Interact CardioVasc Thorac Surg 2007;6:700-704. doi:10.1510/icvts.2007.161463
© 2007 European Association of Cardio-Thoracic Surgery
Work in progress report - Coronary |
Fibrinolysis in coronary artery surgery: detection by thromboelastography
Tomas Vaneka,*,
Martin Jaresa,
Jana Snircovaa and
Marek Malyb
a Department of Cardiac Surgery, 3rd Faculty of Medicine, Charles University Prague and University Hospital Kralovske Vinohrady, Czech Republic
b Department of Biostatistics and Informatics, National Institute of Public Health, Prague, Czech Republic
Received 13 June 2007;
received in revised form 30 July 2007;
accepted 2 August 2007
 Financial support by the Cardiovascular research project of the Charles University Prague, Czech Republic, no. MSM0021620817.
*Corresponding author. Department of Cardiac Surgery, FNKV, Srobarova 50, 100 34 Prague 10, Czech Republic. Tel.: +420 267 163 422; fax: +420 267 163 260.
E-mail address: vanek{at}fnkv.cz (T. Vanek).
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Abstract
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Sixty-five patients scheduled for coronary surgery were randomized into three groups: A – conventional coronary artery bypass grafting, B – off-pump surgery, C – coronary artery bypass grafting with modified, rheoparin coated cardiopulmonary bypass with the avoidance of re-infusion of cardiotomy blood into the circuit. On the completion of peripheral bypass anastomoses, highly significant inter-group differences were found in the thromboelastographic parameter lysis of set time at 60 min of assessment (P=0.003) and at 150 min of assessment (P<0.001), the mean values of these parameters were significantly lower in group A as compared with both groups B and C, which were statistically indistinguishable. Lysis on set time on the completion of peripheral bypass anastomoses <50% was detected in 12 patients (52.2%) originating from group A. At the other sampling times (preoperatively, 15 min after sternotomy, at the end of the procedures, and 24 h later) thromboelastographic parameters were similar in all groups. In group A no significant correlations between lysis on set time, postoperative blood loss and D-dimer levels were found. Based on our results, thromboelastographic signs of fibrinolysis were clearly detectable during cardiopulmonary bypass in group A, but not at any time in groups B and C.
Key Words: Coronary artery surgery; Beating heart surgery; Cardiopulmonary bypass; Hemostasis; Thromboelastography; D-dimer
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1. Introduction
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Although in many centers pharmacological strategies based on fibrinolytic inhibitors are used on a routine basis, detailed knowledge of fibrinolysis during cardiac surgery is still limited. The aim of this prospective, randomized study was to search for fibrinolysis by the method of rotation thromboelastography/thromboelastometry (ROTEM) in different settings of coronary artery surgery.
Thromboelastography is a measuring method, based on the continuous registration of blood clot firmness during the entire coagulation process. Thus, the beginning of clot formation, clot formation kinetics and the maximum clot firmness are assessed as well as its stability or lysis [1]. The most important parameter for detection of fibrinolysis in ROTEM analysis is lysis on set time (LOT), which describes the reduction of clot firmness during measurement (Fig. 1).
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Fig. 1. Parameters of ROTEM analysis (scheme). [ -angle – the angle between the center line and a tangent to the curve through the 2 mm amplitude point (°); CFT=clot formation time – time from the onset of clot formation until an amplitude of 20 mm is reached (s); CT=clotting time – time from the start of measurement until the start of clot formation (s); LOT= lysis on set time (% of MCF); MCF=maximum clot firmness (mm)].
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2. Material and methods
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With the Medical Faculty Ethics Committee approval, and after obtaining the informed consent from all participants, 65 patients with ischemic heart disease scheduled for coronary surgery were enrolled in the study. The criteria for non-enrollment to the study were as follows: emergency procedures, previous cardiac surgery, concomitant surgery (valvular or aortic), myocardial infarction <7 days prior to surgery, history of hematological or liver disorders, renal insufficiency (serum creatinine >150 µmol/l), and preoperative anemia (hemoglobin <11 g/l, hematocrit <32). A strict contraindication to the inclusion in the study was preoperative treatment with antiaggregative or anticoagulant drugs. No fibrinolytic inhibitors were used in the perioperative period in any of the evaluated patients.
