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Ann Thorac Surg 1997;63:438-444
© 1997 The Society of Thoracic Surgeons
Departments of Anesthesiology, Thoracic, and Cardiovascular Surgery, University of Helsinki, Helsinki, Finland
Accepted for publication August 29, 1996.
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Abstract |
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Methods. Thirty patients scheduled to undergo myocardial revascularization were randomized to have either a heparin-coated or an uncoated cardiopulmonary bypass circuit. Anticoagulation was induced with heparin (100 IU/kg in the coated group and 300 IU/kg in the uncoated group) and the activated clotting time was kept over 200 and 480 seconds in the coated and uncoated groups, respectively.
Results. The postoperative overnight loss of hemoglobin through the drains was lower in the heparin-coated group (43.6 g; range, 18.5–69.0 g) than in the uncoated group (73.0 g; range, 32.2–137.7 g) (p = 0.0015). Plasma concentrations of prothrombin fragment 1 + 2 and D-dimer were significantly more elevated after cardiopulmonary bypass in the coated group than they were in the uncoated group. Two patients in the coated group had a stroke postoperatively.
Conclusions. The reduction in systemic heparinization was associated with thrombin formation, which may predispose to intravascular and cardiopulmonary bypass circuit clotting. Therefore, generous systemic heparinization may still be prudent despite the improved biocompatibility offered by heparin-coated surface.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Various ways to improve biocompatibility and the thromboresistance of blood-exposed surfaces have been explored. In this regard, the reduced thrombogenicity of heparin-coated circuits has been documented by blood coagulation assays and scanning electron microscopy [4, 5]. Further, intact hemostasis during CPB has been observed to result in a reduced blood loss and transfusion requirements. Heparin-coated equipment has also permitted systemic heparinization to be reduced during CPB [6–11].
This study was performed to evaluate the effect of a completely heparinized extracorporeal system, including cannulas and the cardiotomy reservoir, and reduced systemic heparinization on the hemostatic variables in patients undergoing coronary artery bypass grafting. The study was also designed to yield information about the clinical status of patients in the early postoperative period.
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Material and Methods |
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Cardiopulmonary Bypass
Cardiopulmonary bypass was performed in the heparin-coated group using a Duraflo II heparin-coated circuit (Baxter-Bentley Laboratories, Irvine, CA). All surfaces in contact with blood were coated with 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), and a woven, hollow polypropylene fiber membrane oxygenator (Univox). Porcine intestinal heparin (Heparin Lövens, 5000 IU/mL; Lövens Kemiske Fabrik, Ballerup, Denmark) was used for anticoagulation. In the heparin-coated group, 2,500 IU of heparin was added to the priming solution and a bolus dose of 100 IU/kg was given intravenously. The activated clotting time (ACT) (Hemochron; International Technidyne Corporation, Edison, NJ) was kept at 200 seconds before and during CPB. The bolus dose of protamine (Protamini sulfas, 10 mg/mL; Leiras Oy, Turku, Finland) for neutralization of the heparin effects was 1 mg per 100 IU of the heparin loading dose. Cardiopulmonary bypass was performed in the uncoated group using an identical, but uncoated, circuit. Five thousand international units of heparin was added to the priming solution, and the initial dose of heparin was 300 IU/kg which was administered intravenously. The ACT was kept at more than 480 seconds during CPB. The protamine-to-heparin ratio was identical to that in the coated group.
The ACT was determined after the induction of anesthesia, 5 minutes after heparin administration, 5 minutes after the start of CPB, each 20 minutes during CPB, just after termination of CPB, 5 minutes after protamine administration, and 1 hour and 2 hours after protamine administration. Additional heparin (2,500 IU in the coated group, 5,000 IU in the uncoated group) was given if the level was less than the target level.
Extracorporeal circulation was performed using a nonpulsatile flow at a rate of 2.4 L•min-1•m-2. Cardiopulmonary bypass was conducted with the patient under moderate hypothermia (nasopharyngeal temperature, 32°C). The heart-lung machine was primed with 2,500 mL of Ringer's acetate. During CPB the hematocrit was maintained at more than 0.20. A cardiotomy suction device was used from the time of the initial heparinization (ACT, >200 seconds) until the beginning of protamine administration. Care was taken to maintain blood flow within the circuit through the internal shunt while the inlets and outlets to the patient were clamped after CPB and before the circuit was emptied of the residual blood.
Anesthesia, Operation, and Postoperative Care
The patients were premedicated with lorazepam, given orally 2 hours before anesthesia induction. The regular oral cardiovascular medications were given at the same time as the premedication. Anesthesia was induced with fentanyl, midazolam, and pancuronium and maintained until the end of operation with a continuous infusion of fentanyl and midazolam. When required, isoflurane was administered during the operation.
