Eur J Cardiothorac Surg 2002;22:200-205
© 2002 Elsevier Science NL
Significant merits of a fibrin sealant in the presence of coagulopathy following paediatric cardiac surgery: randomised controlled trial
M. Codispoti,
P.S. Mankad*
Department of Cardiac Surgery, Royal Hospital for Sick Children, Sciennes Road, Edinburgh EH3 9YW, UK
Received 19 September 2001;
received in revised form 25 March 2002;
accepted 1 May 2002.
* Corresponding author. Tel.: +44-131-536-3692; fax: +44-131-536-3482
e-mail: pankaj.mankad{at}luht.scot.nhs.uk
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Abstract
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Objectives: The efficacy of a fibrin sealant in paediatric cardiac surgery has been demonstrated. However, its effectiveness in the presence of significant untreated coagulopathy has not been addressed. This study was designed to investigate the role of the topical application of a fibrin sealant, Beriplast® P (BP), in the presence of coagulopathy following paediatric cardiac surgery. Methods: After confirming the presence of significant post-bypass coagulopathy, patients undergoing repair of congenital heart defects using cardiopulmonary bypass were randomised to the use of BP (group BP) or no intervention (group C). BP was applied over suture lines and microvascular bleeding sites. Criteria for transfusion of blood and blood products were standardised for both groups. Outcome variables were: (1) post-operative bleeding; (2) transfusion of blood and blood products; (3) theatre time to achieve haemostasis; (4) ventilation time, intensive therapy unit (ITU) and hospital stay. Results: Fifty-two patients (n=26 in each group), aged 3 days to 17.4 years were recruited. There were no hospital deaths and no significant differences in demographic or intraoperative variables that might have affected the chosen endpoints. After protamine, all patients in both groups had significant coagulopathy (P
0.05 versus baseline). There were fewer patients receiving transfusions of fresh frozen plasma (FPP) in the intervention group, when compared to the control group (P0.05). Patients receiving BP spent less time in theatre to achieve haemostasis (P0.05), had a lesser amount of bleeding intraoperatively (P0.01), at 4 h (P0.05) and at 24 h (P0.05), required a lower amount of transfusions of red cells (P0.01), FPP (P0.05) and platelets (P0.05). There were no differences in ventilation time, length of stay in ITU or in hospital. Conclusions: Even in the presence of significant coagulopathy, intraoperative use of fibrin sealant in paediatric cardiac surgery reduces the amount of bleeding and need for transfusions of blood and blood products. The theatre time necessary to achieve haemostasis is also significantly reduced. These findings have a potential to improve clinical outcomes and enhance cost benefits.
Key Words: Fibrin sealant • Paediatric cardiac surgery • Haemostasis • Blood conservation • Coagulopathy
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1. Introduction
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Coagulopathy following paediatric cardiac surgery is a common occurrence [1]. This is mainly due to haemodilution and consequent depletion of clotting factors plus platelet dysfunction [1–4]. A direct association between this post-cardiopulmonary bypass (CPB) coagulopathy, blood loss and transfusion requirements has been documented [5].
A number of adjunctive systemic pharmacological and topical haemostatic agents are often used clinically to reduce blood loss, and blood and blood product transfusions in paediatric cardiac procedures. These include aprotinin, 
-aminocaproic acid and topically applied haemostatic agents, such as Gelfoam, Surgicel, Thrombinar, Spongistat and various fibrin preparations [6].
Fibrin sealants contain fibrinogen, thrombin, factor XIII, an antifibrinolytic agent, and calcium chloride. By reproducing the final steps in the coagulation cascade, they form a stable clot, arrest blood loss, and promote wound healing. A few controlled clinical trials of fibrin preparations in adult population indicate that their use is safe and effective in promoting blood conservation [6,7]. Stark and de Leval have explored potential use of a fibrin sealant in paediatric cardiac surgery [8].
However, the efficacy of fibrin sealants in the presence of coagulopathy has not been investigated. The aim of this study was to evaluate the safety and efficacy of Beriplast® P (BP, Aventis Bohering, Marburg, Germany), a fibrin sealant set with highly purified and pasteurised individual components (fibrinogen concentrate, factor XIII, aprotinin, human thrombin, and calcium chloride) as a topically applied haemostatic agent in paediatric open-heart surgery.
