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Ann Thorac Surg 2005;80:586-593
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Hemostasis in Off-Pump Compared to On-Pump Coronary Artery Bypass Grafting: A Prospective, Randomized Study

^a Department of Cardiothoracic Surgery and Anesthesia, Karolinska University Hospital, Stockholm, Sweden
^b Department of Coagulation Research, Karolinska University Hospital, Stockholm, Sweden
^c Department of Surgery, Ullevål University Hospital, Oslo, Norway

Accepted for publication February 3, 2005.

^_* Address reprint requests to Dr Vedin, Department of Thoracic Surgery, Karolinska University Hospital, 171 76 Stockholm, Sweden (Email: jenny.vedin{at}karolinska.se).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: We hypothesized that off-pump coronary artery bypass grafting has less impact on the hemostatic systems than on-pump surgery.

METHODS: Thirty-one patients were randomized to on-pump or off-pump coronary artery bypass grafting. Factors of hemostasis as well as markers of endothelial activation were measured up to 24 hours after the operation: Fibrin D dimer, prothrombin fragment 1+2, ₂-macroglobulin, protein C1 esterase inhibitor, fibronectin, and von Willebrand factor. Overall hemostasis potential, overall coagulation potential, and overall fibrinolysis potential were determined with a previously developed assay. We also measured platelet count before and after surgery.

RESULTS: Fibrin D dimer and prothrombin fragment 1+2 concentrations were lower during surgery in the off-pump group (p < 0.001). Four hours after admission to the intensive care unit, these differences were eliminated. ₂-macroglobulin, protein C1 esterase inhibitor, fibronectin, and von Willebrand factor concentrations did not differ between groups (p = 0.59, p = 0.28, p = 0.22, and p = 0.69). Protein C1 esterase inhibitor and von Willebrand factor concentrations increased over time (p < 0.001) in both groups. Overall hemostasis potential and overall coagulation potential increased over time (p < 0.001), while overall fibrinolysis potential decreased (p < 0.001) with no difference between groups (p = 0.69, p = 0.91). Platelet count decreased on the first postoperative day (p < 0.001), but increased from the first to the third postoperative day (p = 0.004) in both groups without any inter group difference (p = 0.82).

CONCLUSIONS: There was a tendency toward less activation of coagulation and fibrinolysis in low-risk patients during elective off-pump coronary artery bypass surgery when compared with on-pump surgery.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Off-pump coronary artery bypass grafting (OFFCAB) has been established as an alternative to on-pump coronary artery bypass grafting (ONCAB) with cardiopulmonary bypass (CPB). OFFCAB can be performed on all coronary artery systems with good early [1] and midterm [2] results. The potential advantages of OFFCAB are still issues of debate; however, the whole body inflammatory reaction caused by CPB may be attenuated. Previous investigators find higher leukocyte count and more neutrophil activation [3] and increased cytokine activation [4] in ONCAB compared with OFFCAB surgery. We have recently demonstrated that the complement system is less activated by OFFCAB [5].

Cardiopulmonary bypass activates platelets and coagulation factors, which causes impairment of hemostasis [6, 7]. Several investigators found reduced blood loss or less need for transfusions after OFFCAB [1, 2, 8]. In a nonrandomized study, Casati and colleagues [9] find less activation of fibrinolysis in OFFCAB patients. There have also been concerns that a more procoagulant activity in OFFCAB patients may lead to thromboembolism and reduce graft patency [10, 11]. There has not been a randomized study that has compared hemostasis in patients undergoing ONCAB and OFFCAB.

We hypothesized that OFFCAB had less effect than ONCAB on the hemostatic systems. In this prospective, randomized study we measured standard coagulation and fibrinolytic factors as well as platelet count and release of some markers of endothelial activation in low-risk patients undergoing elective coronary surgery with or without CPB. The measured parameters were: fibrin D dimer (D dimer), prothrombin fragment 1+2 (F1+2), ₂-macroglobulin, protein C1 esterase inhibitor (C1 inhibitor), fibronectin, and von Willebrand factor (VWF). D dimer is a measure of fibrinolysis or increased coagulation; F1+2 is a degradation product from prothrombin indicating thrombin formation; ₂-macroglobulin is a protease inhibitor; C1 inhibitor is the only inhibitor of C1 esterase in the complement system, also inhibiting plasmin, kallikrein, and coagulation factors XI and XII; fibronectin is a marker of endothelial activation and involved in opsonization; and VWF, in addition to being carrier of factor VIII, is a platelet activating factor that is also suggested to be a marker of endothelial activation.

