Peri-operative blood loss1–3 and also the transfusion of red blood cell (RBC),1,2,4 plasma,5 and platelets6 are associated with adverse outcomes1,2,7 and high costs.8 Although, in a considerable percentage of individual surgical procedures it is the surgical technique itself that results in the increased surgical blood loss, anaesthesiologists are generally required to solve the problem. The European Society of Anaesthesiology and Intensive Care (ESAIC) therefore has created guidelines on the management of severe peri-operative bleeding, the first being published in 2013.9
In this issue of the Journal, Kietaibl et al.10 publish the second update of these guidelines. These updated guidelines are elaborate and contain all you ever wanted to know about peri-operative bleeding management. We all are grateful for our Society's vision to decide to update these guidelines in 2020 and for the authors’ hard work during the last 2.5 years. The recommendations cover 13 clinical fields and are presented in the form of 16 recommendations each comprising between 3 and 27 graded sub-recommendations – a total of 193!
The invitation to write an editorial to accompany these guidelines is, of course, a great honour! However, commenting on such comprehensive work by the European experts is quite challenging! Since it would be rather arrogant to comment on such tremendous work systematically, we opted to comment on a few points that we considered were worthy of note. This is deliberately unsystematic and does not claim completeness.
The best strategy in coagulation management is to prevent peri-operative bleeding. Such preventive action starts during the pre-anaesthesia consultation with a drug and bleeding history. It is important to identify patients with an increased peri-operative bleeding risk (e.g., due to underlying coagulation disorders, or anticoagulant or platelet inhibitor drugs) so that appropriate preventive measures can be instituted pre-operatively. Conventional coagulation tests (e.g., prothrombin time, activated prothrombin time, etc.) are not reliable predictors of the peri-operative bleeding risk, and normal results give the physician a false sense of security.11 Although still regularly performed, routine coagulation tests are therefore not recommended. Instead, a standardised coagulation questionnaire is more powerful to detect an underlying coagulation disorder if it is suspected clinically.12,13
Which patients should be optimised, and how, before surgery? Pre-operative anaemia detection and treatment is recommended (Recommendation 1): of course, this is of outmost importance. However, it is suggested that parenteral pre-operative treatment would correct anaemia within 1–2 weeks (grade 2C). In our experience, this is a rather optimistic expectation. Recent studies show that treatment of iron deficiency anaemia prior to cardiac surgery using intravenous iron with14 or without15 erythropoiesis stimulating agents increase the haemoglobin by 12 g l−1 and 8 g l−1, and this was after these treatments were given for 30 days before surgery. Interestingly, transfusion needs were reduced by the combined treatment14 as shown in ultra-short term treatment.16 Nevertheless, the exact contribution of type and dose of erythropoiesis stimulating agents, intravenous iron, subcutaneous vitamin B12 and oral folic acid and the timing of such stimulation is still unclear today.
Patients undergoing obstetric surgery (Recommendation 12): the ESAIC guidelines suggest that ‘dynamic platelet count decrease or a level <150 Ă— 10−9 l−1 at the onset of labour, particularly if combined with plasma fibrinogen level <2.0 g l−1, may indicate an increased risk of postpartum haemorrhage (grade C)’.10 However, in a prospective cohort study of 1300 women, prepartum factor XIII activity had the strongest correlation with postpartum blood loss.17 Therefore, additionally measuring prepartum factor XIII levels may help in anticipating an increased risk of postpartum haemorrhage. Whether factor XIII replacement reduces postpartum haemorrhage needs to be evaluated in future studies.
Use of recombinant factor VIIa in postpartum haemorrhage (Recommendation 12): we strongly agree with the recommendation against the prophylactic/general use of recombinant factor VIIa in postpartum haemorrhage (grade 1C). Nevertheless, classifying all use of recombinant factor VIIa in postpartum haemorrhage as off-label is not entirely correct. Recombinant factor VIIa has been approved by the European Medical Agency in 2022 to ‘treat patients with severe postpartum haemorrhage, when medicines that stimulate the muscles of the womb to contract (uterotonic medicines) are not effective at controlling the bleeding’.18
The future will show the best indication of recombinant factor VIIa in severe postpartum haemorrhage.
