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Ann Thorac Surg 1995;60:365-371
© 1995 The Society of Thoracic Surgeons
Departments of Cardiac Surgery and Anesthesiology, Oslo Heart Center, and Research Institute of Internal Medicine, Rikshospitalet, Oslo, Norway
Accepted for publication March 24, 1995.
| Abstract |
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Methods. Two hundred three patients undergoing first-time elective myocardial revascularization were prospectively randomized either to a group in which a completely heparin-coated circuit was used for perfusion (group H; n = 101 patients) and in which a reduced heparin dose was given (activated clotting time, >250 seconds) or to a control group (group C; n = 102 patients) in which an uncoated, but otherwise identical, circuit was used and in which full systemic heparinization was induced (activated clotting time, >480 seconds). Indicators of thrombin generation, platelet activation, and fibrinolytic activity were studied in a subset of 34 patients.
Results. The total amount of postoperative mediastinal drainage was significantly reduced in group H (median, 575 mL) compared with that in group C (median, 635 mL; p = 0.002). Two patients in group C but none in group H received homologous red blood cell transfusions (p = not significant). The loss of hemoglobin in group H was a median of 21 g/L, and this was significantly lower than the 25 g/L noted in the control group (p = 0.006). During cardiopulmonary bypass, the plasma levels of thrombin-antithrombin complex and prothrombin fragment 1.2 increased in both groups. At the end of cardiopulmonary bypass the plasma levels of these markers of thrombin formation were significantly higher in group H, although the increase was modest compared with the major increase observed 2 hours after operation in both groups. There were no significant intergroup differences in the platelet counts, the concentration of ß-thromboglobulin, or the plasma levels of fibrinogen and D-dimer. No differences in perioperative morbidity, the postoperative kidney function, or the intubation time were observed, and there were no hospital deaths.
Conclusions. The combination of complete heparin-coated cardiopulmonary bypass circuits and low systemic heparinization is safe for patients undergoing elective coronary artery bypass procedures and reduces the perioperative blood loss. There was no evidence of increased thrombogenicity, fibrinolytic activity, or consumption of coagulation factors. No clinical or technical side effects were observed.
| Introduction |
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The heparin-coated surfaces in the circuits used for extracorporeal circulation have been shown to be more biocompatible and less thrombogenic [811], allowing a reduction in systemic heparinization and subsequently a reduced need for protamine [12, 13]. However, previously only the oxygenator and tubings could be coated with heparin, and when the intravenous heparin dose was reduced, the cardiotomy reservoir for shed blood return had to be excluded or replaced with various cell preservation devices. These circumstances made it difficult to assess the effects of heparinized CPB circuits when the systemic heparin level was also reduced. When a completely heparinized extracorporeal system, including all cannulas, the arterial filter, and the cardiotomy reservoir, became available in 1993, the present randomized study was initiated to evaluate the clinical effects and the influence of this system on the hemostatic variables in a select group of patients who were at low operative risk. The design of the coated and uncoated extracorporeal circuits was identical, and they met all requirements for routine coronary artery bypass procedures.
| Material and Methods |
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Initially, 210 patients were randomly allocated to one of two groups: group H, in which heparin-coated circuits were used, and group C; the control group in which an uncoated circuit was used. Informed consent was obtained from all patients, and the study protocol was approved by the local ethics committee. All operations were performed by one of two surgeons (E.Ø. or G.T.). The surgical team, but not the anesthesiologist and the perfusionist, were blinded to the randomization.
