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J Thorac Cardiovasc Surg 2004;128:83-91
© 2004 The American Association for Thoracic Surgery
Cardiopulmonary support and physiology |
a Division of Cardiovascular Anesthesia and Intensive Care, Policlinico di Monza, Monza, Italy
b Coagulation Service and Thrombosis Research Unit, San Raffaele Hospital, Milan, Italy
c Department of Anesthesia, San Raffaele Hospital, Milan, Italy
d Division of Cardiac Surgery, San Raffaele Hospital, Milan, Italy
e Epidemiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
Received for publication April 16, 2003; revisions received September 30, 2003; accepted for publication October 7, 2003.
* Address for reprints: Valter Casati, MD, Division of Cardiovascular Anesthesia and Intensive Care, Policlinico di Monza, via Amati 111, Monza (20052), Italy
valter.casati{at}policlinicodimonza.it
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Abstract |
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 Top Abstract Materials and methodsResultsDiscussionReferences |
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METHODS: We enrolled 102 patients scheduled for on-pump (n = 51) or off-pump (n = 51) coronary artery bypass grafting. Patients were separately double-blind randomly assigned to treatment with tranexamic acid (1 g as 20-minute bolus before skin incision, followed by continuous infusion of 400 mg/h, with 500 mg added to priming in patients undergoing on-pump coronary artery bypass grafting) or placebo (saline solution of equivalent volume). Bleeding in the first 24 postoperative hours was the primary outcome. Requirement for allogeneic transfusions, thrombotic complications, outcomes, and monitoring of coagulation, fibrinolysis, and inflammation were also recorded.
RESULTS: Tranexamic acid reduced total postoperative bleeding by 43% in patients undergoing on-pump coronary artery bypass grafting and by 27% in those undergoing off-pump coronary artery bypass grafting (P < .0001), with 80% reduction in bleeding exceeding 600 mL (P < .001), 58% reduction in the requirement for all allogeneic transfusions (P = .07), and no apparent effect on thrombotic complications or outcome. This was associated with a reduction in plasma D-dimer levels (P < .0001), to a greater degree in patients undergoing on-pump coronary artery bypass grafting (P < .0001), and interleukin 6 levels (P < .0001), to a greater degree in patients undergoing off-pump coronary artery bypass grafting (P < .001).
CONCLUSIONS: By affecting fibrinolysis, tranexamic acid significantly reduces bleeding both in off- and on-pump coronary artery bypass grafting and may modulate inflammation in these surgical settings.
Recently, CABG without CPB (OPCAB) was reintroduced in cardiac surgery, initially for selected patients and then for an increasing number of indications.7-9 Avoidance of CPB may reduce the prevalence of perioperative complications, particularly bleeding. However, there are large differences in terms of postoperative bleeding and allogeneic transfusions reported in published studies.10-12 At our institution, prophylactic infusion of tranexamic acid (TA), a synthetic antifibrinolytic drug with demonstrated hemostatic properties in cardiac surgery,13 has been previously studied in different types of patients undergoing cardiovascular surgery with CPB,14-17 and it was also found promising in a pilot study of patients undergoing OPCAB.18 In this study we compared the hemostatic effects of TA in patients undergoing CABG with and without CPB and evaluated the effects of this drug on selected coagulation, fibrinolysis, and inflammation variables.
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Materials and methods |
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TopAbstractMaterials and methodsResultsDiscussionReferences |
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A total of 102 patients were enrolled: 51 patients constituted the OPCAB group, and 51 constituted the ONCAB group. By means of two separate computer-generated random number sequences, the patients assigned to OPCAB and ONCAB were double-blind randomly assigned to receive TA or placebo. TA was administered as a bolus injection of 1g in 20 minutes before skin incision, followed by a continuous infusion of 400 mg/h until completion of surgery. Placebo consisted of an equivalent volume of saline solution. In ONCAB surgery, 500 mg of the drug or an equivalent volume of saline solution was added to the priming of CPB. The staff in the operating room and the intensive care unit (ICU) were blinded regarding treatment: the correct procedure was ensured by means of coded syringes, prepared by a fellow in anesthesia not directly involved in the perioperative patient care and in the treatment of clinical data. The institutional review board approved the study, and written informed consent was obtained from each enrolled patient.