Direct oral anticoagulants (DOACs) (Recommendation 2): the ESAIC guidelines suggest that ‘in severe bleeding patients treated with dabigatran, a specific antidote (idarucizumab) could be considered (2C)’ and ‘the use of prothrombin complex concentrate (25 IU kg−1 at first) over andexanet alfa in bleeding patients treated with anti-Xa agents (rivaroxaban, apixaban, edoxaban) (2C)’. In bleeding patients, the first measure is to assess whether they are anticoagulated, with which anticoagulant and to quantify the residual DOAC plasma concentration. This information can be achieved with anti-Xa activity for anti-Xa inhibitors, prothrombin time for vitamin K antagonists and (diluted) thrombin time for dabigatran.19 In an ongoing and life-threatening bleeding case, DOAC reversal is indicated only if there is a relevant residual plasma concentration. For reversal of anti-Xa inhibitors the choice between prothrombin complex concentrate (PCC) and andexanet alfa is difficult at the present time due to very limited scientific evidence. A recent propensity score-matched analysis showed that the adjusted 30-day mortality rates were lower for patients treated with andexanet alfa than in matched patients receiving PCC.20 Further studies comparing these two drugs on different outcomes are necessary to reach a final conclusion. The recommendation regarding the use of idarucizumab for dabigatran reversal in an ongoing haemorrhage is surprisingly restrained. Alternatives to idarucizumab are lacking and PCC has been shown to be ineffective for dabigatran reversal.21 Moreover, an underlying coagulopathy can be only detected and appropriately treated after the dabigatran effect has been neutralised.22
The only clinical field that is not covered by the guidelines is trauma. This was a deliberate choice by the authors and may be due to the fact that there have been European guidelines on the management of major bleeding and coagulopathy following trauma since 2007. The update of the current version number 519 will be published in the first months of 2023. These guidelines cover all the aspects of trauma treatment from the prehospital period to the treatment in the emergency room, surgical and interventional procedures and intensive care management.19
With all the amount of information in the ESAIC guidelines on the management of severe peri-operative bleeding, we might expect all problems to be solved. Unfortunately, this is not the case. Which physician can find the one sub-recommendation out of nearly 200 that is pertinent for the sudden problem encountered at 2 AM in complex emergency surgery? None. Therefore, within anaesthesia departments this information needs to be taught, and easy to follow algorithms established (Table 1). Algorithms that guide the pre-operative optimisation of patients undergoing high (>500 ml) blood loss surgery who have anaemia and iron deficiency,23 algorithms that guide the pre-operative cessation of anticoagulants without bridging, and algorithms that guide the pre-operative cessation of or continuation of antiplatelet treatment. In addition, we need an algorithm that guides intra-operative coagulation management. This algorithm needs to include the necessary coagulation monitoring including traditional laboratory data and viscoelastic tests to find out whether there is a coagulation issue and, if so, what needs to be done to correct the coagulation situation in an individualised goal-directed manner. The success of such coagulation algorithms has been shown in trauma,24 cardiac surgery,25 liver transplantation,26 and burns.27 Such algorithms are strongly recommended by the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists28 and the European Society of Cardiology, endorsed by the ESAIC.29
Table 1 -
Anaesthesia departments should provide algorithms for
| Pre-operative anaemia detection and treatment |
| Peri-operative management of patients with anticoagulant and/or antiplatelet treatment |
| Peri-operative bleeding management |
| Postpartum haemorrhage |
| Patients under anticoagulant therapy with intracranial haemorrhage |
Such algorithms are not freely floating in the medical universe but are, as stated by the authors, part of patient blood management (PBM). PBM has been taken up by the World Health Organization (WHO) and documented by the publication of their Policy Brief on October 19, 202130 in which they call on their 194 member states to action and announce the upcoming WHO initiative to develop PBM implementation guidelines directed towards healthcare leaders of all member states. By this unprecedented campaign the WHO sets standards. PBM has become the new standard. Likewise, the above-described algorithms have become standard. Thus, implementation is mandatory – nobody wants to deliver substandard care.
