Epsilon-aminocaproic acid influence in postoperative bleeding and hemotransfusion in mitral valve surgery

1. Master’s Degree, Assistant Professor of Cardiovascular Surgery at UFMS. 2. Resident Physician in Cardiology at Heart Hospital – HCOR – São Paulo, SP. 3. Graduate Student of Medicine; Academic Director of the League of Cardiology and Cardiovascular Surgery at UFMS. 4. Specialist; Auxiliary Professor of Cardiovascular Surgery at UFMS. 5. Nurse; Head Perfusionist at UFMS. 6. PhD; Associated Professor of Cardiovascular Surgery at UFMS. Ricardo Adala BENFATTI1, Amanda Ferreira CARLI2, Guilherme Viotto Rodrigues da SILVA3, Amaury Edgardo Mont’serrat Ávila Souza DIAS4, José Anderson GOLDIANO5, José Carlos Dorsa Vieira PONTES6 Rev Bras Cir Cardiovasc 2010; 25(4): 510-515 ORIGINAL ARTICLE


INTRODUCTION
Cardiopulmonary bypass (CPB), because it is an event that exposes the blood to a non-endothelial surface, provids changes to the blood crasis, determining a particular tendency to bleeding interfering with the physiology of the organism [1].
Some authors have shown that bleeding postperfusion may be due to inadequate surgical hemostasis and/or disorders of coagulation and fibrinolysis, which justifies the need to proceed with several studies related to its effects and complications, with the purpose of that adversities of the method can be circumvented or minimized [2,3].
During CPB, due to hemodilution, hypothermia, trauma of the blood cells and the release of vasoactive substances, there are changes in platelets, proteins related to coagulation and fibrinolytic system [3][4][5]. About 10 to 20% of CPB patients (adults and children) have excessive bleeding in the immediate postoperative period [3,4].
The risks associated with blood transfusion and its components have encouraged the search for pharmacological agents capable of reducing blood loss as a result of CPB [6][7].
The interventions of pharmacological nature in the prevention of bleeding after infusion based on the administration of several agents, among which the most effective appear to be protease inhibitor, such as aprotinin (APT) and the lysine analogues, such as epsilonaminocaproic acid (EACA) and tranexamic acid (TA). The effectiveness of the preventive regimen with aprotinin has been thoroughly demonstrated in literature. The high cost of the product and the various adverse effects have stimulated the search for alternatives of equal efficacy and lower costs [6][7][8][9][10][11].
Epsilon aminocaproic acid is an antifibrinolytic agent commonly used in cardiovascular surgery in order to inhibit fibrinolysis and reduce bleeding after CPB. This drug blocks the production of plasminogen and tissue plasminogen activator. The EACA combines with plasminogen and plasmin and prevents fibrinolytic enzymes bind to the lysine residues present in the molecule of fibrinogen, thereby preventing fibrinolysis [12].
The doses of epsilon-aminocaproic acid are not as well standardized as doses of aprotinin, however, it is often the administration of a loading dose of 150 mg/kg. The administration should be continued by a continuous infusion of 10 mg/kg/hour for four or five hours, the maximum dose of 24 grams, or one gram per hour [13].
Considering the need to standardize the dose of epsilonaminocaproic acid and evidence of its effectiveness, this research aims to analyze the influence of the use of aminocaproic acid in a dose recommended by the authors in bleeding and the need for blood products in the first 24 hours postoperative of mitral valve surgery.

METHODS
A prospective study in the Department of Cardiovascular Surgery, University Hospital of the Federal University of Mato Grosso do Sul, approved by the hospital Ethics Committee, with the inclusion criteria based on patients undergoing mitral valve surgery and exclusion criteria patients with renal failure, blood, liver or digestive disease, with ischemic heart disease, lesions of two or more valves in patients in cardiogenic shock and emergency surgery, and 42 patients were enrolled in this study according to these criteria.
The mitral valve surgeries were performed by longitudinal median sternotomy with mild hypothermia at 27°C and roller pump.
Patients were randomly divided into two groups: Group I -control, Group II -epsilon-aminocaproic acid, both with 21 patients. In group I, were infused 40 ml saline (SS) 0.9% in central venous access during anesthetic induction, 80 ml in priming of the CPB circuit after full heparinization, 40 ml after heparin reversal with protamine sulfate in 1:1 ratio and 40 ml one hour after the end of surgery in the cardiac recovery in the postoperative period, in group II were infused 5 g of epsilon-aminocaproic acid at the same times in which saline was infused in group I, in a total of 25 grams of epsilon-aminocaproic acid. It should be emphasized that patients and physicians did not know who was using EACA.
The evaluation criterion for blood transfusion in cardiac output was estimated according to the metabolic needs and oxygen transport individualized, or that is, hemoglobin below 7 mg/dL, central venous oxygen saturation less than 50% and arterial oxygen pressure less than 25 mmHg, and bleeding volume greater than 200 ml/ h during the first 4 hours.
The groups were similar with respect to factors that could influence postoperative bleeding and transfusion required: age, sex, weight, height, duration of CPB, valve replacement or repair, blood coagulation and platelet count. We evaluated the volumes of bleeding and infusion of packed red blood cells in the first 24 hours postoperatively. The infusions of blood products (platelets, fresh frozen plasma and cryoprecipitate) were similar between groups.
The analysis of quantitative variables was performed by comparing means (with previous verification of the normal distributions), using the Student t test and Mann-Whitney test, and for analysis of categorical variables we used the chi-square and chi-square test with Yates' correction (2x2 tables). The level of significance was P <0.05.