A standardized protocol of anesthesia was used for all patients.18,19 All the patients were operated on through a full median sternotomy. The left internal thoracic artery was harvested in each patient through conventional pleurotomy access; if required, the saphenous vein was also isolated.
ONCAB technique
Before aortic cannulation, porcine mucous heparin (3 mg/kg) was administered to obtain during CPB an activated clotting time (ACT) longer than 480 seconds. The circuit for CPB included a centrifugal pump for nonpulsatile blood flow and a hollow-fiber membrane oxygenator. The priming solution of the circuit consisted of a balanced crystalloid-colloid solution (1350 mL Ringer lactate, 250 mL 18% mannitol, 150 mL, plasma expander). Blood temperature was kept between 32°C and 35°C. Myocardial protection during aortic crossclamping was achieved with blood cardioplegia according to the Buckberg method. At the end of CPB, the total dose of heparin administered was antagonized with protamine sulfate (1:1 ratio); if required, further doses of 50 mg were administered to obtain an ACT value equal to or shorter than the baseline ACT. The remaining blood in the circuit and that aspired from the surgical field was concentrated with a cell separator and reinfused. During the postoperative period, no autotransfusion of mediastinal shed blood was performed.
OPCAB technique
After the opening of the pericardium, the stabilizing system (Medtronic-Utrecht Octopus System; Medtronic Inc, Minneapolis, Minn) was positioned in the sternal wound. A heparin dose of 1 mg/kg was administered, and an ACT longer than 250 seconds was maintained until the anastomoses were performed with supplementary doses of 50 mg. No drugs were administered to diminish heart frequency. Vessel occlusion was achieved, proximally and distally, with a 4-0 polytetrafluoroethylene suture passed through a silicone tube to avoid the direct contact between the suture and the wall of the coronary artery and tightened by tourniquets. After completion of all anastomoses, the total dose of heparin administered was antagonized with protamine sulfate (1:1 ratio); if required, further doses of 50 mg were administered to obtain an ACT value equal to or shorter than baseline ACT. Only in cases of significant intraoperative bleeding was the shed blood concentrated in a cell separator and reinfused. No postoperative autotransfusion of mediastinal shed blood was performed. In the absence of perioperative bleeding complications patients received acetylsalicylic acid (orally) or lysine-acetylsalicylate (intravenously), starting on the evening of the first postoperative day.
Blood sampling and processing
Samples for hematochemical evaluation were obtained and analyzed as previously reported elsewhere.19 Briefly, sequential venous samples were obtained in all cases through the heparinized distal line of the central venous catheter and collected in siliconized Vacutainer tubes (Becton Dickinson, Plymouth, UK) at the following times: after the induction of anesthesia (time 1), 10 minutes after patient arrival in the ICU (time 2), and 24 hours after the operation (time 3). All samples were obtained with a two-syringe technique with minimal stasis: 10 mL of blood was aspired in the first syringe and discarded, and another 10 mL was then obtained with the second syringe for hematochemical evaluation. Within 1 hour from blood collection, platelet-poor plasma was obtained by centrifugation for 20 minutes at 2000g at room temperature. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured in fresh plasma samples. Aliquots of platelet-poor plasma (0.5 mL) were snap-frozen and stored at –80°C until assay.
