We thank Dr Dietrich and colleagues for their comments1 on the European Society of Anaesthesiology Guidelines on the management of severe perioperative bleeding that were recently published in the European Journal of Anaesthesiology.2 We have always been aware that there would be differing points of view and we consider follow-up discussions to be vital for an evolving understanding of the evidence-based approaches available to anaesthesiologists.
The grading system used to analyse the existing evidence and developing recommendations, suggestions and statements is pivotal to any set of guidelines, but it is imperative to remember that the numbers representing the level of recommendation do not have the same meaning for each system. In our case, the initial choice of grading system was the Scottish Intercollegiate Guidelines Network (SIGN) grading system. However, as detailed in the Methods section, during the process of developing the guidelines we made the decision to switch to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, and specifically to use the UpToDate system,3 the details of which are presented in Table 1 of the guidelines.2 Our rationale was to align with the many other scientiﬁc organisations who also favour the GRADE system (including American College of Chest Physicians, Scandinavian Society of Anaesthesiology and Intensive Care Medicine, Society of Critical Care Medicine, Society for Vascular Surgery and European Society of Thoracic Surgeons).4 Thoughtful application of this grading system led to the development of 91 strong recommendations and 81 weak recommendations/suggestions (we note that these figures differ from those calculated by Dietrich et al.1 in Figure 1 of their letter). Dietrich et al.1 note that the recommendations with GRADE >1B should be analysed with caution. We would like to point out that the number 1 in the GRADE system defines recommendation strength, whereas number 1, for example in the SIGN system, defines the level of evidence. Second, we believe that clinicians should be cautious when applying any of the recommendations, suggestions or statements from guidelines to daily practice and should be familiar with, and critical towards, the evidence evaluation criteria of the guideline in question. The GRADE system provides a transparent basis for both defining and interpreting recommendations; it includes elements that are objective and reproducible (i.e. assessment of the quality of the evidence) and elements that will often be subjective and dependent upon circumstances (i.e. deciding on the strength of recommendations), which depend on the balance of desirable and undesirable outcomes and judgement about the patients’ values and preferences. The goal is to enable readers of guidelines to benefit from the systematic analysis of evidence and then to apply that information to their own situation, using their own judgement as necessary.
As noted by Dietrich et al.,1 many of our assessments of the quality of the evidence were weak. We stress that this does not mean that the included studies were all of low quality. Rather, that when considering all of the relevant evidence, we had limited confidence in what effect the intervention had on the outcomes that we deemed important. This assessment involved evaluating risk of bias, imprecision, inconsistency and indirectness. In many cases, the fact that the quality of the body of evidence was low meant that associated recommendations were graded as weak. In these cases, we made suggestions rather than recommendations. In others, we decided to grade the recommendations as strong despite the lack of strong evidence. Either way, we believe that it is imperative to provide guidance in form of recommendations or suggestions for physicians in treating severe bleeding based on the best evidence that is currently available. By quoting both the assessment of the quality of the body of evidence and the strength of the recommendation, and understanding what these assessments mean, the reader should be able to appreciate what part is our judgement and what part is objective assessment of the quality of evidence.
Dietrich et al. address the use of algorithms for the treatment of intraoperative bleeding. The evidence for the 1B recommendation (which we point out is not 1C, as stated by Dietrich et al.) to use transfusion algorithms incorporating predefined intervention triggers to guide haemostatic intervention during intraoperative bleeding is presented in chapter 5.2 However, the guidelines include a further 1C recommendation for the use of point-of-care testing, specifically in the setting of cardiac surgery, supporting evidence for which is also presented in chapter 5.2 This recommendation was broadly based on studies that used an approach of administering haemostatic therapy guided by algorithms, according to point-of-care test results; therefore, the evidence presented supports the use of these variables in combination. Studies capable of separating the impact of the haemostatic treatment algorithm from that of point-of-care monitoring might be interesting, though it is ultimately only haemostatic treatments themselves that can control bleeding. Furthermore, although we agree that further studies are needed to better define the benefit of using point-of-care devices, we find the reference to platelet function testing in intraoperative algorithms puzzling because our panel of experts only assigned a 2C suggestion for the preoperative use of platelet function testing.
With regard to the recommendations on the use of fibrinogen concentrate as first-line therapy in cardiac surgery, we agree that the best supporting evidence available to date is the randomised controlled study by Rahe-Meyer et al.,5 despite that only 29 patients received fibrinogen concentrate. However, a large amount of lower quality but consistent evidence also contributes to a compelling evidence base. Many patients have been treated with fibrinogen concentrate, including those listed in two systematic reviews,6,7 which are cited in the guidelines and support the efficacy of fibrinogen concentrate in cardiac surgery across multiple endpoints. One review alone cited 21 trials, three of which were prospective studies. Together, we feel that these data, including the well designed, randomised controlled trial by Rahe-Meyer et al.,5 support the 1B recommendation that fibrinogen concentrate infusion guided by point-of-care viscoelastic coagulation monitoring should be used to reduce perioperative blood loss in complex cardiovascular surgery. It will of course be necessary to revisit, and if appropriate, revise this and all other statements and recommendations in the guidelines when new data become available.