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2. Methods
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After receiving approval of our regional ethics committee and informed parental consent, neonates, infants and children undergoing elective open-heart surgery were enrolled in this prospective, open-label, controlled study. All children were operated on by a single surgeon at one institution. Patients with hepatic or renal disease, congenital or acquired conditions leading to bleeding diathesis, those undergoing redo procedures and who had taken antiplatelet or anticoagulant agents within 7 days before surgery were excluded from the study.
Extracorporeal circulation was accomplished with a roller pump (Stockert Instruments, Munich, Germany), flexible venous reservoir, cardiotomy reservoir (Avecor Cardiovascular Ltd), and a membrane oxygenator (Avecor solid silicone membrane type 0400, 0800, 1500-2A) in all cases. Systemic anticoagulation was achieved using porcine unfractionated heparin (300 IU/kg) throughout the duration of CPB, maintaining an activated coagulation time (ACT) greater than 480 s. Modified ultrafiltration was performed at the end of bypass for all patients, to achieve a haematocrit value between 33 and 36%. After reversing the heparin effect with protamine sulphate and confirming absence of residual circulating heparin by means of a heparinase ACT test (Medtronic HemoTec ACT II, Colorado, USA), prothrombin time (PT) and activated partial thromboplastin time (aPTT) were obtained on site (Hemochron Jr, International Technidyne Corp, Edison, NJ, USA) and subsequently confirmed on laboratory-based tests performed on the same blood sample. Patients showing a prolongation of PT or aPTT equal to or greater than 50% from baseline were randomly assigned to either topical application of BP (group BP) or standard treatment alone (group C). BP was supplied on a named patient basis under Doctors and Dentists Review Body (DDRB) Drug Exemption certificate held by the senior author. After securing the ‘surgical’ sites of bleeding, a subjective assessment of the generalised oozing in the operative field was made by the operating surgeon on a 5-point scale (1 being the lowest and 5 the highest grade of bleeding – Table 1). Patients randomised to the BP group received topical application of BP (patients' body weight 10 kg, 1 ml; body weight >10 kg, 2 ml) as per manufacturer's guidelines to multiple sites, including: suture lines of vascular anastomoses (needle application); raw myocardial surface (spray application); mediastinal tissues and pericardium (spray application). The mediastinum was packed with swabs. Five minutes after the application of BP, a second assessment was performed and graded as described earlier. In patients with chest drainage 
3 ml/kg/h in the first 4 h post-operatively, blood and blood products were given according to a previously validated and standardised transfusion algorithm (Table 2) [9]. Intraoperative bleeding was measured from neutralisation of heparin effect until chest closure and post-operative bleeding at 4 and 24 h from chest closure. Chest drains were connected to the collecting chamber at the time of insertion of the first sternal suture. Time to chest closure was measured from neutralisation of heparin effect to insertion of the first sternal suture.
Based on data from our previous study on a similar patient population [10], a sample size of 25 patients in each group was selected to give a power of 0.8 to detect as significant at the 5% level, a true mean difference of one standard deviation for the primary outcome measures under consideration. Primary endpoints were blood loss, usage of blood and blood products, and time spent in theatre from neutralisation of heparin to sternum closure, whilst secondary outcome measures were ventilation time, duration of stay in the intensive care unit, duration of hospital stay, and status at discharge. All parametric data were analysed by two-tailed Student t-test, whilst non-parametric variables were compared using the 
2 Fisher's exact test. A P value less than 0.05 was considered significant.
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3. Results
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During a 9-month period, 52 patients out of 84 operated for repair or palliation of congenital cardiac defects, on CPB, satisfied the selection criteria and were enrolled in the study. One patient in each group was subsequently excluded from the analysis due to an obvious source of surgical bleeding found at re-exploration. There were no hospital deaths and no re-explorations for non-surgical bleeding in either of the groups. There were no adverse reactions to BP in the intervention group. The study groups were comparable with regards to age, weight, complexity of surgical repair, duration of CPB, pre-operative coagulation profile and a number of other variables, as outlined in Table 3.
A significant degree of coagulopathy was observed in both treatment groups after administration of protamine (Table 4). In particular, there was a significant percentage reduction in the number of platelets (BP group: -72.4%; control group: -65.5%. P0.01 versus baseline in both groups) and in the concentration of fibrinogen (BP group: -62.5%; control group: -71.8%. P0.01 versus baseline in both groups). The significant depletion of clotting factors was further demonstrated by prolongation of PT (P0.01) and aPTT (P0.01) (Table 4) observed after administration of protamine.