Assay methods
All determinations of hemostatic variables were carried out with a fully automated coagulometer (STA Diagnostica; Stago, Asnier sur Seine, France). Reagents for APTT (STA APTT Kaolin), fibrinogen (STA Fibrinogen), D-dimer (STA Liatest D-DI), antithrombin III (amidolytic activity, STA Antithrombin III), and 
2-antiplasmin (amidolytic activity, STA Antiplasmin) determinations were obtained from Roche Diagnostic (Mannheim, Germany). PT was measured with Hemoliance Recombiplastin IL (Instrumentation Laboratory, Lexington Mass), and plasminogen levels (amidolytic activity) were measured with the Coamatic kit (substrate S-2403; Chromogenix AB, Mölndal, Sweden). APTT and PT results were expressed as ratios, with the APTT and PT values measured in normal pooled plasma obtained from 40 healthy volunteers as denominators. The same normal pooled plasma, arbitrarily given a value of 100%, was used to construct calibration curves for all the amidolytic assays.
Plasma immunoglobulin G (IgG) levels were measured by immunonephelometry (Tina-Quant IgG Kit; Boehringer Mannheim, Mannheim, Germany) in a Modular Hitachi 917 (Roche Diagnostic). Interleukin (IL) 6 was measured in citrated plasma by a commercially available enzyme-linked immunosorbent assay kit (Amersham Pharmacia Biotech UK Limited, Buckinghamshire, UK).
Criteria for allogeneic transfusion and surgical reexploration
Patients were transfused only in the presence of signs or symptoms of hypovolemia (hypotension or tachycardia) or diffuse bleeding. Perioperative criteria for allogeneic transfusions were standardized: in both groups packed red blood cells were transfused if the hemoglobin value was less than 8 g/dL or the hematocrit was less than 24% . Fresh-frozen plasma was infused if the PT value after protamine administration was at least 1.5 times the baseline, and platelet concentrates were transfused with platelet counts of 50,000/mm3 or less.
Blood loss was recorded during the first 24 hours, and excessive bleeding was defined as a blood loss greater than 600 mL in 24 hours. Chest drains were removed when bleeding was less than 100 mL in the preceding 4 hours. Surgical reexploration occurred when bleeding in the first 2 hours was greater than 300 mL/h, or when it was greater than 200 mL/h for 4 consecutive hours, with normal coagulation variables.
Secondary outcomes
During the first 24 postoperative hours, possible thrombotic complications as consequence of antifibrinolytic therapy were recorded. These were myocardial infarction (new Q waves at electrocardiography, creatine kinase MB isoenzyme ratio greater than 10%, and troponin I >0.1 ng/dL), acute renal insufficiency (creatinine value twice the baseline or need for dialysis), major neurologic dysfunction (transient ischemic attack or stroke), deep venous thrombosis, and pulmonary embolism.
Statistical methods
Considering as primary outcome the effects of TA on postoperative bleeding, the trial was designed to detect a difference of 200 mL in postoperative bleeding (SD 250 mL) between the groups undergoing the same surgical approach. This design was based on data emerging from a previous study.14 To achieve significance, 25 patients per group were required, with a 1-tailed error of .05 and 80% power. Analysis was conducted on an intent-to-treat basis.
Normality of the distribution of continuous variables was evaluated with the Kolmogorov-Smirnov test. Data are reported as mean ± SD or median with interquartile range (25-75th percentile). Comparisons in continuous variables between patients randomly assigned to treatment in the two surgical groups were performed by analysis of variance after log transformation of nonnormally distributed variables. The 
2 test, the Fisher exact test, or Mantel-Haenszel odds ratios (adjusted for the surgical techniques) were used for comparisons of discrete variables.
The changes in hematochemical variables were evaluated by analysis of variance for repeated measures after log transformation of nonnormally distributed variables, including treatment and surgical technique as factors and preoperative values as covariate. Analysis was conducted on both unadjusted data and data adjusted for hemodilution according to the following formulas: [IgG]initial – [IgG]timepoint/[IgG]initial for hematochemical variables and Hematocritinitial – Hematocrittimepoint/Hematocritinitial for platelet counts. IgG levels were chosen as an indicator of hemodilution because they are not affected by surgery and are not involved in metabolic pathways altered early by trauma. Bonferroni correction was applied for post hoc comparisons.