At least one internal mammary artery anastomosis was constructed in all but 1 patient, supplemented with saphenous vein grafts. Myocardial protection consisted in the antegrade administration of crystalloid cardioplegia. The aorta was cross-clamped during suturing of the anastomoses.
After CPB, all of the contents in the extracorporeal circuit were collected in citrate-containing blood bags and returned to the patient. Postoperatively the hematocrit was maintained at approximately 0.30 by giving the patient packed red blood cells, Ringer's acetate, 6% hydroxyethyl starch solution (Plasmafusin; Leiras), or 4% albumin solution. If postoperative bleeding through the mediastinal tubes exceeded 200 mL/h, the ACT, platelet count, activated partial thromboplastin time, and prothrombin time were determined. If the ACT was prolonged by more than 10 seconds more than the value obtained 5 minutes after protamine administration, a supplemental dose of protamine (20 mg) was given. If the platelet count was decreased by less than 100 x 109/L, eight units of platelets were transfused. If the activated partial thromboplastin time and the prothrombin time were prolonged more than 1.5 times the preoperative values, two units of fresh frozen plasma were transfused.
Drain loss through the chest tubes was measured from the time of sternal closure until 16 hours postoperatively, and the total hemoglobin loss through the chest tubes was calculated from this. The amount of blood products, colloid solutions, and Ringer's acetate transfused and the urine output were registered until the first morning postoperatively. The hemoglobin concentration was determined the first morning postoperatively.
The CK-MB fraction was determined and new Q-wave changes on the electrocardiogram were registered the first morning postoperatively. The patient's gross neurologic status was assessed during his stay in the intensive care unit. The length of the intensive care unit stay and hospitalization was also recorded.
Laboratory Analyses
Blood samples for determination of the hemostatic variables were collected in plastic syringes inserted through a radial artery cannula, except the blood samples used for fibrinopeptide A determinations, which were obtained each time through a fresh venous cannula. Samples were obtained preoperatively, before heparinization; 10 minutes after protamine administration; and 2 hours after protamine administration. All samples were immediately cooled on ice and centrifuged and the plasma stored at -70°C before being assayed.
Thrombin generation was evaluated using the plasma concentration of prothrombin fragment F 1 + 2, measured using an enzyme-linked immunosorbent assay (Thrombonostika F1.2; Organon Teknika, Durham, NC). Samples were collected into heparin and handled according to the manufacturer's instructions. Fibrinopeptide A levels, an indicator of fibrinogen degradation, were determined using a CELIA technique (Asserachrom FPA; Diagnostika Stago, Asnières, France). Blood for the measurement of fibrinopeptide A was obtained in tubes containing special anticoagulant solution (citrate, heparin, specific protein inhibitors, sodium azide). Plasma D-dimer levels, which are an indicator of fibrin degradation, were determined using an enzyme-linked immunosorbent assay (Asserachrom D-Di; Diagnostika Stago). Blood was collected into 0.129-mol/L sodium citrate (one part anticoagulant to nine parts blood). The plasma levels of tissue plasminogen activator (both the activity and the level of antigen) and plasminogen activator inhibitor were used as markers of fibrinolytic activity. Blood for the determination of the activity and the level of the antigen to tissue plasminogen activator was collected in special tubes (Stabilyte tube; Biopool AB, Umeå, Sweden) and measured by a chromogenic method and an enzyme-linked immunosorbent assay, respectively (Coatest t-PA; Chromogenix AB, Mölndal, Sweden, and Imulyse t-PA; Biopool AB, Umeå, Sweden). The level of the plasminogen activator inhibitor was determined by a chromogenic method (Coatest PAI; Chromogenix AB). Blood for this was collected into 0.129-mol/L sodium citrate. The level of protein C, a physiologic inhibitor of activated coagulation factors VIII and V, was measured with a chromogenic method using substrate S-2366 (Chromogenix AB) and protein C activator (American Diagnostika Inc, CT). Blood for this was collected into 0.129-mol/L sodium citrate. The platelet count and hematocrit were determined using a Cell Dyn 610 analyzer (Cell Dyn, Mountain View, CA). Platelet activation was assayed by the release of ß-thromboglobulin and was quantified using an enzyme-linked immunosorbent assay (Asserachrom ß-TG). Samples were collected into Diatube H (Diagnostika Stago). The template bleeding time was determined on the volar surface of the forearm with a Simplate II device (General Diagnostics, Organon Teknika, Turnout, Belgium). For the platelet-aggregation studies, platelet-rich plasma was prepared by centrifuging citrate blood at 150 g for 10 minutes, and platelet-poor plasma was prepared by centrifuging blood at 1,400 g for 30 minutes. The platelet count in the platelet-rich plasma was adjusted to 100 to 150 x 109/L with autologous platelet-poor plasma. Aggregation (Payton Aggregometer; Scarborough, UK) was induced with adenosine diphosphate, and the concentration of adenosine diphosphate causing 50% of maximum aggregation was calculated. The plasma heparin level was determined by measuring the anti-Xa activity in the samples using an amidolytic method (Stachrom Heparin; Diagnostiga Stago), calibrated with unfractionated heparin (Hepanorm H; Diagnostica Stago) using an automated coagulometer (Thrombolyzer; Behnk Elektronik, Norderstedt, Germany).
