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*Department of Anesthesiology,
Department of Hematology, and
Heart-Lung Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands; and
Department of Thoracic Anesthesiology and Intensive Care, Isala Clinics, Zwolle, The Netherlands
Address correspondence and reprint requests to Rob Fijnheer, MD, PhD, Department of Hematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. Address e-mail to r.fijnheer{at}azu.nl
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Abstract |
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IMPLICATIONS: Coronary artery bypass grafting with cardiopulmonary bypass is associated with excessive thrombin generation and fibrinolytic activity immediately after surgery compared with off-pump procedures. However, after off-pump coronary surgery, patients demonstrated a delayed postoperative response that became equal in magnitude to that of those having on-pump procedures in the later (20–96 h) postoperative period.
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Introduction |
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The performance of off-pump CABG (OPCAB) might offer hemostatic advantages when compared with the need for CPB during routine CABG surgery. Eliminating exposure of blood to the extracorporeal circuit could reduce hemostatic defects. Clinically, reduced postoperative blood loss and smaller transfusion requirements have been reported in comparison to conventional CABG with CPB (11). However, major surgical trauma may also lead to activation of hemostasis, and several studies suggest that OPCAB surgery can lead to a procoagulant state, possibly contributing to early thrombotic complications (1,12–17).
No randomized trials have directly compared perioperative hemostatic variables in these two types of surgery. Our hospital participated in a randomized trial comparing neurocognitive dysfunction after on-pump and off-pump procedures (the Octopus Trial) (18,19). Using patients from this trial, we compared changes in coagulation, fibrinolysis, and endothelial cell activation during CABG surgery with or without CPB in a prospective, randomized study.
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Methods |
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In the CPB group, anesthesia was induced with midazolam (0.1 mg/kg), sufentanil (2–3 µg/kg), and pancuronium (0.1 mg/kg) and was maintained with a combination of midazolam (0.1 mg · kg–1 · h–1) and sufentanil (0.5 µg · kg–1 · h–1). Anesthetic management for OPCAB and the Octopus Trial has been described in detail (18,20). In short, anesthesia was achieved with sufentanil (2–3 µg/kg at induction and continued at 0.25–0.5 µg · kg–1 · h–1), propofol (2 mg/kg at induction and continued at 2–3 mg · kg–1 · h–1), and pancuronium (0.1 mg/kg). Anticoagulation or antiplatelet therapy was discontinued 7 days before surgery. The CPB patients received dexamethasone 1 mg/kg after the induction of anesthesia. In both groups, surgical access to the heart was achieved by midsternal incision.
In the CPB group, the extracorporeal circuit consisted of a membrane oxygenator and a roller pump. Only the oxygenator and the venous reservoir (Baxter Healthcare Corp., Irvine, CA) were partially heparin coated. Before connection to CPB, porcine heparin (300 IU/kg; Heparin Leo; Leo Pharmaceutical Products BV, Weesp, The Netherlands) was administered to achieve an activated coagulation time (ACT) of more than 450 s. CPB was managed according to the 
-stat principle, with a minimal nasopharyngeal temperature of 32°C, and the CPB flow rate was maintained at 2.4 L · min–1 · m–2. Myocardial protection was achieved with cold (4°C) potassium cardioplegia (Plegisol; Abbott Inc., Chicago, IL). During CPB, blood was recollected by using a suction cardiotomy reservoir and, without processing, was reinfused to the CPB system. At the end of CPB, heparin was neutralized by protamine chloride 3 mg/kg (Hoffman/La Roche, Mijdrecht, The Netherlands), and additional protamine was administered until the ACT was less than 150 s.
In the OPCAB group, CABG was performed on the beating, normothermic heart with local cardiac wall immobilization using the Octopus Tissue Stabilizer® (Medtronic, Minneapolis, MN). Before the anastomosis was started, porcine heparin (150 IU/kg) was administered to achieve an ACT of more than 250 s. A cell-saving device was used to reduce the need for blood transfusion. At the end of the operation, protamine (25–50 mg) was administered if an ACT >150 s was measured.