We also used a previously developed global hemostatic assay for determination of overall hemostasis potential overall coagulation potential and overall fibrinolysis potential in plasma [12].

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
This trial was approved by the Karolinska Hospital Research Ethics Committee and informed consent was obtained from all patients. Thirty-one patients admitted for elective coronary artery bypass grafting (CABG) were randomized to either ONCAB or OFFCAB. Exclusion criteria were age under 50 or over 80 years old, ejection fraction less than 30%, serum creatinine more than 150 µmol/L, tight main stem stenosis, redo operation, diffuse distal coronary artery disease, unstable angina, and history of cerebrovascular disease. Revascularization of the circumflex artery territory and the number of bypasses needed were not exclusion criteria.

Surgery
The patients underwent a standard median sternotomy operation. All proximal anastomoses were performed by the use of a side-biting clamp. Protamine was administered at the end of the operation to fully reverse the heparin effect in both groups. Tranexamic acid or desmopressin was given if required by the surgeon because some surgeons in our clinic routinely use tranexamic acid during CABG. All together 6 surgeons with variable experience performed operations on the patients included in the present study. No patient received aprotinin.

ONCAB
Heparin 300 IU/kg was administered to obtain activated clotting time over 480 seconds before start of CPB. ACT was measured with an automated coagulation timer (Medtronic HemoTech, Parker, CO). Standard cannulation of the ascending aorta with a two-stage cannula in the right atrium was used. The CPB circuit consisted of tubings (Medtronic Inc, Minneapolis, MN) without an arterial filter, primed with 1500 to 1800 mL Ringer’s acetate and 7500 IU heparin, a membrane oxygenator (Affinity NT; Medtronic Inc) and a centrifugal pump (Biomedicus; Medtronic Inc). CPB was conducted with a flow rate of 2.4 L/m²/min, alpha-stat acid-base management and a nasopharyngeal temperature of 34 to 35°C. After aortic cross clamping, 700 to 1000 mL of antegrade cold blood cardioplegia was infused. During cross clamping cardioplegia was given antegradely or retrogradely every 10 to 15 minutes. Rewarming was initiated when the last distal anastomosis was started and the patients were weaned from CPB when the nasopharyngeal temperature was above 36°C.

OFFCAB
Heparin 150 IU/kg was initially given and activated clotting time was kept above 300 seconds while the anastomoses were performed. The temperature in the operating room was 23°C and a patient warming device (Warm Touch; Mallinckrodt Medical, Hazelwood, MO), which blew warm air over parts of the patient, was used.

The position of the heart was achieved with a deep pericardial stay suture or a suction device (Xpose CTS; Guidant, Indianapolis, IN). The following stabilizers were used: OFFCAB multi use stabilizer (Guidant), CTS stabilizer Axius or Ultima (Guidant), or an Octopus II/III stabilizer (Medtronic Inc). An intracoronary shunt was only used in a few patients when an anastomosis was performed on the main stem of the right coronary artery. No cell saver system was used.

Anesthesia and Postoperative Care
All patients were anesthetized according to clinical routine of the department. After premedication with morphine, anesthesia was induced with fentanyl, midazolam, and propofol; muscular relaxation was achieved with pancuronium or atracurium. Volume-controlled ventilation with 40% to 50% O₂ in air was performed. Anesthesia was maintained with intermittent fentanyl and isoflurane, and continuous propofol was used as a supplement when needed. Mean arterial pressure was kept over 50 mm Hg and norepinephrine was given if required.

Postoperative bleeding was measured from the time the drains were activated in the operating room until they were removed on the first postoperative day. The patients received 500-mg acetylsalicylic acid rectally on the evening of the operation and then 160 mg daily from the first postoperative day.