Acknowledgements relating to this article
Assistance with the article: none.
Financial support and sponsorship: none.
Conflicts of interest: DRS's academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland, the Swiss Society of Anesthesiology and Perioperative Medicine (SSAPM), Berne, Switzerland, the Swiss Foundation for Anesthesia Research, Zurich, Switzerland, Vifor SA, Villars-sur-GlĂ¢ne, Switzerland and Vifor (International) AG, St. Gallen, Switzerland. DRS is co-chair of the ABC-Trauma Faculty, sponsored by unrestricted educational grants from Novo Nordisk Healthcare AG, Zurich, Switzerland, CSL Behring GmbH, Marburg, Germany, LFB BiomĂ©dicaments, Courtaboeuf Cedex, France and Octapharma AG, Lachen, Switzerland. DRS received honoraria / travel support for consulting or lecturing from: Alliance Rouge, Bern, Switzerland, Danube University of Krems, Austria, European Society of Anesthesiology and Intensive Care, Brussels, BE, International Foundation for Patient Blood Management, Basel, Switzerland, Korean Society of Anesthesiologists, Seoul, Korea, Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis, Paris, France, Society for the Advancement of Blood Management, Mount Royal NJ, Alexion Pharmaceuticals Inc., Boston, MA, AstraZeneca AG, Baar, Switzerland, Bayer AG, ZĂ¼rich, Switzerland, B. Braun Melsungen AG, Melsungen, Germany, Baxter AG, Glattpark, Switzerland, CSL Behring GmbH, Hattersheim am Main, Germany and Berne, Switzerland, CSL Vifor (Switzerland) Villars-sur-GlĂ¢ne, Switzerland, CSL Vifor (International), St. Gallen, Switzerland, Celgene International II SĂ rl, Couvet, Switzerland, Daiichi Sankyo AG, Thalwil, Switzerland, Haemonetics, Braintree, MA, USA, LFB BiomĂ©dicaments, Courtaboeuf Cedex, France, Merck Sharp & Dohme, Kenilworth, New Jersey, USA, Novo Nordisk Healthcare AG, Zurich, Switzerland, Octapharma AG, Lachen, Switzerland, Pharmacosmos A/S, Holbaek, Denmark, Pierre Fabre Pharma, Alschwil, Switzerland, Portola Schweiz GmbH, Aarau, Switzerland, Roche Diagnostics International Ltd, Reinach, Switzerland, Sarstedt AG & Co., Sevelen, Switzerland and NĂ¼mbrecht, Germany, Shire Switzerland GmbH, Zug, Switzerland, Takeda, Glattpark, Switzerland, Werfen, Bedford, MA, Zuellig Pharma Holdings, Singapore, Singapore. AK has received support from Bayer AG (Switzerland) and CSL Behring GmBH (Switzerland) for lecturing.
This manuscript was handled by Charles Marc Samama.
References
1. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery.
Ann Thorac Surg 2013; 96:478–485.
2. Vivacqua A, Koch CG, Yousuf AM, et al. Morbidity of bleeding after cardiac surgery: is it blood transfusion, reoperation for bleeding, or both?
Ann Thorac Surg 2011; 91:1780–1790.
3. Le Manach Y, Collins GS, Ibanez C, et al. Impact of perioperative bleeding on the protective effect of beta-blockers during infrarenal aortic reconstruction.
Anesthesiology 2012; 117:1203–1211.
4. Musallam KM, Tamim HM, Richards T, et al. Preoperative anaemia and postoperative outcomes in noncardiac surgery: a retrospective cohort study.
Lancet 2011; 378:1396–1407.
5. Welsby IJ, Troughton M, Phillips-Bute B, et al. The relationship of plasma transfusion from female and male donors with outcome after cardiac surgery.
J Thorac Cardiovasc Surg 2010; 140:1353–1360.
6. Pereboom IT, de Boer MT, Haagsma EB, et al. Platelet transfusion during liver transplantation is associated with increased postoperative mortality due to acute lung injury.