Intraoperative transfusion protocols were different for each group. In the CPB group, hematocrit was kept more than 22% during CPB, whereas in the OPCAB group, hematocrit was kept more than 25%. Less hematocrit was accepted in the CPB group because of the dilutional effect of the priming of the CPB system, the use of crystalloid St. Thomas cardioplegic solution, and hypothermia during the procedure. The postoperative transfusion trigger was a hematocrit of 28% in both groups.
Requirements for intraoperative and postoperative allogenic blood transfusions and the amount of postoperative bleeding in the first 12 h after surgery were recorded in all patients. Major complications such as myocardial infarction or stroke were assessed and have been described in detail (18).
Postoperative patient treatment in the intensive care unit was similar for both groups. If chest tube drainage was more than 150 mL/h in the first hour or 100 mL/h for 2 successive hours, ACT was measured, and additional protamine was administered if ACT exceeded 150 s. Hypertension was treated with nicardipine. Thrombosis prophylaxis consisted of nadroparin 2850 IU (Sanofi Winthrop, Maassluis, The Netherlands) subcutaneously the day before surgery, and acetylsalicylic acid 80 mg daily was started on the first postoperative day.
We used a different target ACT for both procedures, because there were different indications for the use of anticoagulation. Whereas in the CPB group heparin was mainly used to prevent clotting in the CPB system, in the OPCAB group it was needed to prevent clotting in the harvested internal mammary arteries and in the native coronary system during grafting. Nevertheless, the postoperative ACT (<150 s, after protamine infusion) was the same in both groups. Because these factors mostly influence perioperative coagulation, and hypothesizing that OPCAB would not influence hemostasis, we decided to study only the effects after the operation and to exclude intraoperative differences.
Blood samples were drawn at the following intervals: after the induction of anesthesia; at the end of the surgical procedure after reversal of heparin during wound closure; and 2, 20, and 96 h later. All samples were immediately cooled on ice and centrifuged twice at 2000g for 15 min. Plasma was stored at –80°C.
Platelet counts were determined with an automatic cell counter (Cobas Minos ST; Roche, Montpellier, France). Activation of platelets was assessed by the release of soluble P-selectin (sP-selectin) and quantified by enzyme-linked immunosorbent assay (ELISA) with specific monoclonal rabbit antibodies (R&D Systems Ltd., Abingdon, UK). P-selectin arises from granules and is released when they fuse with the platelet membrane. Thrombin generation was assessed by the measurement of F1.2 (proteolytic fragment of prothrombin), as analyzed by ELISA (Enzygnost F1.2 Micro; Behringwerke AG, Frankfurt, Germany), and soluble fibrin (proteolysis of fibrinogen by thrombin, studied by an ELISA technique; Diagnostica & Analys, Senice AB). Fibrinolysis was assessed by the measurement of D-dimer formation (Diagnostica Stago, Roche, Mannheim, Germany). D-Dimers are derived from the lysis of cross-linked fibrin, in contrast to split products that arise from the lysis of noncross-linked fibrin. Concentrations of von Willebrand Factor (vWF), as a marker of endothelial cell activation, were determined by an ELISA as described previously (21).
Priming of the CPB circuit results in acute hemodilution immediately after the start of CPB. To correct for resultant hemodilution in the CPB group caused by the administration of crystalloid or colloid solutions and CPB priming, we quantitated immunoglobulin G (IgG) by a nephelometric method (Dade Behring, Leusden, The Netherlands). A volume correction of all obtained data (of both groups) was made based on the ratio of the plasma levels of IgG (1). Thereafter, the values of each variable were transformed to percentages with respect to the preoperative level.
Post hoc calculation of sample size, based on a desired decrease in key variables of thrombin generation (F1.2) and fibrinolysis (D-dimer) by 50% and a power of 0.9 at = 0.05, resulted in 19 patients for each group. In our study, 40 patients were included. All data are presented as mean ± SD or as median (interquartile range). The Friedman test was used to compare longitudinal changes over time in both patient groups. When significant differences were observed, these were further evaluated by using Wilcoxon’s matched pairs test for comparison between baseline and consecutive time points. A general linear model for repeated measurements was used to detect overall treatment effects. When significant differences were observed, these were further evaluated by using the Mann-Whitney U-test to assess intergroup differences at a single predetermined time point.
