Cardiac surgery with cardiopulmonary bypass (CPB) is frequently associated with the development of coagulopathy, resulting in increased blood loss and transfusion of blood products.1 These factors have been associated with increased postoperative morbidity and mortality.2 The incidence and the severity of the coagulopathy are particularly high in children undergoing cardiac surgery.3 Indeed, the relative immaturity of the coagulation system and the degree of haemodilution due to the CPB prime represent additional factors to standard triggers of coagulopathy: contact between blood and nonendothelial surfaces, anticoagulation using unfractionated heparin (UFH), protamine underdosage and overdosage and hypothermia.4,5
Rotational thromboelastometry (ROTEM, TEM International GmbH, Munich, Germany) allows a bedside assessment of coagulation in both adults and children, and is used increasingly during and after cardiac surgery.6 Using this technique, the therapeutic approach has significantly evolved from blinded transfusion therapy to algorithm-based haemostatic management, which leads to an increased interest in factor concentrates.7,8
Fibrinogen concentrate has been used in Europe for many years in cases of congenital fibrinogen deficiency.9 However, a growing literature in adults has demonstrated the efficacy of fibrinogen concentrate in patients with acquired hypofibrinogenaemia associated with trauma,10 cardiac surgery11,12 or massive bleeding.13 This relatively new approach for fibrinogen replacement is based on (patho)physiological considerations. Fibrinogen is a major substrate for clot formation, but it is also the first factor to decrease below a critical level during major haemorrhage. Recent trauma guidelines recommend maintaining the plasma fibrinogen concentration above 1.5 to 2.0 g l−1 in bleeding patients.14 In the cardiovascular setting, the European Society of Anaesthesiology has recommended the administration of fibrinogen concentrate to maintain a plasma fibrinogen concentration of more than 3.8 g l−1.15 However, the exact relationship between plasma fibrinogen concentration and perioperative blood loss is not well studied in the paediatric population.
The aim of the present study was to assess the relationship between plasma fibrinogen concentration and postoperative blood loss in children undergoing cardiac surgery with CPB. In addition, we assessed the correlation between plasma fibrinogen concentration determined by the Clauss method16 and ROTEM parameters.
Materials and methods
The local ethics committee approved this study (QFCUH CEH No. 06/12) but waived the requirement for written informed consent due its retrospective design. Ethical committee: Queen Fabiola Children's University Hospital, QFCUH ethics committee, 15 Avenue JJ Crocq, 1020 Brussels, Belgium. Phone: +3224772266. Fax: +3224772589. E-mail address: [email protected]
This study was a retrospective review of data systematically recorded in our departmental database, which included all children who underwent elective cardiac surgery with CPB between September 2010 and January 2012. Exclusions criteria were emergency procedures, Jehovah's Witnesses and children in a moribund state.
Anaesthetic management was standardised during the whole study period. We used a standard monitoring regimen including a five-lead electrocardiogram, pulse oximetry, noninvasive blood pressure, arterial and central venous pressures, urinary output, and rectal and cutaneous temperature probes. Intravenous general anaesthesia using midazolam, sufentanil and rocuronium was preferred in all children, with the exception for those with univentricular physiology undergoing a cavopulmonary connection; in these children, propofol, remifentanil and atracurium were preferred to ensure that the trachea could be extubated in the operating room. Tranexamic acid (TXA) was administered according to our local dosing scheme (10 mg kg−1 loading dose before CPB, 10 mg kg−1 h−1 until the end of wound closure, 10 mg kg−1 in the CPB prime). In addition, all children received methylprednisolone 30 mg kg−1 and cefazoline 25 mg kg−1 after induction of anaesthesia. Before aortic cannulation, UFH 4 mg kg−1 was administered. Activated clotting time (ACT) (ACTII monitor; Medtronic BV, Kerkrade, The Netherlands) was used to guide UFH administration and maintain a target ACT of more than 480 s. At the end of CPB, protamine was administered (dose: half the total UFH dose administered during CPB) to antagonise heparin activity. Adequate reversal was controlled using the ACTII monitor comparing ACT measured in the cartridge with and without heparinase (Medtronic BV).