Cardiopulmonary Bypass
Cardiopulmonary bypass was performed in group H patients with a Duraflo II heparin-coated circuit (Baxter-Bentley Laboratories, Irvine, CA). All surfaces in contact with blood were coated with a water-insoluble heparin complex. The circuit consisted of silicone and polyvinyl chloride tubings connected to a hard-shell cardiotomy reservoir (DII BCR-3500), a soft-shell venous reservoir (DII BMR-1900), a woven, hollow polypropylene fiber membrane oxygenator (Univox Gold; Baxter-Bentley), and a 25-µm arterial filter (DII AF-1025). Heparin (5000 IU/mL, Nyco Med Pharma, Oslo, Norway) was used for anticoagulation. A bolus dose of 100 IU/kg was given intravenously. The activated clotting time (ACT) (HemoTec Inc, Englewood, CO) had to exceed 250 seconds before bypass was started. The bolus dose of protamine (protamine sulfate; Novo Nordisk, Baksverd, Denmark) for neutralization of the heparin effects was 1.3 mg/100 IU of heparin. The extracorporeal bypass was disconnected before the administration of protamine sulfate.
Cardiopulmonary bypass was performed in group C patients with an identical, but uncoated, circuit. The two sets of equipment did not differ visibly, and thus no bias on the part of the surgeons was possible. Heparin was given at the standard dosage for our institution: 400 IU/kg. The ACT had to be at least 480 seconds before CPB was started. The protamine-to-heparin ratio was identical to that in group H.
The activated clotting time was determined preoperatively, after heparin administration, before CPB, 10 minutes after the start of CPB, each 20 minutes during CPB, after protamine administration, and 2 hours postoperatively. Additional heparin was given if the level was below the target level in both groups of patients. The administration of supplemental doses of protamine was considered when the postoperative ACT was more than 130 seconds.
Extracorporeal circulation was performed using pulsatile flow at a rate of 2.4 L min-1 m-2, and mild hypothermia (blood temperature, 32°C) was instituted immediately after the start of CPB. The heart-lung machine was primed with 2000 mL of Ringer's acetate, and hemodilution was further accentuated by autologous blood removal for blood conservation (see later discussion). Each circuit was examined visually for evidence of clots or fibrin formation. Gross thrombi had to be reported and quantified and the circuits returned to the manufacturer for further verification and evaluation.
Operation and Blood Conservation
The anesthesia protocol was designed to permit early extubation and mainly consisted of a combination of diazepam (0 to 0.2 mg/kg), midazolam hydrochloride (0 to 0.2 mg/kg), fentanyl (6 to 8 µg/kg), and pancuronium bromide supplemented with isoflurane and nitrous oxide.
At least one internal mammary artery anastomosis was constructed in all but 1 patient, supplemented with saphenous vein grafts. The aorta was cross-clamped during performance of the distal anastomoses. Myocardial protection consisted of the antegrade administration of crystalloid cardioplegia (St. Thomas' Hospital solution No. 2) and topical cooling with ice slush. The proximal anastomoses were sutured during partial occlusion of the ascending aorta while the patient was being rewarmed. A cardiotomy suction device was used deliberately during the entire period of heparinization. The blood conservation protocol of the institution has already been described in detail [14] and includes autologous blood removal before CPB with later retransfusion, returning all contents of the extracorporeal circuit to the patient, as well as the autotransfusion of shed mediastinal blood until 18 hours after the operation. The amount of postoperative bleeding from the time of sternal closure until the drains were removed was recorded. Normovolemic anemia was accepted to a hematocrit of 0.25 postoperatively; a level below this was considered an indication for homologous red blood cell transfusion. The hemoglobin concentration was used to monitor the effects of blood conservation, and was determined preoperatively, at 3 and 18 hours postoperatively, and at discharge on the fifth to seventh day postoperatively. Kidney function was monitored by repeated measurement of the serum creatinine level before and after the operation.
Coagulation and Fibrinolysis
The effects of the two systems on the coagulation and fibrinolytic systems were investigated in 34 patients. Because the study design included block randomization, 17 patients were allocated from each group. Blood samples were drawn with a syringe from the central venous cannula at the following intervals: after the induction of anesthesia, immediately after the start of CPB, after release of the aortic cross-clamp, at the end of CPB after the onset of lung ventilation, and 2 hours postoperatively. The first 10 mL of the sample was discarded. All samples were immediately cooled on ice and centrifuged and the plasma stored at -70°C before being assayed.