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Results |
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TopAbstractMaterials and methodsResultsDiscussionReferences |
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Baseline characteristics and operative data are shown in Tables 1 and 2. There were no significant differences for patients assigned to TA or placebo within each surgical group. Patients undergoing OPCAB had lower left ventricular ejection fraction (P = .004) and higher Higgins score20 (P = .0004) than did those undergoing ONCAB (Table 1). Surgical time was significantly longer for ONCAB than for OPCAB (P = .001), and higher doses of heparin and protamine were used in ONCAB (P < .0001).
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The changes in hematochemical variables (unadjusted for hemodilution) are reported in Table 4. Baseline levels of the variables considered were similar in all patient groups (P > .2). With the exception of PT and APTT values (not shown), all variables showed significant variations with time. Changes in hemoglobin, hematocrit, fibrinogen, antithrombin III, and 2-antiplasmin were influenced only by the surgical technique. With the exception of 2-antiplasmin, all these values decreased after the operation (P < .0001), but they decreased to a greater extent in patients undergoing ONCAB than in those undergoing OPCAB (P < .01) and were still lower in patients who underwent ONCAB 24 hours after the operation (P < .0001). Platelet counts decreased to a significant extent after the operation only in patients undergoing ONCAB (P < .0001), and they were still lower 24 hours after the operation in these patients (P < .0001). Both treatment and type of surgery influenced the changes in the other variables examined. Plasminogen levels decreased significantly in all patient groups after the operation (P < .0001), but they decreased to a greater extent in those treated with TA (P < .0001) and in those undergoing ONCAB (P < .0001), and they were still lower in these patients 24 hours after the operation (P < .001).
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After correction for hemodilution, antithrombin III and fibrinogen levels decreased to similar extents in patients undergoing OPCAB and ONCAB, irrespective of treatment (data not shown). Changes in selected hemostatic variables adjusted for hemodilution are shown in Figure 1. Irrespective of treatment, platelet counts decreased after the operation only in patients undergoing ONCAB (P < .0001), whereas, irrespective of type of surgery, plasminogen and 2-antiplasmin levels were lower after the operation in patients receiving TA (P < .0001). In addition, 2-antiplasmin levels were higher in patients undergoing ONCAB than in those undergoing OPCAB (P = .037). D-dimer levels were higher after the operation in patients receiving placebo (P < .001) and in those undergoing ONCAB (P = .002). Fibrinogen and 2-antiplasmin levels 24 hours after the operation (adjusted for hemodilution) were strongly associated with IL-6 levels measured at the end of the procedure (unadjusted for hemodilution, P < .0001). Mirroring IL-6 levels, both variables were higher in patients undergoing ONCAB (P = .0001) and in those treated with placebo (P = .0001), with the modulating effect of TA more pronounced in patients undergoing OPCAB (P = .01, Figure 2).
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Discussion |
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TopAbstractMaterials and methodsResultsDiscussionReferences |
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One of the most common blood-sparing maneuvers in cardiac surgery is the use of drugs with antifibrinolytic properties, such as aprotinin, 
-aminocaproic acid, and TA.13 At our institution TA is widely used in patients undergoing surgery with CPB.14-17 In a previously published pilot study, we tested the effects of TA in patients undergoing OPCAB, showing reduction in postoperative bleeding and in the requirement for allogeneic transfusions.18 This is the first double-blind study to compare the effects of TA treatment on clinical and laboratory variables in patients undergoing OPCAB and ONCAB. Our pharmacologic protocols for TA reduced by 30% to 50% early and 24-hour postoperative blood losses both in patients undergoing OPCAB and in those undergoing ONCAB. Accordingly, the probability of bleeding exceeding 600 mL in the first postoperative day was reduced 80% by TA. Because of the insufficient sample size, we could not show a significant reduction in the requirement for allogeneic transfusions, which were, however, between 40% and 80% lower in patients treated with TA, irrespective of the type of surgery. Reduced bleeding was not counterbalanced by an increased rate of postoperative thrombotic complications, although our study was not powered adequately to examine this issue.