RESULTS
Analysis of anthropometric variables showed no statistically significant difference.
The CPB time had an average of 45.48 minutes (min) in the control group and the EACA of 50.24 min (P = 0.3447).
The group I had a mean bleeding volume of 633.57 milliliters (ml) during the first 24 hours postoperatively, and Group II average of 308.81 ml, observing a statistically significant difference (P = 0.0003) - Figure 1. The mean volume of blood transfusion (Figure 2) in the first 24 hours in groups I and II were, respectively, of 942.86 ml and 214.29 ml, significant difference (P <0.0001), as shown in Tables 1-4.
As to the need for blood transfusion, it was found that all patients in group I needed infusion of blood products, and only eight patients in group II required the same (P <0.0001). Comparing the type of surgery performed, whether plasty or valve replacement, there was no statistically significant difference between the two groups (Tables 3  and 4).    (1) 0.0003 (1) <0.0001 (2) Note: if P < 0.05 -significant difference, (1)

DISCUSSION
The risks associated with blood transfusion and its components have encouraged the search for pharmacological agents capable of reducing blood loss as a result of CPB [6]. The frequency of excessive bleeding is variable. It was considered, in 13% to 16% of patients observed, an abnormal bleeding, translated by the need for transfusions of 10 units of packed red blood cells, or more in the perioperative period [14].
Among the patients analyzed in this investigation, there was no bleeding exceeding 1200 ml, with a mean of 308.81 ± 210.1 bleeding ml, showing that the use of epsilonaminocaproic acid, in this sample, in mitral cardiac surgery with use of CPB reduced bleeding and use of blood products. It should be noted the difficulty in quantifying the bleeding during surgery. It is justifiable, and in some cases and in accordance with the criteria mentioned in the method of blood transfusion, blood transfusion volumes greater than volumes of postoperative bleeding in the first 24 hours.
Karski et al. [15] reported incidence of 18% of patients undergoing surgery using CPB, with a great need for blood and blood products, increasing the risk of infection and transfusion reactions.
DelRossi et al. [16] concluded that prophylactic treatment with epsilon-aminocaproic acid in cardiac surgery requiring CPB may reduce bleeding in a safe and tolerable manner.
Montesano et al. [17] analyzed the effects of low doses of epsilon-aminocaproic acid in patients undergoing coronary artery bypass grafting. It was used 5 g of epsilonaminocaproic acid immediately before the start of the infusion, a single dose. It was observed a lower bleeding and less need for blood transfusion, statistically significant.
Breda et al. [18] concluded that the topical use of antifibrinolytic agents in pericardial cavity of epsilonaminocaproic acid had a favorable effect in reducing bleeding in the first 24 hours postoperatively and in the need for blood transfusion after coronary artery bypass grafting when performed.
In this study, two groups of patients were similar in all parameters except the amount of bleeding and blood transfusions. It can be verified that the group I had an average volume of 633.5 ± 305.7 bleeding ml and group II, 308.8 ± 210.1 ml, with a significance level statistically significant (P = 0.0003). There was also a decrease in the use of blood products, since in group I (control) were infused a mean of 942.8 ± 345.8 ml, whereas in group II (epsilon-aminocaproic acid), the average was 214.3 ± 330.6 ml, with a significance level less than 0.0001. With the decrease of blood products it can be reduced the risk of infection and transfusion reactions, further supporting the need for the use of EACA. Efficacy of epsilon-aminocaproic acid, among the current options for use of antifibrinolytic agents in relation to the reduction of postoperative bleeding and the need for blood transfusions is questioned and conflicting in many studies literature [19][20][21].
Despite the use of antifibrinolytic is not included in consensus guidelines determining its use as mandatory everyday and in valve surgery, the results of this study, in the dose used, show that epsilon-aminocaproic acid has real importance in relation to postoperative bleeding and use of blood products in mitral valve surgery. It should be emphasized that in the dose given, in patients with normal hepatic and renal function, there is an absence of thrombosis and hypersensitivity reactions [22].

CONCLUSION
The present investigation shows that the epsilonaminocaproic acid, in the prescribed dose, was able to reduce the amount of bleeding and need for blood products in the immediate postoperative period of patients undergoing mitral valve surgery.