Evidence of thrombin generation was evaluated by the plasma concentration of the thrombin-antithrombin (TAT) complex and prothrombin fragment 1.2 (PF1.2), both determined using enzyme-linked immunosorbent assays (Enzygnost TAT micro and Enzygnost F 1.2 micro; Behringwerke, Marburg, Germany). Platelet counts were determined using an automatic cell counter (Cobas Minos ST; Roche, Basel, Switzerland). Platelet activation was assessed by the release of ß-thromboglobulin and was quantified by an enzyme-linked immunosorbent assay using specific rabbit antibodies (Asserachrom ß-TG; Diagnostica Stago, Asnieres-sur-Seines, France). For this assay, samples were collected in a Diatube (Diagnostica Stago) according to the manufacturer's instructions. The D-dimer levels, an indicator of fibrin degradation, were determined with an immunoassay technique using monoclonal antibodies specific to a neo-antigen on the D-dimer structure (Nycocard D-dimer; Nycomed Pharma, Oslo, Norway). The fibrinogen level was determined according to the method of Clauss [15].
Statistical Analysis
Comparison of the two groups was done using the Mann-Whitney U test for continuous variables. Discrete variables were treated by means of contingency tables, with Yates' correction and Fisher's exact test performed when one of the expected cell values was less than 5. Longitudinal changes between two time points only were analyzed using the paired Student's t test and Wilcoxon paired test. The data are presented as median values with quartiles (or range, if indicated). A p value of less than 0.05 was considered significant. All data were recorded prospectively and stored in a database.
| Results |
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The two groups did not differ significantly in terms of any major preoperative variables (Table 1
). There were no operative differences, and the aortic cross-clamping and extracorporeal times were similar. The doses of heparin and protamine administered are shown in Table 2
and reflect the fact that some patients were given additional heparin and protamine so that the desired ACT was reached before and after CPB. However, the protamine-to-heparin ratio remained similar for the two groups. The ACTs in the two groups are shown in Figure 1
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Postoperative Blood Loss and Transfusions
Postoperative bleeding was significantly reduced in group H (median, 575 mL) compared with the blood loss in group C (median, 635 mL; p = 0.002) (Table 4
). In both groups more than 95% of the shed mediastinal blood was autotransfused without any pretreatment. Two patients in group C received two units each of homologous red blood cells, one of whom had anemia preoperatively and postoperatively; the other required transfusion because of hematoma formation in the thigh after vein harvesting. No patients in group H received transfusions, but the difference between the two groups was not significant. No other homologous banked blood products were given to any patients. Excluding the 2 patients who received blood transfusions, the difference in the hemoglobin concentrations preoperatively and at discharge was assumed to reflect the total intraoperative and postoperative blood loss. The hemoglobin loss was significantly less in group H than it was in group C (p = 0.006). The lowest hematocrit value during CBP was similar in the two groups, indicating the same extent of intraoperative hemodilution.
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| Comment |
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This report focuses on the effects of the combination of a completely heparin-coated extracorporeal circuit and reduced systemic heparinization to 30% of the normal dose on low-risk patients undergoing coronary artery bypass grafting. The median total postoperative mediastinal drainage was reduced in group H (575 mL) compared with that in group C (635 mL). Although this amount is not very impressive from a clinical point of view, the number of patients created sufficient statistical power to reveal highly significant differences between the groups (p = 0.002). Furthermore, the blood-saving effect was demonstrated by the reduction in the total hemoglobin loss in group H (p = 0.006). This indicates the blood loss in the surgical field was reduced in these patients, as the retransfusion volumes intraoperatively and postoperatively were similar in the two groups. Because the design of the two circuits was visually identical and the surgeons were blinded to the randomization of patients, there was no possibility for the operative hemostasis to differ.
Comparison of perioperative bleeding among patient groups managed in different ways ideally requires the existence of accepted baseline values with respect to blood loss and homologous blood use. In the present study the limited amount of postoperative bleeding and low transfusion rate in group C may obscure the effects observed in group H that received a reduced systemic heparin dose. In a series of 22 patients in whom heparin-coated circuits were used and who were given either a reduced heparin dose (without cardiotomy reservoir) or a full heparin dose, the postoperative blood loss was reduced from 2,345 ± 1,815 mL in the group given the full heparin dose to 831 ± 373 mL in the group given the low heparin dose [20].