Blood Sampling and Analysis
Nine milliliters of arterial blood was drawn in tubes containing 1 mL 0.129-M trisodiumcitrate (Vacutainer, Becton Dickinson, Plymouth, United Kingdom). Blood was sampled preoperatively after anesthesia, but before surgery ("before"); 30 minutes after start of CPB (ONCAB) or 20 minutes after start of suturing first distal anastomosis (OFFCAB) ("during"); at start of suturing sternum ("end") 4 hours ("4 hours"); and 20 to 24 hours ("24 hours") after admission to the intensive care unit. The samples were immediately put on ice and centrifuged within 10 minutes. The plasma was transferred to Eppendorf tubes in aliquots and stored at –70°C until the analyses were performed.

We used the following commercially available kits: D dimer was analyzed with latex immunoturbidimetric assay (Boehringer-Mannheim, Marburg, Germany), F1+2 with sandwich enzyme-linked immunoabsorbant technique (Dade Behring Marburg, Marburg, Germany), ₂-macroglobulin with immunonephelometry (Dade Behring Marburg), C1 inhibitor with immunonephelometry (Beckman Coulter, Fullerton, CA), fibronectin with immunonephelometry (Dade Behring Marburg), and VWF with immunologic LIA-technique (Diagnostica Stago, Asnieres, France). Prothrombin complex (international normalized ratio [INR]) was analyzed with nephelometry (Sysmex CA1500; Dade Behring Marburg). Immunoglobulin M (IgM) was analyzed with immunonephelometry (Beckman Coulter).

The IgM concentrations were measured in order to correct for hemodilution according to the equation:

Corrected parameter = (measured parameter x initial IgM)/measured IgM.

Overall Hemostasis, Coagulation, and Fibrinolysis Potentials
We have developed [13] and recently modified [14] a new method for determining overall hemostasis potential, based on analysis of fibrin aggregation curves performed in a microplate. For overall coagulation potential 70 µL of plasma sample was mixed with 10 µL platelet reagent (Unicorn Diagnostics Ltd, London, United Kingdom) as a source of phospholipids and with 50 µL of Tris-HCl buffer containing CaCl₂ and thrombin (final concentration 17 µmol/mL and 0.04 IU/mL, respectively). For the overall hemostasis potential tissue plasminogen activator (final concentration 300 ng/mL) was also added to the buffer. Absorbance at 405 nm was measured each minute for 40 minutes to construct the two fibrin-aggregation curves giving overall hemostasis and coagulation potentials. The area under the curve was expressed as a summation of the absorbance values obtained after deducting the background absorbance, which corresponds to the initial optical density of the plasma sample before initiation of clotting. The difference between the two areas represents the overall fibrinolysis potential, calculated as:

Overall fibrinolysis potential = (overall hemostasis potential – overall hemostasis potential)/overall hemostasis potential x 100%.

Statistics
The present study was primarily intended to study biochemical parameters, and was not powered to investigate clinical data and outcome. The time courses within and between groups were analyzed by multivariate analysis of variance for repeated measures (ANOVA), STATISTICA 6 (StatSoft Inc., Tulsa, OK). For between group analysis of operative and postoperative clinical data Fisher's exact p test and Mann-Whitney U test were used. Data are presented in the graphs as mean with standard deviations (SD). Differences were considered significant at p values less than 0.05.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patient Characteristics and Operative Data
There were no major inter-group differences in baseline characteristics (Table 1). The number of distal anastomoses and grafting of the different coronary artery territories were similar in the 2 groups (Table 2). There were no significant differences between groups in the number of patients receiving inotropic drugs, vasopressor drugs or intraaortic balloon pump. There was no stroke, deep vein thrombosis, pulmonary embolism, acute renal failure, or sternal wound infection during hospital stay. The body temperature did not differ between groups during surgery or the first hours after surgery. All patients received acetylsalicylic acid until the day before surgery and had normal INR preoperatively. No patient used heparin before surgery.

Plasma Cascade Systems
The D dimer and F1+2 concentrations (Fig 1 and Table 3) were higher in the ONCAB group during the operation, but the difference was eliminated 4 hours postoperatively. When analyzing these 2 parameters dependent on the use of tranexamic acid, irregardless of the use of CPB or not, there was no difference in the levels of F1+2 (p = 0.61) whereas D Dimer was reduced by tranexamic acid (p = 0.06). The concentrations of ₂-macroglobulin, C1 inhibitor, fibronectin and VWF did not differ between ONCAB and OFFCAB (Table 3). C1 inhibitor and VWF increased over time in both groups (Table 3).