When the repeated-measurements model and the Friedman test were used, a P value of <0.05 was considered significant. To accommodate for multiple testing with further evaluation, differences were considered significant at P values <0.01.
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Results |
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In the CPB group, we showed a different change in D-dimer levels over time than in the OPCAB group (P = 0.004). In the CPB group, plasma concentrations of D-dimers peaked immediately after surgery (538% [318%–1192%]) and remained increased up to Day 4, whereas in the OPCAB group, levels increased gradually from 137% (118%–199%) immediately after surgery up to 555% (387%–882%) on Day 4 (Fig. 1). In both groups, postoperative D-dimer levels were increased at all time points compared with baseline (P < 0.001; Fig. 1).
The sP-selectin concentrations were corrected for the number of circulating platelets (22). As an indicator of platelet activation and release, no differences could be demonstrated in P-selectin concentrations between groups. In both groups, sP-selectin levels were increased, with a peak of 187% (96%–261%) at 2 h after surgery in the CPB group and a peak of 133% (96%–195%) in the OPCAB group. At Day 4, levels had returned to baseline in both groups.
Immediately after surgery, the number of platelets had decreased to 60% of the baseline level in the CPB group. When corrected for dilution, however, platelet counts were similar to those in the OPCAB group. At Day 4, the quantity of circulating platelets had increased significantly to approximately 130% in both groups, without intergroup differences.
There were no differences in postoperative levels of vWF between the groups. In both groups, plasma concentrations were increased compared with baseline during the entire observation period and reached maximum levels at Day 4 after the operation (CPB group: 308% [228%–405%], P < 0.001 compared with baseline; OPCAB: 288% [167%–334%], P < 0.001 compared with baseline).
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Discussion |
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Despite the use of commonly accepted methods of anticoagulation and heparin reversal, we found evidence of marked increases in thrombin (F1.2) activity in the early postoperative period in patients undergoing CABG surgery with CPB. The demonstration of significant increases in fibrinolytic activity (D-dimer levels) at the same time suggests that this may be, in part, a response that may be secondary to excessive thrombin activity. During CPB, thrombin is generated via the contact system activation and via the liberation of tissue factor (2,3,5). The latter is released by the cutting of blood vessels or is introduced by reinfusion of cardiotomy suction blood during bypass (2). Activated monocytes in the wound blood express tissue factor on the surface when exposed to the pericardial cavity (3). Consequently, unprocessed pericardial blood that is routed back to the bypass system is highly activated and could produce a procoagulant state (3). Washing the collected blood by means of a cell-saving device will reduce the amount of proinflammatory cytokines and the procoagulant properties of the returned blood, although it cannot eliminate these entirely (4).
Our findings are in accordance with other studies showing massive activation of hemostasis during and early after cardiac surgery performed with the use of CPB (1,12). The only recent study that compared coagulation and fibrinolysis in on-pump CABG and OPCAB directly was a nonrandomized trial by Casati et al. (1), which showed a similar transient increase in D-dimer levels immediately after surgery in the CPB group compared with OPCAB. However, the authors measured coagulation data only up to 24 hours after surgery. In contrast to our study, they also found that CPB was associated with smaller platelet counts and lower plasminogen levels. Although we could demonstrate marked platelet activation directly after surgery, as demonstrated by plasma P-selectin per platelet, it was not significantly different between groups, nor could we detect a postoperative decrease in platelet number after correction for hemodilution.
The activated state of hemostasis immediately after on-pump surgery, as evidenced by increased F1.2 and D-dimer concentrations, may reflect the formation of microthrombi and could theoretically contribute to the organ dysfunction associated with CPB (8,9). Immediately after OPCAB, there is much less hemostatic activation, and this may have been a contributing factor in the better reported clinical outcome (9,23). Moreover, less consumption of clotting factors may explain the reduced postoperative blood loss and transfusion requirements that have been reported in OPCAB (10,11). However, this will need to be confirmed in larger studies.
