Topical use of antifibrinolytic agent to reduce postoperative bleeding after coronary artery bypass surgery

Objective: Antifibrinolytic agents reduce bleeding after cardiac surgery, but there are adverse effects after their systemic use. These effects are avoided by topical application of antifibrinolytic agents in pericardial cavity. We compared the effects of topically applied epsilon-aminocaproic acid Trabalho realizado na Disciplina de Cirurgia Cardiovascular da Faculdade de Medicina do ABC e Serviço de Cirurgia Cardiovascular do Hospital Estadual Mário Covas, Santo André, SP, Brasil. Endereço para correspondência: João Roberto Breda. Rua Antonio Bastos, 755 Apto. 31. Santo André, SP, Brasil. CEP: 09040-220. E-mail: jrbreda@hotmail.com Artigo recebido em 5 de janeiro de 2009 Artigo aprovado em 20 de julho de 2009

randomized double-blind study.The selected candidates were patients holding chronic coronary insufficiency referred to myocardial revascularization surgery, performed with the aid of extracorporeal circulation (ECC).
The criteria for exclusion were: previous diagnosis for coagulation disorder, associated operations (in addition to myocardial revascularization), minimally invasive myocardial revascularization, reoperations, urgent or emergency procedures.
The clinical and demographic characteristics of both groups of patients are described in Table 1.
The protocol of the study was approved by the Ethics and Research Commission of the Faculdade de Medicina do ABC (FMABC) and the patients agreed in participating of the study by signing an agreement term.

Surgical technique
The operation started with hemodynamic monitoring with mean blood pressure measurement, central venous pressure and urinary debt, as well as pulse oximetry control.
The operation was performed in a conventional manner; the method of access in all cases was mean sternotomy.It was used an aortic cannula from the inferior vena cava through the right atrium after the endovenous administration of heparine (400 UI/Kg) in order to obtain activated coagulation time (ACT) higher than 480 seconds, with mild hypothermia and myocardial protection by controlled hypoxia with intermittent aortic clamping.In all cases it was used protamine sulfate for complete reversion of anticoagulation (proportion of 1:1).
At the end of the operation, the patients in normothermia were conveyed to the Postoperative Unit and kept under continuous monitoring.
All patients were followed-up during hospital evolution

INTRODUCTION
The systemic use of antifibrinolytic agents remains controversial, with conflicting evidences in terms of benefits and adverse events [1].Therefore, the topical use of these agents, in the pericardial cavity, started to be considered as an alternative for reducing bleeding after cardiovascular surgeries [2,3].
Nevertheless, similarly to the systemic use, the topical application of antifibrinolytics in the pericardial cavity is not a routine procedure in cardiac surgeries [4].The topical application of tranexamic acid (TA) and aprotinine have already been tested in previous works and, one of the main reasons not to recognize the regular use of these agents is the lack of evidences of their potential benefits [3,4].
In 2000, De Bonnis et al. published a randomized study demonstrating a small clinical benefit favorable to the topic use of TA when compared to a placebo [5].More recently, in 2007, Baric et al. compared the effects of topical application of TA, aprotinine and placebo over postoperative bleeding of 300 patients submitted to cardiac surgery, concluding the benefits in the topical use of antifibrinolytic agents [6].
The objective of this work is verifying the effect of the topical application of EACA in the pericardium of patients submitted to myocardial revascularization surgery, comparing the postoperative bleeding volume and the need for hemoderivative transfusion, between the antifibrinolytic and placebo groups.by the same member of the surgical group, filling out a protocol for analysis of the preoperative and postoperative data.

Pharmacologic protocol
After the selection, the patient was randomized in one of the two study groups.A paramedic not directly involved in the research prepared the medication that was used topically in the patient, in an appropriate place and outside the operation room, containing 24g of EACA diluted in salty solution (in a total volume of 250 ml) or simply salty solution (also 250 ml).The solution was sent to the operation room containing only an identification number; none of the members of the surgical group or the postoperative unit were aware of the liquid content to be applied in the pericardial cavity.
In all patients the anti-aggregating therapy was interrupted 5 days prior to the operation and restarted 24 hours after the surgical procedure with the introduction of an acetylsalicylic acid (ASA) dosage of 100 mg/day.