View larger version (18K): [in this window] [in a new window]   Fig 1. (Left) D dimer and (right) F1+2 concentrations during and after the operation in patients randomized to on-pump or off-pump coronary artery bypass grafting (ONCAB, n=14; OFFCAB, n=17). The timepoints were as follows: before (after induction, before surgery); during (30 minutes after start of cardiopulmonary bypass or 20 minutes after suturing first distal anastomosis); end (at suturing sternum); and 4 hours and 24 hours (4 hours and 24 hours after admission to the intensive care unit). = on; = off.

View larger version (19K): [in this window] [in a new window]   Fig 2. (Left) Overall hemostasis potential (OHP) and (right) overall fibrinolysis potential (OFP) before and after the operation in patients randomized to on-pump or off-pump coronary artery bypass grafting (ONCAB, n = 14; OFFCAB, n = 17). The horizontal dotted lines are reference values, (see Results). = on; = off.

View larger version (13K): [in this window] [in a new window]   Fig 3. Platelet count in patients before and after the operation who were randomized to on-pump or off-pump coronary artery bypass grafting (ONCAB, n = 14; OFFCAB, n = 17). = on; = off.

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This prospective, randomized study demonstrated a tendency towards decreased activation of both coagulation and fibrinolysis in low risk patients during elective OFFCAB compared with ONCAB. To exactly evaluate the role of CPB the same level of heparinization would have been needed. However, we wanted to investigate these two surgical techniques in a way comparable to how they are performed in most centers.

To our knowledge coagulation and fibrinolysis in ONCAB and OFFCAB have been previously investigated in nonrandomized studies [9, 15]. Casati and colleagues [9] reported consumption of antithrombin and fibrinogen in both groups but plasminogen activation and D dimer formation during surgery in the ONCAB group only. Englberger and coworkers [15] found reduced activation of both coagulation and fibrinolysis in OFFCAB patients.

Several investigators [7, 16, 17] have previously demonstrated increased levels of F1+2 in patients undergoing cardiac operations with CPB. In our study the concentration of F1+2 increased in the ONCAB, but not in the OFFCAB group, indicating less activation of coagulation in the OFFCAB group in spite of lower heparin dose.

Higher D dimer levels during surgery indicate activation of fibrinolysis in the ONCAB group. This might be due to a primary activation of fibrinolysis by CPB or a secondary activation caused by coagulation during ONCAB. In addition, heparin has been reported to increase D dimer concentrations and higher heparin dose might have increased the D dimer values.

We found no difference in fibronectin concentrations over time or between groups. These results are in accordance with Vanek and associates [18], which measured fibronectin in patients undergoing ONCAB surgery through a median sternotomy, or OFFCAB surgery trough median sternotomy, or OFFCAB surgery through a left anterior small thoracotomy. No differences were found between groups or over time. However, an earlier study has demonstrated fibronectin consumption during CPB [19], but in this study fibronectin levels were not corrected for dilution and fibronectin consumption may have been overestimate.

Von Willebrand factor has been suggested as a marker of endothelial injury [20]. Valen and coworkers [21] have shown increased levels of VWF during and after CPB. Our study indicated that the surgical trauma per se lead to an increase in VWF, not the CPB.

We found no difference over time in either group concerning ₂-macroglobulin. A previous study [22] has shown a slight decrease in ₂-macroglobulin 6 hours after CPB, with no difference after 24 hours. Because C1 inhibitor did not differ between groups, activation of C1 inhibitor can not explain less complement activation during OFFCAB [5].

Overall hemostasis potential in plasma is a newly developed laboratory method based on spectrophotometric measurement of the area under the curve for fibrin activation in citrated plasma samples [12, 13]. It has previously been shown that overall hemostasis potential can be used to screen immediate changes in the hemostatic system after administration of low molecular weight heparin (dalteparin, Fragmin) [23] as well as to detect hypocoagulable states [14]. This technique is interesting beyond the discussion concerning ONCAB and OFFCAB. It is potentially useful for a rapid, and simple, bedside evaluation of patients with hemostatic dysfunction.