The objective assessment of the amount of bleeding noted in the surgical field by the operating surgeon showed no differences between groups after administration of protamine and prior to chest closure. Mean volume of BP applied was 1.7±0.1 ml. Significant and immediate subjective difference was noted in the treatment group with respect to microvascular oozing and general bleeding. This was reflected in the observed bleeding score at 5 min after BP application (Table 4).
Blood loss, intraoperatively (post-heparin neutralisation), and post-operatively at 4 and at 24 h, was significantly reduced at all time points in patients treated with BP compared with the control group (Fig. 1
).
With regard to post-operative transfusion requirements, fewer patients in the BP group required transfusions of blood and blood products than in the control group (Table 5). Furthermore, after administration of protamine, patients treated with BP required significantly smaller volumes of red cell concentrate (RCC), fresh frozen plasma (FFP) and platelets than patients in the control group (Table 5).
Time to chest closure was also significantly shorter for patients treated with BP compared with controls (11.6±0.9 versus 28.8±1.4 min, respectively; P<0.001).
No significant differences were seen between the two groups with respect to ventilation time (group BP: 37.1±7.2 h; group C: 42.5±15.3 h, P=0.76), length of stay in intensive care (group BP: 100±20 h; group C: 101±42 h, P=0.97) and in hospital (group BP: 13.4±1.9 days; group C: 12.1±1.8 h, P=0.63).
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4. Discussion
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Excessive perioperative bleeding is a major cause of increased morbidity and mortality in patients undergoing cardiac surgery [11]. Management of excessive bleeding often includes the administration of blood products and occasionally reoperation may be necessary [12]. Blood transfusions carry with them the risk of transmission of potentially fatal blood-borne infections, such as hepatitis C [13]. Furthermore, the use of homologous transfusions has been found to be associated with a dose-dependent increase in the risk of post-operative infection, which may be due to transfusion-induced immunosuppression [14]. The additional risks posed by the transfusion of blood and blood products in paediatric patients have been described [15], and are mainly due to their adverse effects on the pulmonary vascular bed and on the myocardium. Meticulous surgical haemostasis and careful management of excessive post-operative bleeding are, therefore, essential to minimise the need for transfusions in patients undergoing cardiac surgery.
Although the safety of fibrin sealants and their efficacy in reducing blood loss have been demonstrated [16,17], there is a relative paucity of prospective clinical trials, especially in paediatric cardiac surgical practice. This study demonstrates the efficacy of BP in reducing blood loss and the requirements for transfusion of blood and blood products in a group of paediatric cardiac surgical patients with significant post-CPB coagulopathy.
Fibrin sealants have been shown to reduce the incidence of perioperative haemorrhagic complications in patients affected by coagulation disorders undergoing a variety of orthopaedic, dental and general surgical procedures [18]. In spite of meticulous surgical techniques, miniaturisation of bypass circuits, optimal management of extracorporeal circulation [10], of anticoagulation and its reversal [9], the use of antifibrinolytics and of modified ultrafiltration, paediatric patients undergoing cardiac surgery still show a significant degree of coagulopathy that results in considerable blood loss and need for transfusions [2]. The risks of these adverse events and their negative consequences increase inversely with patients' age and body weight. For these reasons, paediatric cardiac surgical patients could benefit greatly from surgical adjuncts aiming at counteracting pronounced bleeding diathesis. In this study, the application of BP in patients with documented coagulopathy had several positive effects:
- The amount of perioperative haemorrhage was significantly reduced immediately after administration of protamine. During this time, often used to pack the operating field with swabs and waiting for results of the coagulation screen and/or for the arrival of blood products, we noted the highest difference in the amount of haemorrhage between patients treated with BP and the untreated control group. An increased tendency to bleeding during this crucial phase of the operation perpetuates the vicious cycle of coagulopathy
bleedingdepletion of clotting factors and haemodilution; thus worsening coagulopathy. This renders attempts at correcting the coagulation disorder even more difficult. The use of BP has been shown to be effective in breaking this vicious cycle in its early stages by forming a transparent superficial haemostatic film. This particular characteristic is highly desirable in fibrin sealants, especially when they are applied over vascular anastomoses, as they preserve the possibility of inspecting needle holes in vascular prostheses and other bleeding sources amenable to conventional surgical repair. The persistence of a significantly lower amount of chest drain output in the intervention group underlines the efficacy of BP in preventing clot lysis and controlling haemorrhage in the post-operative period.