In children older than 1 month of age, third-generation hydroxyethyl starch diluted in sodium chloride 0.9% (6% HES 130/0.4, Voluven; Fresenius-Kabi GmbH, Bad Homburg, Germany) was used for CPB priming in combination with 20% mannitol 1.5 ml kg−1, sodium bicarbonate 20 mmol l−1, UFH 50 mg l−1 and cefazoline 25 mg kg−1. All patients were rewarmed to a rectal temperature of more than 36°C before weaning from bypass. At the end of bypass separation and before protamine administration, modified ultrafiltration was used to eliminate the excess volume in the CPB circuit.
Our transfusion algorithm was defined through a multidisciplinary approach involving surgeons, anaesthesiologists and paediatricians. During CPB, red blood cells (RBCs) were transfused to maintain a haemoglobin concentration (Hb) of more than 7 g dl−1. After CPB, RBCs were administered to maintain Hb between 7 and 10 g dl−1 according to the clinical condition, the presence of cyanotic disease, pulmonary hypertension and cardiac dysfunction. In cases with abnormal bleeding, fresh frozen plasma (FFP) was administered at a dose of 15 ml kg−1. The same dose could be repeated if there was persistent bleeding. In addition, platelets were administered in cases with significant loss associated with a platelet count of less than 100 × 109 l−1, measured by our standard laboratory tests after protamine administration. Our transfusion algorithm was not based on ROTEM parameters in the intraoperative or postoperative periods, but was left to the discretion of the clinician in charge, whose decisions were based on the clinical situation and the results of standard laboratory tests.
ROTEM was performed 10 min after protamine administration. The sample was drawn from the arterial line after removing three times the dead space before blood was considered suitable for analysis. Blood was inserted into a citrated tube and used for ROTEM measurements. The following ROTEM parameters were recorded: clotting time [CT (min)], angle α (degrees), clot formation time [CFT (min)], maximum clot firmness [MCF (mm)], A10 (mm) and A20 (mm). These variables were analysed in an extrinsic test (EXTEM, using tissue factor), an intrinsic test (INTEM, using ellagic acid), an extrinsic test after platelet inhibition obtained by the addition of cytochalasin D (FIBTEM) and an intrinsic test with heparinase (HEPTEM).
Plasma fibrinogen concentration (measured by the Clauss method), haemoglobin concentration, platelet count, activated partial thromboplastin time (aPTT) and prothrombin time (PT) were determined at the same time in our accredited university hospital laboratory.
Other demographic, transfusion and outcome parameters were also recorded in our database, and analysed. The RACHS-1 (Risk Adjustment for Congenital Heart Surgery)17 score was used to classify surgical operative procedures.
Blood loss was determined by weighing sponges and measuring surgical suction. In the postoperative period, blood loss was assessed by measuring chest tube drainage. Clinically significant postoperative bleeding was defined as a blood loss more than 10% of the child's total blood volume (TBV) within the first 6 postoperative hours. This definition was adapted from the study published by Williams et al.18 and considering the 75th percentile of our population.
Continuous variables were tested for normality with the Kolmogorov–Smirnov test. Data are presented as mean and standard deviation (SD) or median and interquartile range (IQR; 25th to 75th percentile). Categorical variables are expressed as number and percentage (%). When appropriate, continuous variables were compared using the Wilcoxon Rank Sum Test. The χ2 test was used for categorical variables. Repeated measures were compared using a two-way analysis of variance (ANOVA) for repeated measures, testing for a difference between groups, a difference between values at various times and for interaction (group X time). If significant, the Bonferroni's multiple comparison test was performed.
For all determinants, univariate logistic regression analysis was performed and we calculated odds ratios (ORs) with their 95% confidence interval (CI). A P value of less than 0.05 was defined as the cut-off for inclusion into the multivariate logistic regression analysis. This second analysis was used to define the most significant determinants that could be considered to be associated with postoperative blood loss.
Finally, receiver operating characteristic (ROC) curves were considered for plasma fibrinogen concentration and MCF on FIBTEM obtained 10 min after protamine administration. Area under the curve (AUC) with 95% CI was calculated. A P value of less than 0.05 was considered as significant for all tests.