Statistical analysis
The choice for central tendency measures and value dispersion of which the samples are composed, as well as the statistical tests for their comparison was based on the distribution type by the Kolmogorov-Smirnof test.For all the analysis it was used the program SPSS ® version 13.0 (SPSS Inc ® , Illinois, U.S.A.).
The values obtained by the study of each quantitative variable were organized and described by the mean and standard deviation.For the qualitative variables there were used absolute and relative frequencies.
Comparisons of frequency events between qualitative variable groups were performed by the application of the exact test of Fisher and qui-square.For the comparison between the averages of two sample populations there were used the "t" test of Student and the "U" test of Mann-Whitney for parametric and non-paramedic variables, respectively.
The postoperative bleeding through the drains in the first 24 hours (EACA group 154,66±74,64 x placebo group 220,21±136,42 ml; P=0,031) it was lower in the EACA group, although, in 48 hours (EACA group 259,14±420,07 x placebo group 141,67±142,58 ml; P=0,197) and the accumulated loss until the removal of the drains (EACA group 832,07±576,86 x placebo group 827,50±434,12 ml;P=0,975), no statistically significant difference was observed.The need for transfusion in the EACA group was lower with statistically significant difference (EACA group 185,90±342,07 x placebo In 1993, Tatar et al. published the first work on the topical use of antifibrinolytic agents, demonstrating a positive effect in reducing bleeding and the need for transfusion in 25 patients holding coronary disease, using aprotinine [2].This result was later confirmed in a randomized and doubleblind study, in 100 patients submitted to myocardial revascularization surgery (MRS) [3].
In 1995, Ciçek et al. verified that after the topical application of aprotinine in the pericardium there was no evidence of this substance in the blood of the operated patients and this factor could indicate a decrease in the fibrinolytic "state" of the patients submitted to surgery with the aid of extracorporeal circulation (ECC) [7].
De Bonnis et al. published a randomized double-blind study, with 40 patients submitted to myocardial revascularization surgery and observed a reduction of 25% in the drainage volume in the first 24 hours, although, it did not occur reduction in the transfusion of hemoderivatives [5].
In 2007, Baric et al.Published an analysis of 300 patients submitted to open heart surgery, that were randomized in three group: placebo, tranexamic acid and aprotinine.In this double-blind and prospective study, it was verified a positive effect in the topical application of antifibrinolytic agent: both agents tested (tranexamic acid and aprotinine) reduced in approximately 20% a cumulative blood loss compared to the placebo group.Nevertheless, the work did not revealed significant reduction in the blood and hemoderivative transfusion in the comparison between groups [6].
Starting in 1990, the parenteral use of antifibrinolytic agents was broadly adopted in the cardiovascular operations; this fact was followed of increasing preoccupation with the efficiency and security of these agents.Amongst the three main available drugs, the aprotinine was the most used and tested [8][9][10].In 2007, Ferraris et al. published a recommendation based on the evidences available in the literature as class I (evidence level A): 1. Aprotinine in high doses is indicated for reducing transfusion, the total loss of blood and the need of reexploration in high risk patients submitted to cardiac surgery.The benefits of this application need to be evaluated against the risk of renal adverse effects.2. Aprotinine in low doses is indicated for reducing the number of patients that require blood transfusion and still group 439,42±349,07 ml; P=0,016).The hemoglobin (EACA group 9,18±0,92 x placebo group 8,85±1,48 g/dL; P=0,331) and hematocrit (EACA group 28,15±3,35 x placebo group 26,67±4,15%; P=0,162) no statistically significant difference was evidenced when comparing both groups (Table 5).

DISCUSSION
This study revealed a positive effect of the topical application of the antifibrinolytic agent tested for bleeding reduction, evaluated by the volume drainage by the drains.When comparing both groups it was noticed a decrease of approximately 30% in the drain debt.Blood transfusion was less required with positive results for the EACA group.The cumulative loss of blood during the first 24 hours was lower in the EACA group than in the placebo group (with significant difference).The absence of difference in the accumulated drainage volume until the removal of the drains was expected and had already been identified in previous works, that demonstrated that the best haemostatic effect of these agents lasts up to 6 hours of its introdution [5,7].reduce the total loss of blood in cardiac operations.3. Analogous of the lisine, such as the EACA and tranexamic acid, are indicated for reducing the need of transfusion and reducing the total loss of blood.These agents are less effective than the aprotinine and its security requires additional studies [11].Recently, the sales of aprotinine were temporarily suspended by the laboratory responsible for its production, and this decision was based on the information supplied by the Canadian Study Executive Commission BART (The Blood Conservation Using Antifibrinolytics in a Randomized Trial), whose preliminary results demonstrated that the benefits of the drugs administration in blood reduction were not sufficient for maintaining the continuity of the study [12].
Regarding the uncertainties about the security of the parenteral application of antifibrinolytic agents, its topical application in the pericardial cavity could be a better alternative, with the possibility of reducing the adverse effects of these medications (including renal risk of graft acute thrombosis after myocardial revascularization surgery).We have used the routine parenteral EACA in cardiac operations.However, after reading the article from Baric et al., that analyzed the topical effect of the aprotinine and of the tranexamic acid, we decided to test the efficiency of the EACA applied topically in the pericardium, once this agent was not previously evaluated.Therefore, despite the number of patients included, the results obtained in this work imply a positive effect of the EACA applied topically in the pericardium, possibly representing an acceptable alternative with reduction of the collateral effects of the systemic use of antifibrinolytic agents.A possible complication of the topical use would be the increase of pericardial adherence, thus, causing further complications in an eventual reoperation, however, this situation was suggested in a work that tested the aprotinine and needs additional confirmation [13].
Therefore, based on the results achieved, we concluded that the topical use of the epsilon-aminocaproic acid presented a positive effect in reducing bleeding, particularly in the first 24 hours of postoperative, with a lesser requirement of blood transfusion when compared with the use of placebo.Additional prospective works with a larger number of patients will be necessary to confirm these results.

Table 1 .
Demographical and clinical characteristics of the patients Variables

Table 4 .
Operative data Variables