After the enrollment into the study, the patients were randomized into three groups: A (conventional CABG), B (OPCAB surgery), and C (CABG with modified cardiopulmonary bypass), the envelope method with random numbers was used. The feasibility of randomization for on-pump or off-pump coronary surgery in our center was proven by previous experiences [2, 3].
2.1. Surgical and cardiopulmonary bypass techniques
2.1.1. Group A – conventional CABG
Cardiopulmonary bypass in a standard setting was established by ascending aortic cannulation and two-stage venous cannulation of the right atrium, non-coated extracorporeal circuit (Dideco D 903 Avant, Mirandola, Italy) with crystalloid pump prime 750 ml was used. Heparin was given at an initial dose of 300 IU/kg to achieve an activated clotting time (ACT) >480 s. Normothermic perfusion (2.5 l/m2, roller pump) with antegrade intermittent warm blood cardioplegia and re-infusion of cardiotomy suction blood were used. On the completion of all anastomoses, full-dose protamin chloride was given to reverse the effect of heparin.
2.1.2. Group B – OPCAB surgery
The patients were operated on from full midline sternotomy. The verticalization of the beating heart was achieved using an Axius Xpose Device while the Acrobat SUV Vacuum Stabilizer, and Axius Blower/Mister (Guidant, Santa Clara, CA) were used for the stabilization and visualization of the anastomosis site. No cell-saver device was used and no blood was returned to the patients. The dose of heparin, 100 IU/kg, was used with target ACT over 250 s. On the completion of anastomoses, heparinization was partially reversed with a half-dose of protamin, regardless of ACT value.
2.1.3. Group C – modified cardiopulmonary bypass
A rheoparin coated cardiopulmonary bypass system (oxygenator Medos Hilite 7000, Stolberg, Germany+hardshell venous reservoir, tubing, cannules) was utilized. The blood suctioned from the pericardium was collected in a separate reservoir and was not returned routinely into the extracorporeal circulation. Heparin, perfusion, and cardioplegia managements were the same as described in group A.
2.2. Transfusion policy
During the procedures the patients were administered crystalloid solutions and 5% albumin solution, if necessary, synthetic colloidal solutions and fresh frozen plasma were not used. Determined borderlines for administration of red blood cell transfusion (or reinfusion of collected autologous blood in group C) were hemoglobin decrease to <8.5 g/dl and/or hematocrit <26. The same threshold for allogenic blood transfusion was used 24 h postoperatively.
2.3. ROTEM and laboratory analyses
The blood for ROTEM examination was sampled from the arterial line into tubes containing sodium citrate (Greiner Bio-One, Kremsmuenster, Austria) and processed immediately after sampling by ROTEG® Whole Blood Haemostasis System, model 05 (Pentapharm, Munich, Germany) using heparinase HEPTEG for heparin removal and EXTEG (Nobis, Endingen, Germany) including thromboplastin for the extrinsic pathway activation. The sampling time points were as follows: preoperatively (t1), 15 min after sternotomy (t2), on the completion of peripheral bypass anastomoses (t3), at the end of the procedures (t4), and 24 h after the end of surgery (t5). Blood samples for D-dimer examination were taken before the operation, at the end of surgery, and 24 h later.
2.4. Statistical analysis
Statistical analysis was performed by statistical software Stata, release nine (Stata Corp LP, College Station, TX). All statistical tests were evaluated at a significance level of 0.05.
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3. Results
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For all three study groups no significant differences in the basic demographic data and preoperative hematological variables were found.
Only one patient originally randomized to group B was intraoperatively (but before initiating of revascularization) converted to group A. The reason for this was the presence of small intramuscular coronary arteries. One patient from group C was re-infused by collected shed blood (900 ml) during cardiopulmonary bypass, the data of this patient were withdrawn from the study. Four patients (1 originating from group A, 1 from group B, 2 from group C, respectively) underwent re-exploration postoperatively with the finding of an evident surgical source of bleeding, and so their following postoperative data were not included in the study, either.