Concern has been raised regarding the danger of increased thrombogenicity when the level of systemic heparinization is reduced during CPB using heparin-coated equipment [21]. Conflicting data have been yielded by studies examining the hemostatic status of patients whose systemic heparinization level was normal and in whom heparin-coated circuits were used. One study demonstrated that thrombin formation was reduced during CPB [22], but this could not be confirmed by others [23]. However, little is known about the effects on the hemostatic systems of a heparinized extracorporeal circuit in combination with reduced doses of heparin and protamine.
Thrombin contributes to the generation of fibrin as well as to the activation of fibrinolysis. The plasma thrombin concentration is difficult to measure directly, but recently enzyme-linked immunosorbent assay methods that can evaluate thrombin generation have become commercially available. Prothrombin fragment 1.2 is formed by the proteolytic cleavage of prothrombin when it is transformed to thrombin and is thus a direct indicator of thrombin formation. Thrombin is inactivated through a complex formation with antithrombin, forming TAT complexes, and assay of TAT complex formation is accordingly another indicator of thrombin generation. Platelet activation takes place in response to vessel wall injury and thrombin formation, and its status can be assessed by the amount of ß-thromboglobulin released into plasma from the
-granules. In the present study the levels of PF1.2, TAT complex, and ß-thromboglobulin increased during CPB, indicating that thrombin is steadily formed during bypass, even with standard heparinization with an ACT of more than 480 seconds. This compares well with the findings cited in other reports and supports the view that heparin is only partially effective as an anticoagulant during CPB procedures [23, 24]. The somewhat higher concentrations of the TAT complex and PF1.2 in group H which received a reduced heparin dose could be of concern. However, the extensive elevation in the levels of these thrombogenic markers 2 hours after the end of operation indicate that the degree of thrombin generation during CPB remained within acceptable limits in both groups. The immense thrombin formation that occurs after operation must be regarded as part of the normalization of the hemostatic mechanisms, which have been suppressed by heparin during the surgical procedure. Our postoperative findings of major thrombin formation are comparable to those of others using CBP with ordinary uncoated circuits [25], as well as to those of investigators using heparin-coated CPB circuits and full systemic heparinization [23].
Another indication of adequate anticoagulation in group H was the absence of hyperfibrinolysis. Thrombin activates endothelial cells to produce tissue plasminogen activator [26], and evidence of increased fibrinolysis would be more likely in the setting of undesired thrombin levels. In fact there were no intergroup differences with regard to the plasma levels of D-dimer. The increased levels observed 2 hours after operation in both groups confirm the normal occurrence of fibrinolytic activity triggered by the surgical trauma and the extracorporeal circulation. The postoperative platelet counts and fibrinogen levels were close to preoperative values, indicating no excessive consumption of coagulation factors.
Most important is the fact that there were no clinical findings indicating harmful thrombogenicity. The incidence of perioperative myocardial infarction was 1%, and there was no evidence of stroke. No visible clot formation was noted in the surgical field or in any part of the extracorporeal circuit. This compares well with the findings from other studies [12, 13, 19, 20] in which no adverse thrombotic events were noted, even for patients whose systemic heparin dose was more reduced than that in the patients in the present series [20].
When the intravenously delivered dose of heparin is reduced, the subsequent reduced need for protamine may be of importance, as protamine is known to cause hemodynamic instability, hypersensitivity, and complement activation [6, 7, 27]. Although no beneficial effects of reduced protamine doses could be demonstrated in the present low-risk patient population, both a reduction in hemoglobin loss and a lowering of the heparin and protamine volumes may have a clinical impact in patients at higher operative risk. In particular, heparin-coated circuits and reduced systemic levels of heparin represent an alternative option for patients known to react adversely to protamine and for patients at high risk of bleeding [28].
| Acknowledgments |
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| Footnotes |
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| References |
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