We express concern with regard to the statement of Dietrich and colleagues on an assumedly recommended target of 22 mm maximum clot firmness (MCF) in the thromboelastometric FIBTEM test following cardiac surgery. This value is only mentioned in a single instance and is only discussed because it features in clinical studies that form supporting evidence; we have not made any recommendations or suggestions for a target FIBTEM MCF. Consequently, the 2C recommendation for an initial dose of 25 to 50 mg kg−1 fibrinogen concentrate does not refer to achieving a FIBTEM MCF target of 22 mm. Of note, the level of recommendation for dosing of many haemostatic agents mentioned in the guideline, including for example, cryoprecipitate, is 2C.
With regard to the recommendation for prophylactic infusion of 2 g fibrinogen concentrate in coronary artery bypass graft (CABG), we point out that our recommendation is not based on the studies by Blome et al.8 and Karlsson et al. (2009)9 as incorrectly detailed by Dietrich et al.1; neither of these studies assessed the effect of prophylactic administration of fibrinogen concentrate. Instead, evidence was provided by results from another randomised controlled study by Karlsson et al. (2010).10 This study provides the only direct evidence to date to support prophylactic administration of fibrinogen concentrate in patients undergoing CABG. However, the published evidence provides only a low level of confidence about what effect this intervention has in this population on the outcomes that we deemed important; therefore, we suggested considering the use of fibrinogen concentrate preoperatively and allocated a grade of 2C.2
We are in agreement with Dietrich et al.1 that despite no clear safety concerns about thromboembolic complications following fibrinogen supplementation, the existing body of literature is not large enough to clearly exclude such potential risk. A 22-year pharmacovigilance study indicates a low thrombogenic potential of fibrinogen concentrate, but additional large studies are required to evaluate the frequency of rare events such as thromboembolism. Thus, our statement regarding thromboembolic complications and fibrinogen concentrate was graded evidence level C. It should be noted that the thrombogenic potential of fibrinogen concentrate was reported as low, with 3.48 thromboembolic events per 100 000 infusions11 (by comparison, for recombinant factor VIIa, 24.6 thromboembolic events per 100 000 infusions12 have been reported). It should also be considered that the thrombogenic risks of platelets, therapeutic plasma and cryoprecipitate have not been assessed in long-term pharmacovigilance studies, although they continue to be used as standard of care.
Regarding the use of prothrombin complex concentrates (PCC) in the perioperative period of cardiovascular surgery, we made suggestions to be adopted cautiously, and not recommendations. We felt it important to include such statements, despite gaps in the data, because to omit them would be to ignore possibly important advances. In the guidelines, we recommended that ‘goal-directed therapy with coagulation factor concentrates (fibrinogen and/or PCC) may reduce transfusion associated costs in trauma, cardiac surgery and liver transplantation (B)’.2 We agree with Dietrich et al.1 that no study alone has demonstrated the advantage of using PCC and further studies in this area are needed. However, a number of studies have shown the benefit of using PCC, together with fibrinogen concentrate, as part of a successful strategy to reduce transfusion associated costs,13,14 as per our recommendation.
We are grateful to Dietrich et al.1 for their valuable input regarding the recommendation on use of erythropoietin (EPO)-stimulating agents to treat anaemia if iron deficiency has been ruled out (2A). There are some conflicting reports regarding the efficacy and safety of EPO in different patient populations and we therefore took a cautious approach. As noted above though, there is a degree of subjectivity in arriving at strengths of recommendations and it is important that the guidelines process provides room for amendments. In retrospect, we agree that the body of evidence largely supports efficacy and is insufficient to conclude that significant safety issues exist. Further safety data on the risk of deep vein thrombosis with EPO treatment would be valuable, but we nonetheless agree that a grade 1 (strong recommendation, likely to apply to most patients) could be considered here. The grading will be revisited in the next update of the guidelines.
We believe that in the setting of life-threatening haemorrhage, the best available data must be relied upon to guide best practice evidence-based medicine. The alternative is to continue with a standard of care that may be suboptimal and often relies upon allogeneic blood products despite insufficient evidence of their efficacy and safety. We continue to welcome any suggestions for refining our assessments. We also expect the recommendations to evolve as new data become available; an update of the guidelines is planned in 2015.
Acknowledgements relating to this article
Assistance with the letter: none.
Financial support and sponsorship: none.
Conflicts of interest: SKL received honoraria for lecturing, travel reimbursement and consulting fees within the last 10 years from Baxter, B. Braun, Biotest, Pfizer-BMS, CSL Behring, Fresenius Kabi, Mitsubishi Pharma, Novo Nordisk, Octapharma, TEM International and Verum Diagnostics. NR-M is a member of advisory boards for CSL Behring and MSD, and received unrestricted grants for clinical studies from these companies. AA and GI did not report any conflicts of interest.
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2. Kozek-Langenecker SA, Afshari A, Albaladejo P, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol
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4. GRADE working group. Organizations that have endorsed or that are using GRADE*. http://www.gradeworkinggroup.org/society/index.htm
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13. Spalding GJ, Hartrumpf M, Sierig T, et al. Cost reduction of perioperative coagulation management in cardiac surgery: value of ‘bedside’ thrombelastography (ROTEM). Eur J Cardiothorac Surg
14. Gorlinger K, Dirkmann D, Hanke AA, et al. First-line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: a retrospective, single-center cohort study. Anesthesiology