The differences between groups in the mean number of grafts [arithmetic means and 95% confidence intervals – group A: 2.43 (2.12; 2.75), group B: 2.09 (1.73; 2.45), group C: 2.63 (2.34; 2.92)] were close to the significance level (P=0.059) due to the lower number of grafts per patient in group B. The mean intraoperative blood loss was slightly higher in group C [geometric means and 95% confidence intervals – group A: 326.0 (269.1; 394.9) ml, group B: 346.2 (258.6; 463.6) ml, group C: 441.9 (354.3; 551.1) ml, P=0.066]. In this group the volume of blood collected in the separate reservoir – median 150 ml, min–max 100–650 ml – was included in the evaluated blood loss. The hemodilution during extracorporeal circulation in on-pump groups was just moderate [medians (25–75th percentiles) – group A: hemoglobin 11.6 (10.3; 12.0) g dl–1, hematocrit 35.6 (31.0; 36.9), group C: hemoglobin 10.5 (10.0; 12.0) g dl–1, hematocrit 32.1 (30.9; 36.9)]. Neither cardiopulmonary bypass nor aortic clamp durations showed any differences between groups A and C.
The highest mean postoperative blood loss (in 24 h) was observed in group C, while the lowest mean blood loss was detected in group B [group A: 686.7 (570.8; 826.1) ml, group B: 555.3 (441.3; 698.9) ml, group C: 775.6 (645.1; 932.3) ml, P=0.157].
Only one patient in each group was re-transfused by packed red cells intraoperatively. The number of patients re-transfused postoperatively with packed red cells was 9 (40.9%), 5 (23.8%) and 9 (52.9%) in groups A, B and C, respectively. The differences in proportions are not significant (P=0.176), although transfusion requirements were lower in group B as compared to the other two groups.
3.1. ROTEM analyses, association with blood loss and D-dimer levels
Comparison of LOT in monitored time points is given in Table 1. While parameters were similar in groups A, B and C in sampling times t1, t2, t4 and t5, in sampling time t3 (on the completion of peripheral bypass anastomoses) highly significant inter-group differences were found in LOT (60 min) (P=0.003) and in LOT (150 min) (P<0.001). The mean values of these parameters were significantly lower in group A as compared with both of the other groups B and C, which were statistically indistinguishable – LOT (60 min) (P=0.968), LOT (150 min) (P=0.979). Parameter LOT (150 min) <50% of maximum clot firmness was detected in 12 individual patients (52.2%) originating from the group A. The time course of LOT (150 min) over the sampling times is shown in Fig. 2; group A differs significantly from the other two groups (P<0.001).
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Fig. 2. Time course of LOT (150 min) over the sampling times. Group A differs significantly from the groups B and C (P<0.001).
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In group A, the association between LOT (150 min) in sampling time t3 and postoperative blood loss was tested. Spearman correlation coefficient was 0.39 (P=0.075) in this case. In patients with apparent ROTEM signs of hyper-fibrinolysis (LOT equal to 0) a wide range of bleeding occurred (min–max 440–1310 ml).
The time course of D-dimer levels is presented in Fig. 3. A significant increase in D-dimer levels in all groups was found. In group A the highest mean value of D-dimer was already reached at the end of surgery, while in groups B and C the maximum values were observed as late as on postoperative day one. As a consequence of this fact, a dramatic inter-group difference (P<0.001) was found at the end of procedures; the mean value of D-dimer in group A was distinct from groups B and C (P=0.001, P<0.001, respectively), while the difference between groups B and C was not significant (P=0.231).
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Fig. 3. Time course of D-dimer levels over the sampling times. Significant inter-group difference was found at the end of procedures (P<0.001).
