SA, Afshari A, Albaladejo P, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol 2013; 30:270–382.
2. 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; 118:40–50.
3. Rahe-Meyer N, Pichlmaier M, Haverich A, et al. Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study. Br J Anaesth 2009; 102:785–792.
4. Rahe-Meyer N, Solomon C, Winterhalter M, et al. Thromboelastometry-guided administration of fibrinogen concentrate for the treatment of excessive intraoperative bleeding in thoracoabdominal aortic aneurysm surgery. J Thorac Cardiovasc Surg 2009; 138:694–702.
5. Blome M, Isgro F, Kiessling AH, et al. Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery. Thromb Haemost 2005; 93:1101–1107.
6. Karlsson M, Ternstrom L, Hyllner M, et al. Plasma fibrinogen level, bleeding, and transfusion after on-pump coronary artery bypass grafting surgery: a prospective observational study. Transfusion 2008; 48:2152–2158.
7. Stowell CP, Jones SC, Enny C, et al. An open-label, randomized, parallel-group study of perioperative epoetin alfa versus standard of care for blood conservation in major elective spinal surgery: safety analysis. Spine 2009; 34:2479–2485.
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