We have previously shown that both OPCAB and ONCAB are associated with a net consumption of antithrombin III and fibrinogen, whereas transient decrease in platelet count, greater plasminogen activation, and increased D-dimer formation are only observed with ONCAB.19 TA binds to the high-affinity lysine-binding sites of plasminogen and plasmin, preventing binding to fibrin and the resulting fibrin proteolysis.22 At least in vitro, however, plasminogen activation is paradoxically accelerated, because TA binding alters the conformation of plasminogen so that it becomes more susceptible to proteolytic activation by activators.23 The ex vivo data reported in this article are consistent with these findings. Whereas the changes in fibrinogen, antithrombin III, and platelet counts were not affected, TA prevented postoperative increase in D-dimer levels both in patients undergoing ONCAB and in those undergoing OPCAB to a substantial extent. After correction for hemodilution, however, plasminogen and 2-antiplasmin levels were lower after the operation in patients receiving TA, suggesting increased in vivo plasminogen activation to plasmin, complex formation with 2-antiplasmin, and clearance. In vivo inhibition of fibrinolysis by TA has been previously reported.24,25 With dosages of TA lower than those administered to our patients, Horrow and associates24 observed a significant reduction in plasminogen levels, whereas Blauhut and coworkers25 observed reduced 2-antiplasmin but not plasminogen levels in cardiac surgical patients.
In a study of patients undergoing ONCAB, aprotinin but not -aminocaproic acid reduced IL-10 and IL-6 levels relative to placebo.26 We show for the first time an anti-inflammatory effect of TA treatment in patients undergoing CABG. As expected, CPB induced a greater response in IL-6 levels than that observed in patients undergoing OPCAB; however, postoperative increase in IL-6 was lower in patients treated with TA. TA may modulate the inflammatory response related to tissue damage and to the activation of the coagulation system to a greater extent in the presence of "low-grade" inflammation, such as occurs after OPCAB, than in the ONCAB setting. Because of the positive feedback between inflammation and coagulation, control of inflammation may reduce postoperative hypercoagulability and potentially affect the rate of thrombotic complications. Twenty-four hours after the operation, fibrinogen and 2-antiplasmin—two acute-phase reactants—were lower in our patients treated with TA and correlated with postoperative IL-6 levels.
In conclusion, this study indicates that TA is effective in reducing bleeding through the prevention of secondary fibrinolysis both in patients undergoing ONCAB and in those undergoing OPCAB. Further randomized studies, enrolling larger numbers of patients, are needed to confirm the anti-inflammatory effects of TA and to rule out the potential risk of thrombotic complications.