Statistical analyses were performed with Prism 6 for Mac OS (Version 6.0a; GraphPad software Inc., San Diego, California USA, http://www.graphpad.com), Statistix software for Windows (Version 9; Analytical Software, Tallahassee, USA, http://www.statistix.com) and MedCalc software for windows (Version 188.8.131.52; MedCalc Software, Ostend, Belgium, http://www.medcalc.org).
Data obtained from 191 consecutive children undergoing cardiac surgery with CPB in our institution were screened. The patient flow chart of the study is shown in Fig. 1. We excluded 29 children aged less than 1 month because they received FFP in the CPB prime. Six children were also excluded because data were lacking due to technical problems. On the basis of the definition of blood loss, 36 children were included in the ‘bleeders’ group while 120 were included in the ‘nonbleeders’ group.
Demographic data are presented in Table 1. Children in the ‘bleeders’ group were younger, had a lower preoperative weight and suffered more frequently from a cyanotic disease. They underwent more complex surgical procedures with longer aortic clamp and CPB times. No differences in preoperative laboratory tests were observed between the two groups of children, but a statistically significant difference was found for INR, aPTT, PT and plasma fibrinogen concentration 10 min after protamine administration and on admission to the paediatric ICU (PICU) (Table 2).
The preoperative plasma fibrinogen concentration did not differ between ‘bleeders’ [2.82 g l−1 (2.3 to 3.14)] and ‘nonbleeders’ [2.89 g l−1 (2.46 to 3.41)]. The plasma fibrinogen concentration was significantly lower in the ‘bleeders’ group than in the ‘nonbleeders’ group after protamine administration [1.30 g l−1 (0.99 to 1.50) versus 1.59 g l−1 (1.38 to 1.95)] with a mean difference of 0.37 g l−1 (95% CI 0.07 to 0.67) and at PICU admission [1.45 g l−1 (1.18 to 1.63] versus 1.77 g l−1 (1.56 to 2.10)] with a mean difference of 0.46 g l−1 (95% CI 0.14 to 0.79) (Fig. 2). Two-way ANOVA showed that plasma fibrinogen concentration was significantly influenced by the time of measurement (difference 41%, P < 0.0001) and the group (difference 2.8%, P < 0.0001).
No child received either FFP or platelet concentrate before protamine administration. In the postoperative period, children included in the ‘bleeders’ group were given FFP more frequently (P = 0.03) and received significantly more RBC (P = 0.02) and FFP (P = 0.03) (both expressed in ml kg−1) than the ‘nonbleeders’ group (Table 3). No child required re-thoracotomy for haemostasis in either group. No child received either fibrinogen concentrate or cryoprecipitate.
The ROTEM parameters are summarised in Table 4. There were differences in all the parameters between the ‘bleeders’ and ‘nonbleeders’ groups. No significant hyperfibrinolysis, as assessed by maximum lysis (ML) and lysis measured after 30 min (LI30), was observed in any patient. Univariate logistic regression analysis showed that 34 parameters were associated with significant postoperative blood loss (Table 5). When computed into a multivariate logistic regression analysis model, only wound closure time (P < 0.001), CFT on INTEM (P = 0.008), MCF on FIBTEM (P = 0.003) and plasma fibrinogen concentration (P = 0.006) were significantly associated with significant postoperative blood loss (Table 6).
Figure 3 shows the correlation between plasma fibrinogen concentration measured by the Clauss method and the MCF on FIBTEM (r = 0.70, 95% CI 0.58 to 0.77, P < 0.0001).
ROC curve analysis demonstrated a significant relationship between blood loss and both plasma fibrinogen concentration (Fig. 4a; AUC 0.78, 95% CI 0.70 to 0.85) and MCF (Fig. 4b; AUC 0.73, 95% CI 0.63 to 0.81) on FIBTEM.
A cut-off value of 1.50 g l−1 for plasma fibrinogen concentration measured by the Clauss method predicted significant postoperative bleeding with a sensitivity of 68.9% and a specificity of 83.8%, while a cut-off of 3 mm for MCF on FIBTEM predicted significant postoperative bleeding with a sensitivity of 78.6% and a specificity of 70%.