Other techniques for similar determinations, such as thromboelastography, require special equipment. With thromboelastography the measurements should be performed on whole-blood samples within 8 hours after sampling and frozen samples cannot be used. Moreover, the observation time is up to several hours if the whole hemostatic process, especially fibrinolysis part, is monitored. In contrast, global hemostatic assay for determination of overall hemostatic potential in plasma is inexpensive and relatively rapid. Estimation of overall hemostasis, coagulation, and fibrinolysis potential is finished in 40 minutes. Except a common kinetic microplate reader no special equipment is necessary. Finally, this technique is also useful for research purposes because frozen samples may be used.

The present results further demonstrate the sensitivity of the overall hemostasis potential for monitoring the anticoagulant effects. Before surgery all patients had overall hemostasis potential levels within, or slightly above the reference range. Because of heparin administration during surgery, overall hemostasis potential levels were decreased to undetectable levels. When the effect of heparin was reversed due to administration of protamine, overall hemostasis potential levels gradually increased, and at 4 hours returned to preoperative levels. However, this increase continued 24 hours after surgery indicating a shift of hemostatic balance toward hypercoagulability. The decrease in overall hemostasis potential was followed by increased fibrinolysis (increase in overall fibrinolysis potential) during surgery. Twenty-four hours postoperatively very low levels of overall fibrinolysis potential was observed. These findings may explain the increased overall hemostasis potential after heparin withdrawal. Moreover, some of the patients received tranexamic acid, which may affect the overall hemostasis and fibrinolysis potentials.

The platelet count decreased on the first postoperative day and increased from the first to the third postoperative day in both groups without any difference between groups. Casati and colleagues [9] reported a decrease in platelet count during surgery and an increase 24 hours after surgery in the ONCAB and no important changes in the OFFCAB group. Their study was not randomized. Moller and coworkers [24] demonstrated an increase in platelet activation after OFFCAB and a temporary platelet dysfunction in the ONCAB group. A limitation of our study was that we did not measure platelet function.

There is concern that OFFCAB leads to a hypercoagulation, which may affect graft patency. Several studies described good graft patency [25, 26], but some report decreased vein graft patency [11] in OFFCAB materials. Our study does not indicate a difference in hypercoagulability within the first 24 hours.

In our study there was increased postoperative bleeding in the OFFCAB group. However, in OFFCAB patients, others demonstrate less blood loss [1] and less intraoperative transfusions, but no difference in postoperative transfusions or hemoglobin value at discharge [2].

Limitations of our study are the high number of surgeons as well as the use of tranexamic acid. We believe that this represents "the real world" in CABG, with not only OFFCAB "super-specialist" performing the surgery.

Tranexamic acid is a well-documented fibrinolytic inhibitor [27] used in many clinics. Tranexamic acid was not supposed to be used and it was an undesirable effect caused by the routine of some surgeons. This only became evident when the study was finished. The present data demonstrate that the use of tranexamic acid did not have a decisive influence on our major findings. The number of patients receiving tranexamic was not different between the groups, although there was a tendency toward more patients in the OFFCAB group.

In conclusion this prospective, randomized study showed a tendency toward less activation of both coagulation and fibrinolysis during OFFCAB compared with ONCAB. However, among measured parameters the differences were few, and may suggest that the importance of the surgical trauma may be underestimated in comparison to the effect of CPB.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank Professor Margareta Blombäck, Coagulation Research, Karolinska University Hospital, for important discussions including views on the manuscript; and Associate Professor Nils Egberg, Clinical Sciences, Karolinska University Hospital, for help with the blood analyses. For statistical analysis, we gratefully acknowledge Magnus Backheden, Department of Medical Information and Educational Development, Karolinska Institutet, Stockholm, Sweden. The authors also thank Susanne Hylander for valuable help in handling blood samples. The present work was supported by grants from the Swedish Heart and Lung Foundation, The Swedish Research Council (Grant no. 11235), The Vårdal Foundation, Karolinska Institutet, and Karolinska University Hospital.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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