We found a significant increase in thrombin and fibrinolytic activity in the late (20–96 hr) postoperative period. Thrombin generation persisted, as reflected in a second or maintained increase of F1.2, with a similar increase of D-dimer formation.
These findings confirm previous reports of an increased procoagulant activity in the first postoperative days after OPCAB (1,14,15). Whereas the potential hypercoagulable state is opposed by the administration of IV heparin and hemodilution in standard CABG, doses of heparin and fluids given during OPCAB are usually smaller. Quigley et al. (15) demonstrated a twofold increase in the coagulation index in OPCAB patients 72 hours after surgery, indicating a state of relative hypercoagulability, whereas in patients undergoing standard CABG, the coagulation had returned to preoperative values. This procoagulant activity in the days after OPCAB may lead to an increased risk for early thrombotic complications such as graft occlusion (16,17). It has been shown that OPCAB grafts have lower patency rates than grafts implanted by conventional techniques and limited revascularization, which results in more frequent reinterventions (4,24). Standards for perioperative heparinization and antiplatelet therapy in OPCAB are still lacking but are usually less aggressive than in on-pump surgery (25). Therefore, further research is needed to determine what perioperative anticoagulation regimen is most appropriate for OPCAB.
Levels of vWF were increased from the first postoperative day after both surgical procedures and peaked at high levels on the fourth postoperative day. Plasma vWF is one of the most useful markers for vascular endothelial activation because it is a specific, stable, circulating product of the endothelial cell (21). Forming a part of a molecular bridge between platelets and the subendothelium of an injured vessel wall in the presence of increased plasma vWF levels, platelet adhesion consequently can be increased beyond normal. Therefore, the increased release of vWF could have contributed to increased thrombogenicity in both surgical groups during the first days after surgery.
Although this study was a randomized (single-center) trial, it has several limitations. The number of patients is rather small, so it should be considered more as a pilot investigation to direct the most appropriate analyses of coagulation variables in a larger cohort. Because the small sample size precludes excluding Type II error, small differences between groups at certain time points could have been missed. In addition, the number of sampling periods is limited, so only data from these predefined sampling periods can be supplied; therefore, hemostatic abnormalities at other time points after CABG could have been missed. Second, the Octopus Trial was designed as a practical rather than an explanatory trial: it compared OPCAB with conventional CABG, both performed according to standard practice in The Netherlands at that time. This included additional factors associated with the on-pump procedure that could have influenced our results. These include 1) use of dexamethasone (to mitigate the systemic inflammatory response), 2) use of moderate hypothermia, 3) use of cardioplegia to arrest the heart, and 4) use of different anticoagulation strategies (target ACT >450 vs 250 seconds). We also used a fixed protamine dosage for heparin reversal. Because ACT may be influenced by other factors, such as hypothermia and hemodilution, it may not accurately reflect the extent of anticoagulation by heparin (5). This could have led to relative protamine overdose and therefore might have influenced our results in the immediate postoperative period (5). In addition, an ACT <150 seconds in the OPCAB group may still have represented significant anticoagulation (activated partial thromboplastin time >100 seconds). The monitoring of whole-blood heparin concentrations or the administration of heparin based on a CPB duration-dependent, fixed-dose regimen might help to avoid this and would be preferable in future studies. It is clearly established that patient-specific heparin dosing leads to less hemostatic activation, better thrombin inhibition, and less transfusion of allogenic blood (5,26). Using monitoring of whole-blood heparin concentrations during CPB could probably decrease or even abolish the pronounced activation of coagulation and fibrinolysis that we demonstrated in the immediate postoperative period. However, measuring ACT currently remains the most commonly used anticoagulation strategy during cardiac surgery.
We conclude that this prospective, randomized study provides evidence that CPB is associated with a significantly more pronounced activation of coagulation and fibrinolysis in the immediate postoperative period. In the OPCAB group, a delayed postoperative response was demonstrated which became equal in magnitude to that in the CPB group in the later (20–96 hours) postoperative period. Levels of vWF were increased from the first postoperative day after both surgical procedures and peaked at high levels on the fourth postoperative day. Further research is needed to determine what perioperative anticoagulation regimen is most appropriate for both on- and off-pump surgery.
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Acknowledgments |
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