The relationship between plasma fibrinogen concentration and postoperative bleeding is well known in adult cardiac surgery patients. Blome et al.19 identified an inverse association between preoperative and postoperative plasma fibrinogen concentrations and postoperative bleeding. In addition, these authors observed that plasma fibrinogen concentration spontaneously increased after surgery and returned to normal ranges after 24 h. These results are in accordance with those observed in a recent study published by Solomon et al.,20 and our own.
In children undergoing cardiac surgery, the relationship between plasma fibrinogen concentration and postoperative blood loss has not previously been adequately assessed. In a small study including 21 children undergoing cardiac surgery, Hayashi et al.6 found that MCF was correlated with postoperative chest tube drainage (r = –0.64, P < 0.001) and surgery time (r = –0.51, P < 0.02), but no correlation with plasma fibrinogen concentration was calculated. In our study, we assessed the relationship between postoperative blood loss and plasma fibrinogen concentration. We found clearly that low plasma fibrinogen concentration is associated with significant postoperative blood loss.
On the basis of the current literature, fibrinogen supplementation might be effective in preventing and treating postoperative blood loss in both adult and paediatric cardiac surgery patients.21 However, several questions remain unresolved.
- What component should be used for fibrinogen replacement?
- What is the best tolerated and effective plasma fibrinogen concentration that should be targeted?
- Which test should be used to guide fibrinogen administration?
Fibrinogen supplementation should be achieved using large volumes of FFP, or administration of either cryoprecipitate or fibrinogen concentrate. However, FFP contains only a ‘physiological’ concentration of fibrinogen (2.0 to 2.5 g l−1) and therefore a large volume of FFP is required to rapidly increase plasma fibrinogen concentration.22 Cryoprecipitate is not available in many European countries, but fibrinogen concentrate can be used as an alternative. In 2009, Rahe-Meyer et al.23 evaluated the efficacy of fibrinogen concentrate administration in patients undergoing complex aortic procedures. The dose of fibrinogen concentrate required was calculated using a formula based on the MCF on the FIBTEM performed after the removal of the aortic clamp. The targeted MCF on FIBTEM used in that small study (15 patients) was as high as 22 mm. They reported that, when compared with patients treated with a standardised algorithm-based therapy, FIBTEM-guided fibrinogen concentrate administration was associated with decreased 24-h postoperative blood loss and a reduction in transfusion requirements. Fibrinogen concentrate was recently used as a first-line therapy in algorithm-based management of the bleeding patient.12 In that first prospective, randomised study performed in patients undergoing aortic surgery, fibrinogen concentrate significantly reduced the transfusion of allogeneic blood products.24 However, further well designed, prospective, randomised controlled trials assessing the efficacy and the safety of fibrinogen concentrate in cardiovascular surgery, in particular in the paediatric population, are required before such therapy could be recommended in routine practice.
Controversies also exist regarding the optimal plasma fibrinogen concentration to be maintained in the bleeding patients in different clinical settings. Recently published trauma guidelines14 recommended maintaining plasma fibrinogen concentration in the range 1.5 to 2.0 g l−1. In addition, they recommend the use of ROTEM to guide fibrinogen administration. Considering that a MCF on FIBTEM greater than 7 mm was correlated with a plasma fibrinogen concentration of more than 2.0 g l−1, a cut-off value of 7 mm for MCF on FIBTEM was proposed.25 In the cardiovascular setting, the recent guidelines published by the European Society of Anaesthesiology recommended the administration of fibrinogen concentrate to maintain a fibrinogen concentration of more than 3.8 g l−1.15 This huge variability between recommendations results from the lack of any dose-finding study for fibrinogen supplementation. This is particularly true in children undergoing cardiac surgery, where no study exists. Therefore, no recommendation can be formulated in this population.
Traditionally, plasma fibrinogen concentration is measured with the Clauss Method using automated coagulation analysers.16 More recently, fibrinogen measurements have been proposed using point-of-care monitoring based on the viscoelastic properties of the clot: thromboelastography (TEG Haemostasis system; Haemoscope Corporation, Niles, Illinois, USA) or ROTEM. Both tests have shown a good correlation with the standard method.26
In the paediatric population, Haas et al.27 reported an excellent correlation between MCF on FIBTEM and plasma fibrinogen concentration (r = 0.88) in children undergoing elective major surgery. A good correlation was also observed in our paediatric cardiac surgical population (r = 0.70).