Anesth Analg 2009; 108:1083–1091.
7. Isbister JP, Shander A, Spahn DR, et al. Adverse blood transfusion outcomes: establishing causation.
Transfusion Med Rev 2011; 25:89–101.
8. Shander AS, Goodnough LT. Blood transfusion as a quality indicator in cardiac surgery.
JAMA 2010; 304:1610–1611.
9. 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.
10. Kietaibl S, Ahmed A, Afshari A, et al. Management of severe peri-operative bleeding: Guidelines from the European Society of Anaesthesiology and Intensive Care: Second update 2022.
Eur J Anaesthesiol 2023; 40:226–304.
11. Levy JH, Szlam F, Wolberg AS, Winkler A. Clinical use of the activated partial thromboplastin time and prothrombin time for screening: a review of the literature and current guidelines for testing.
Clin Lab Med 2014; 34:453–477.
12. Pfanner G, Koscielny J, Pernerstorfer T, et al. Preoperative evaluation of the bleeding history. Recommendations of the working group on perioperative coagulation of the Austrian Society for Anaesthesia, Resuscitation and Intensive Care.
Anaesthesist 2007; 56:604–611.
13. Adler M, Kaufmann J, Alberio L, Nagler M. Diagnostic utility of the ISTH bleeding assessment tool in patients with suspected platelet function disorders.
J Thromb Haemost 2019; 17:1104–1112.
14. Kong R, Hutchinson N, Hill A, et al. Randomised open-label trial comparing intravenous iron and an erythropoiesis-stimulating agent versus oral iron to treat preoperative anaemia in cardiac surgery (INITIATE trial).
Br J Anaesth 2022; 128:796–805.
15. Klein AA, Chau M, Yeates JA, et al. Preoperative intravenous iron before cardiac surgery: a prospective multicentre feasibility study.
Br J Anaesth 2020; 124:243–250.
16. Spahn DR, Schoenrath F, Spahn GH, et al. Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: a prospective randomised trial.
Lancet 2019; 393:2201–2212.
17. Haslinger C, Korte W, Hothorn T, et al. The impact of prepartum factor XIII activity on postpartum blood loss.
J Thromb Haemost 2020; 18:1310–1319.
19. Spahn DR, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition.
Crit Care 2019; 23:98.
20. Cohen AT, Lewis M, Connor A, et al. Thirty-day mortality with andexanet alfa compared with prothrombin complex concentrate therapy for life-threatening direct oral anticoagulant-related bleeding.
J Am Coll Emerg Physicians Open 2022; 3:e12655.
21. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.
Circulation 2011; 124:1573–1579.
22. Eikelboom JW, Quinlan DJ, van Ryn J, Weitz JI. Idarucizumab: the antidote for reversal of dabigatran.
Circulation 2015; 132:2412–2422.
23. Munoz M, Acheson AG, Auerbach M, et al. International consensus statement on the peri-operative management of anaemia and iron deficiency.
Anaesthesia 2017; 72:233–247.
24. Stein P, Kaserer A, Sprengel K, et al. Change of transfusion and treatment paradigm in major trauma patients.
Anaesthesia 2017; 72:1317–1326.
25. Weber CF, Gorlinger K, Meininger D, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients.
Anesthesiology 2012; 117:531–547.
26. Bonnet A, Gilquin N, Steer N, et al. The use of a thromboelastometry-based algorithm reduces the need for blood product transfusion during orthotopic liver transplantation: a randomised controlled study.
Eur J Anaesthesiol 2019; 36:825–833.
27. Sahli SD, Pedrazzi N, Braun J, et al. Effect of a factor-based coagulation management on blood product use after major burn injury: a retrospective cohort study.
Burns 2021; 47:1486–1494.
28. Tibi P, McClure RS, Huang J, et al. STS/SCA/AmSECT/SABM update to the clinical practice guidelines on patient blood management.
Ann Thorac Surg 2021; 112:981–1004.
29. Halvorsen S, Mehilli J, Cassese S, et al. 2022 ESC guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery.
Eur Heart J 2022; 43:3826–3924.