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Footnotes |
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References |
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TopAbstractMaterials and methodsResultsDiscussionReferences |
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-aminocaproic acid in primary cardiac surgery. Ann Thorac Surg. 1999;68:2252–2257-aminocaproic acid decreases interleukin-10 after cardiac surgery with extracorporeal circulation: randomized, double-blind, placebo-controlled study in patients receiving aprotinin and -aminocaproic acid. Circulation. 2001;104(Suppl 1):I265–269This article has been cited by other articles:
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  M. P. Eaton Antifibrinolytic Therapy in Surgery for Congenital Heart Disease Anesth. Analg., April 1, 2008; 106(4): 1087 - 1100. [Abstract] [Full Text] [PDF]
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 T. Vanek, M. Jares, J. Snircova, and M. Maly Fibrinolysis in coronary artery surgery: detection by thromboelastography Interactive CardioVascular and Thoracic Surgery, December 1, 2007; 6(6): 700 - 704. [Abstract] [Full Text] [PDF]
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 V. Casati, A. D'Angelo, L. Barbato, D. Turolla, F. Villa, M. A. Grasso, A. Porta, and F. Guerra Perioperative management of four anaemic female Jehovah's Witnesses undergoing urgent complex cardiac surgery Br. J. Anaesth., September 1, 2007; 99(3): 349 - 352. [Abstract] [Full Text] [PDF]
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 M. M Maddali and M. C Rajakumar Tranexamic Acid and Primary Coronary Artery Bypass Surgery: a Prospective Study Asian Cardiovasc Thorac Ann, August 1, 2007; 15(4): 313 - 319. [Abstract] [Full Text] [PDF]
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 J. R. Brown, N. J.O. Birkmeyer, and G. T. O'Connor Meta-Analysis Comparing the Effectiveness and Adverse Outcomes of Antifibrinolytic Agents in Cardiac Surgery Circulation, June 5, 2007; 115(22): 2801 - 2813. [Abstract] [Full Text] [PDF]
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 G. J. Murphy, E. Mango, V. Lucchetti, F. Battaglia, D. Catapano, C. A. Rogers, and G. D. Angelini A randomized trial of tranexamic acid in combination with cell salvage plus a meta-analysis of randomized trials evaluating tranexamic acid in off-pump coronary artery bypass grafting. J. Thorac. Cardiovasc. Surg., September 1, 2006; 132(3): 475 - 480.e8. [Abstract] [Full Text] [PDF]
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V. Casati, F. Guerra, and A. D'Angelo About the activation of the coagulation system during on-pump and off-pump coronary surgery and the use of antifibrinolytic drugs. J. Thorac. Cardiovasc. Surg., September 1, 2006; 132(3): 733 - 734. [Full Text] [PDF]
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D. Paparella, A. Galeone, and G. Scrascia Reply to the editor. J. Thorac. Cardiovasc. Surg., September 1, 2006; 132(3): 734 - 734. [Full Text] [PDF]
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 P. Federico, F. Annalisa, C. Giuseppe, D. S. Francesco, T. Lucia, and Z. Alberto Anticoagulation management in patients undergoing open heart surgery by activated clotting time and whole blood heparin concentration Perfusion, September 1, 2006; 21(5): 285 - 290. [Abstract] [PDF]
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V. Casati, A. D'Angelo, L. Barbato, E. Rossi, M. A. Grasso, S. Spagnolo, and E. Panzeri Perioperative management of a heterozygous carrier of Glanzmann's thrombasthenia submitted to coronary artery bypass grafting with cardiopulmonary bypass. Anesth. Analg., August 1, 2006; 103(2): 309 - 11, table of contents. [Abstract] [Full Text] [PDF]
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 F. Pappalardo, P. D. Valle, G. Crescenzi, C. Corno, A. Franco, L. Torracca, O. Alfieri, L. Galli, A. Zangrillo, and A. D'Angelo Phosphorylcholine Coating May Limit Thrombin Formation During High-Risk Cardiac Surgery: A Randomized Controlled Trial Ann. Thorac. Surg., March 1, 2006; 81(3): 886 - 891. [Abstract] [Full Text] [PDF]
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D. Paparella, A. Galeone, M. T. Venneri, M. Coviello, G. Scrascia, N. Marraudino, M. Quaranta, L. de Luca Tupputi Schinosa, and S. J. Brister Activation of the coagulation system during coronary artery bypass grafting: Comparison between on-pump and off-pump techniques J. Thorac. Cardiovasc. Surg., February 1, 2006; 131(2): 290 - 297. [Abstract] [Full Text] [PDF]
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 T. Vanek, M. Jares, R. Fajt, Z. Straka, K. Jirasek, M. Kolesar, P. Brucek, and M. Maly Fibrinolytic inhibitors in off-pump coronary surgery: a prospective, randomized, double-blind TAP study (tranexamic acid, aprotinin, placebo) Eur. J. Cardiothorac. Surg., October 1, 2005; 28(4): 563 - 568. [Abstract] [Full Text] [PDF]
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