The cut-off value for plasma fibrinogen concentration determined with the Clauss method in our study is similar to the value reported in the literature (>1.5 g l−1).28 However, we found that the cut-off value for MCF on FIBTEM is much lower than the value defined in previous studies (3 compared with >7 to 9 mm). In our population, applying a cut-off value of 9 mm, 110 children in the ‘nonbleeders’ group should have required a therapeutic intervention, but these patients did not experience significant postoperative blood loss.
The discrepancy between our results and those arising from the literature could be explained by several factors. First, Osthaus et al.29 reported that infants with congenital heart disease, and in particular those with cyanotic disease, exhibited significantly lower baseline ROTEM values than adults. This lower baseline value may partially explain the lower cut-off value we observed in our population of both cyanotic and noncyanotic children.
Second, in our study, children received a starch solution in the CPB prime, and the effects of starches on haemostasis and in particular on ROTEM parameters have been well described.30–32 Starches have also been shown to affect measurement of plasma fibrinogen concentration with the Clauss method.33 Therefore, the use of HES 130/0.4 in our population may have contributed to the lower MCF cut-off value. Alternatively, it may also have influenced the cut-off value we observed for plasma fibrinogen concentration. From a clinical point of view, it should be noted that, in our population, the use of 6% HES 130/0.4 has not been associated with significantly higher perioperative blood loss or other side effects when compared with 4 or 5% albumin.34,35 In addition, the association between HES 130/0.4 administration and increased perioperative blood loss has recently been contradicted in a review of the literature.36 In the present study, although the volume of HES 130/0.4 used was higher in the ‘bleeders’ than in the ‘nonbleeders’, the volume of HES 130/0.4 was not found to be a predictive factor of postoperative bleeding in multivariate logistic regression analysis.37 Finally, 6% HES 130/0.4 was used in all children in this study, which was not designed to assess the relationship between 6% HES 130/0.4 and postoperative blood loss.
Third, this discrepancy could also be explained by different surgical practices. Indeed, as shown in the multivariate regression analysis, wound closure time was independently associated with increased postoperative blood loss. This observation indicates that our surgeon took additional time to perform haemostasis in children with increased bleeding tendencies.
Our study has some limitations. First, we performed a retrospective analysis of prospectively collected data, which led to the inclusion of a smaller number of children in the ‘bleeders’ group. The design could be associated with bias, which we attempted to minimise by using univariate and multivariate logistic regression analyses. Second, the amount of postoperative blood loss used to allocate children into each study group was defined arbitrarily using an approach similar to that used by Williams et al.18 Third, we did not assess platelet function in our population, although platelet function could also potentially influence bleeding. Data regarding the use of platelet function in children undergoing cardiac surgery are sparse. Hofer et al.38 published the only study that has assessed platelet function in children with congenital heart disease. Their results indicate higher blood loss in cyanotic patients when compared with acyanotic patients despite better platelet aggregation. The authors concluded that platelet function assays alone might not be suitable for predicting increased perioperative blood loss. Further studies are needed to better define the relationship between platelet function, ROTEM measurements and postoperative blood loss.
Finally, haemostatic therapy was administered using a well defined protocol, but the definition of abnormal bleeding was left to the discretion of the clinicians.
In conclusion, our study has highlighted the relationship between plasma fibrinogen concentration measured either by the Clauss method or MCF on FIBTEM, and early postoperative blood loss. Because the test is available rapidly at the bedside, MCF on FIBTEM should be preferred to guide fibrinogen replacement. Further prospective studies are needed to assess the effect of fibrinogen replacement on postoperative blood loss and outcomes in children undergoing cardiac surgery with CPB.
Acknowledgements relating to this article
The work is attributed to the Department of Anaesthesiology, CHU-Brugmann – QFCUH, Brussels, Belgium.
Assistance with the study: none.
Financial support and sponsorship: this work was supported solely by sources from the Department of Anaesthesiology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
Conflicts of interest: none.
Presentation: this work was presented at the Network for the Advancement of Transfusion Alternatives symposium, 19 April 2013, Vienna, Austria.
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