- Fewer patients received transfusions of blood and blood products. This represents a desirable outcome in any patient population, since despite the use of increasingly sophisticated screening techniques, the risk of transmission of transfusion-related infection is still not negligible [13]. Therefore, a significant reduction in the need for transfusions of blood and blood products may have direct and indirect beneficial effects in reducing risks of infection and adverse reactions, improving clinical outcomes and reducing hospital costs.
- Even though some patients in the intervention group did require transfusion of blood and/or blood products, the volume of transfused red cells and other blood products was significantly less in patients receiving BP, thereby maintaining a quantifiable benefit compared to the control group. The potential for adverse reactions to transfused blood products, namely pulmonary hypertension and myocardial depression [15], was thus reduced.
- The utilisation of theatre time spent to achieve haemostasis was significantly reduced. This shortening of operating time has the potential of decreasing the risk of developing wound infection and of lowering hospital costs. In an era of increasing awareness for health care costs, even those interventions proven to lead to better patient outcomes need to show financial advantages. This study was not designed to investigate the potential health economics benefits that could occur as a consequence of the decreased blood loss, lower need for transfusions and shorter utilisation of operating rooms. In the UK, in fact, the provision of blood transfusion services is free at the point of use. Moreover, in the absence of a clear billing system, it is difficult to quantify the economic advantages of a shorter operating time.
Recently reported potential ability of fibrin sealants to reduce the formation of post-operative intrapericardial adhesions in experimental studies [19] may provide additional desirable effects in paediatric patients undergoing several cardiac surgical procedures during their life. Despite the above-described benefits, this study did not have sufficient power to demonstrate an improvement in raw clinical outcome measures, such as ventilation time, intensive therapy unit (ITU) and hospital stay. Further multicentre studies on larger patient populations are suggested to illustrate the clinical impact of the use of fibrin sealants in paediatric practice.
Although a theoretical risk of transmission of blood-borne infections via fibrin sealants exists, there have been no reports of such occurrences to date. Nevertheless, there have been reports of development of antibodies to bovine thrombin and human clotting factor V and X following exposure to fibrin sealant [20], leading to bleeding complications and difficulty in monitoring clotting times upon re-exposure [21]; the use of a fibrin sealant containing human thrombin is, therefore, recommended to prevent this undesirable side-effect of fibrin sealants.
In summary, this study demonstrates the effectiveness of BP in reducing not only blood loss but also blood and blood product requirements in paediatric patients undergoing open-heart surgery, even in the presence of coagulopathy. We feel that a serious consideration should be given to the routine use of fibrin sealants in paediatric cardiac surgical patients at risk of developing post-operative coagulopathy.
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Acknowledgments
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This study was part-funded by Aventis Behring. Dr Codispoti was supported by grants from the British Heart Foundation and the National Heart Research Fund. We thank Dr Angela Thomas and her team for their precious technical assistance with the haematological assays, Dr Orestis Papasouliotis for his expert advice on the statistical methods and all the staff members of the Cardiac team for their valuable support.
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Appendix A. Conference discussion
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Dr S. Levitsky (Boston, MA, USA): We performed exactly the same study in 1987 with Tisseel, which is similar to the fibrin sealant that you used, though manufactured by a different company. We did the study in adult patients using the same protocol to prevent bleeding in patients who were undergoing adult cardiac surgery and found exactly the same results.
We also performed a series on children, off-label at that time, with my associate, Dr Pedro Del Nido, when we were both at the University of Illinois, and found exactly the same results. I know Dr Del Nido uses Tisseel at Children's Hospital and we continue to use Tisseel at the Beth Israel Deaconess Hospital in Boston for patients who have bleeding post-operatively, finding very similar results that you have, and with a new added use, which I am certain is occurring in Europe as well as the United States, and that's the problem with antiplatelet drugs.
When we have to operate emergently on patients who are on intravenous antiplatelet drugs, we spend a significant period of time managing the pinpoint bleeders at every suture line, usually on the ascending aorta in elderly patients. We find that Tisseel is extremely useful in stopping bleeding from these pinpoint areas, and, as you found in the children, allowing us to get out of the operating room with lesser amounts of blood product utilization and also for a shorter period of time.
Dr Codispoti: Your centre was, in fact, one of those participating in the multicentre trial looking at Tisseel effects. Since then, as you say, the market has been inundated by a variety of products, most of which, including Beriplast® P, use highly purified human thrombin and fibrinogen. We were indeed very pleased with the results of this study, so that we have now changed our practice and routinely use fibrin sealants in all patients undergoing open-heart surgery.
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References
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Abstract
1. Introduction