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In group A, the relationship between LOT (150 min) in sampling time t3 and D-dimer levels at the end of procedures was examined. The association between the variables was insignificantly negative with Spearman correlation coefficient equal to 0.16 (P=0.463). In patients with apparent ROTEM signs of hyper-fibrinolysis (LOT equal to 0) there was a wide range of D-dimer levels (min–max 520–2210 ng/ml).
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4. Discussion
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The main finding of this randomized trial is apparent thromboelastographic detection of fibrinolysis/hyper-fibrinolysis in conventional CABG (group A) at the time of extracorporeal circulation. In theory, fibrinolytic activity during cardiac surgery is initiated by the release of tissue plasminogen activator; this starts with the skin incision and sternotomy and continues throughout the surgical tissue manipulation. In operations where cardiopulmonary bypass is used, additional massive activation of coagulation occurs related to the contact of blood with foreign, negatively charged non-endothelial surfaces and consequent activation of the fibrinolytic system is described. Re-infusion of the suctioned fluids from the surgical field (shed blood from the pericardium contains large amounts of cytokines, tissue factors and tissue plasminogen activator) thereafter enhances these pathological processes [4–6].
No ROTEM signs of fibrinolysis were detected in OPCAB group B, and in modified cardiopulmonary bypass group C at the critical sampling time of the completion of peripheral bypass anastomoses. No ROTEM signs of fibrinolytic activity were found in all the evaluated groups at the other sampling times. In agreement with available literature we, therefore, consider that the main important triggers of fibrinolytic pathways are the usage of non-coated, less-biocompatible cardiopulmonary bypass and, principally, direct re-infusion of suctioned fluids exposed to pericardial and mediastinal surfaces into the extracorporeal circuit [7]. The actual impact of either biocompatible coating or avoidance of re-infusion of shed blood on ROTEM results should be verified by further investigation with a different study design (modified cardiopulmonary bypass group split into two separate sub-groups). Even though there is growing literary evidence that fibrinolytic inhibitors reduce postoperative blood loss in OPCAB [8–11], based on our results, the impact of sternotomy/surgical tissue manipulations does not seem to be as important as the practice of cardiopulmonary bypass.
The consequences of this study are supported by the results of our prospective, randomized pilot study, which had been realized previously with different patients [12].
Although in the present study approximately half of the patients (52.2%) in the conventional CABG group A expressed thromboelastographic signs of fibrinolysis during the period of cardiopulmonary bypass, these signs of fibrinolysis resolved spontaneously and were not detectable at the end of procedures and 24 h later, and thus no antifibrinolytic treatment was used. Surprisingly, in group A we did not find any association between ROTEM signs of fibrinolysis and postoperative blood loss. This finding is in contrast to results of another thromboelastographic retrospective survey with a poor clinical outcome in cardiac surgery patients with detected fibrinolysis [13]. A limitation of our study was the fact that in group C only modified, but not really condensed (miniaturized) closed ‘minimally invasive’ cardiopulmonary bypass was used, thus our expectations of decreased postoperative blood loss and the subsequent reduction of allogenic blood transfusion were not fulfilled [14].
The observation of significantly increased D-dimer levels in conventional CABG group A at the end of surgery and the equalization of elevated D-dimer levels between the on-pump group A and OPCAB group B 24 h after the surgery is in agreement with the findings of others [15]. According to our observations, the time course of D-dimer levels in modified CABG (group C) is similar to that in OPCAB surgery. In group A, a low and insignificant negative correlation between LOT (150 min) at sampling time t3 and D-dimer levels at the end of surgery seems to be difficult to explain. Presently, we have not enough data in available literature comparing thromboelastographic signs of fibrinolysis with relevant plasma markers.
In conclusion, our prospective, randomized study demonstrated that thromboelastographic signs of fibrinolysis are clearly detectable in the important part of coronary surgery patients operated on with the use of conventional cardiopulmonary bypass, but not in off-pump patients and those operated on with the biocompatible surface-modified circuit without re-infusion of cardiotomy suction blood.
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Acknowledgements
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We are grateful to chief perfusionist BA Stepanka Suchoparova for her helpful contribution to this study.
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Abstract
1. Introduction
