Reply from the authors

Abstract

Editor—We would like to thank Ormonde and colleagues, who requested further data on our study regarding the time course of haemostatic effects of fibrinogen concentration in patients undergoing aortic surgery with cardiopulmonary bypass (CPB),1Solomon C Hagl C Rahe-Meyer N Time course of haemostatic effects of fibrinogen concentrate administration in aortic surgery.Br J Anaesth. 2013; 110: 947-956Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar for their interest in our work. We agree that carrying out fibrinogen concentration measurement during CPB could result in more timely identification of coagulation defects in clinics that do not use point-of-care coagulation testing. The mean (sd) plasma fibrinogen levels observed in our study for all 61 patients (both those treated with fibrinogen concentrate and those treated with placebo) were similar at 20 min before the removal of CPB [1.66 (0.34) g litre−1] and immediately after CPB removal [1.58 (0.34) g litre−1], as were the FIBTEM MCF measurements during and after CPB [9.70 (2.75) and 9.67 (2.90) mm, respectively]. We have examined whether or not Clauss assay measurements taken during CPB can be used to calculate fibrinogen doses similar to those administered during our study, which were calculated using FIBTEM measurements made during CPB using the formula: fibrinogen concentrate dose (g)=(target FIBTEM MCF−actual FIBTEM MCF) (mm)×[bodyweight (kg)/70]×0.5 g mm−1. The target FIBTEM MCF was 22 mm. The relationship between the Clauss assay measurement and the dose administered in the study was examined using linear regression, with the dose administered being the outcome variable. We were able to generate the following equation for calculating the dose of fibrinogen using the Clauss assay measurement taken during CPB: Fibrinogen concentrate dose (g)=[3.73-actual Clauss fibrinogen (g litre-1)]×0.0424×body weight (kg) As this equation was based on the dosage using FIBTEM values, we would expect the mean fibrinogen dose to be the same; this was confirmed as, using this equation, the mean (sd) fibrinogen dose for the patients included in our study would have been 7.7 (1.8) g, compared with the actually administered mean dose (based on FIBTEM measurement taken during CPB) of 7.7 (2.3) g. However, although the average calculated dose is important, it is possible that the equation provides the correct dosing on average while potentially resulting in a different dose for some individual patients. To clarify this, we applied the Bland–Altman limits of agreement method to measure the size of differences between the fibrinogen dose based on the Clauss assay and the dose based on the FIBTEM measurement. The analyses suggested a mean difference between the dose calculations of 0.0 g. The Bland–Altman limits of agreements are from −2.3 to 2.3 g (equivalent to −29.9 to 29.9% of the mean dose), which is the interval into which 95% of all differences between the fibrinogen dose calculated using these two methods will lie. This analysis suggests a dose based on Clauss fibrinogen during CPB may differ from a FIBTEM calculated dose by up to 2.3 g. Clinical judgement is required as to whether this is an acceptable difference, and thus whether the equation is suitable or not. Fibrinogen dose calculated using the Clauss assay equation given above was also compared with that calculated using the FIBTEM measurement taken immediately after removal of CPB (before administration of fibrinogen). The mean fibrinogen dose based on FIBTEM immediately after removal of CPB was 7.7 (2.3) g, with no statistical difference between this and the dose based on the Clauss measurement made during CPB (P=0.86). The Bland–Altman limits of agreement method was used to examine the agreement between individual observed and predicted values. This method gave the 95% limits of agreement interval as being from −2.5 to 2.6 g (equivalent to −32.5 to 33.8% of the mean dose). This analysis suggests that a dose based on Clauss fibrinogen during CPB may differ from a dose based on FIBTEM immediately after removal of CPB by up to 2.6 g. The analyses presented here indicate that the Clauss measurements taken during CPB may be a suitable basis for calculating the fibrinogen dose in these patients, with derived doses largely similar to those calculated using FIBTEM measurements made either during or immediately after removal of CPB. Using the Clauss assay measurement taken during CPB to determine fibrinogen concentrate dosage may be one way to minimize treatment delay when other methods (such as the ROTEM-based FIBTEM test) are not available. It should be noted that although the Clauss assay is widely used to measure plasma fibrinogen concentration, limited agreement has been observed for the measurement obtained using different Clauss methods within the same laboratory, and for measurements between different laboratories.2Solomon C Cadamuro J Ziegler B et al.A comparison of fibrinogen measurement methods with fibrin clot elasticity assessed by thromboelastometry, before and after administration of fibrinogen concentrate in cardiac surgery patients.Transfusion. 2011; 51: 1695-1706Crossref PubMed Scopus (86) Google Scholar This variability could impact on the triggers used to decide whether to administer haemostatic therapy to the patient. Furthermore, it must be kept in mind that the Clauss assay can be affected by the presence of heparin in the sample.3Kozek-Langenecker SA Perioperative coagulation monitoring.Best Pract Res Clin Anaesthesiol. 2010; 24: 27-40Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Commercially available reagents differ in their sensitivity to heparin with some stating that the assay may be affected by heparin levels >2 units ml−1, while others contain heparin neutralizers and high concentrations of thrombin.4Stang LJ Mitchell LG Fibrinogen.Methods Mol Biol. 2013; 992: 181-192Crossref PubMed Scopus (26) Google Scholar Shortly before the removal of CPB, levels of heparin >2 units ml−1 may be present;5Solomon C Baryshnikova E Schlimp CJ et al.FIBTEM PLUS provides an improved thromboelastometry test for measurement of fibrin-based clot quality in cardiac surgery patients.Anesth Analg. 2013; 117: 1054-1062Crossref PubMed Scopus (29) Google Scholar therefore, clinicians must be informed whether the Clauss assay used in their unit is sensitive to heparin, and how this may affect the results of the Clauss fibrinogen measurement. In order to confirm the validity of using the Claus assay during CPB to determine fibrinogen concentrate dosage, we would suggest carrying out a more extensive study across a larger cohort of patients. C.S. is an employee of CSL Behring, but was not an employee of CSL Behring while the study was being conducted, and has received speaker honoraria, research support, or both from Tem International and CSL Behring, and travel support from Haemoscope Ltd. N.R.-M. has participated in advisory boards and received speaker honoraria and research support from CSL Behring and Tem International.