Statistical Analysis
Analysis of variance for repeated measures was applied for statistical comparisons between and within the groups. When significant differences (p < 0.05) were found, Sheffé's F test was used to seek significant contrasts. Single contrasts between the groups were compared with the Mann-Whitney U test and, in the event discrete data were revealed, with the chi-squared t test. Results are given as the arithmetic means and the ranges.
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Results |
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). The doses of heparin and protamine administered are also shown in Table 1. The ACTs in the two groups are shown in Figure 1.
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. One patient in the uncoated group sustained a new Q-wave myocardial infarction perioperatively. The CK-MB fraction was elevated (more than 70 ng/mL) in 1 patient in both groups on the first postoperative morning. Two patients in the coated group had a stroke postoperatively. One patient's stroke was transient, but the other patient suffered a massive stroke after he got up the first morning after the operation. He died of stroke 5 days later. A left cerebral infarct was found at autopsy. Thrombi were found in the left carotid and the left medial cerebral arteries. There was also torsion at the vein graft to the right coronary artery.
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). The mean blood loss in the uncoated group during the 16 postoperative hours was 991 mL (range, 600–1420 mL), and it was 880 mL (range, 410–1600 mL) in the coated group. The hemoglobin loss was significantly less in the heparin-coated group (43.6 g; 18.5–69.0 g) than in the uncoated group (73.0 g; 32.2–137.7 g). Seven patients in the uncoated group received homologous red blood cells postoperatively. Six patients in the coated group needed red blood cell transfusions. No patients in either group needed platelet or fresh frozen plasma transfusions. The hemoglobin concentrations did not differ between the groups at any point in the study period.
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). The fibrinopeptide A levels were measured as an indicator of thrombin action on fibrinogen. The levels increased slightly after CPB in both groups, as compared with the value obtained after anesthesia induction. There were no differences between the groups (Fig 2). The D-dimer levels were measured as a marker of fibrinolytic activity and were found to be increased after CPB in both groups, though they were significantly higher in the coated group (Fig 2).
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. The platelet counts were decreased by CPB and remained a little decreased in the samples obtained 2 hours after CPB. ß-Thromboglobulin release was induced by CPB, and this elevation in the plasma concentrations was still significant in both groups at 2 hours after CPB. The bleeding time was prolonged in both groups, and the difference between the groups was not statistically significant. Platelet aggregation was unchanged in both groups, as measured by the concentration of adenosine diphosphate causing 50% of maximum aggregation. Plasma heparin concentrations (measured as an anti-Xa effect) are presented in Figure 1
and were higher in the uncoated group than in the coated group, as well as in two samples obtained after protamine administration.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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The hemostatic variables studied were poorly able to account for this blood-saving effect of heparin coating or low systemic heparinization. No differences between the groups in the variables reflecting platelet concentration, their activation, or function were observed. However, the neutralization of heparin with protamine was more complete in the heparin-coated group than in the control group. Nevertheless, small amounts of residual heparin in this group did not explain the difference in the hemoglobin loss between the groups, because there was no correlation between the hemoglobin loss and the ACT obtained after protamine administration.
Because heparin is given to prevent clotting during CPB, concern has been raised regarding the danger of increased thrombogenicity if low systemic heparinization is used in conjunction with heparin-coated equipment [14]. Thrombin is produced during CPB despite the doses of heparin given and the use of heparin-coated equipment. Conflicting data have been yielded by previous studies examining thrombin formation in patients in whom heparin-coated circuits were used. When standard systemic heparinization and heparin-coated circuits have been used, thrombin formation has been found to be either reduced or not reduced [13, 15]. In the present study, the use of low systemic heparinization in conjunction with heparin-coated equipment led to the production of more thrombin than that seen in patients in whom standard CPB circuits were used. Thrombin generation was determined by measuring the concentration of prothrombin fragment 1 + 2, which is formed by the proteolytic cleavage of prothrombin when it is transformed to thrombin. In addition, the levels of fibrinopeptide A, a peptide cleaved from fibrinogen when thrombin stimulates fibrin formation, were high after CPB in the heparin-coated group, but the difference between the groups was not statistically significant. There are two previous reports in which low systemic heparinization is noted to have caused thrombin formation, as determined by the concentration of prothrombin fragment 1 + 2 and the thrombin-antithrombin III complex measured immediately after CPB [11, 16]. However, this difference in thrombin formation was not present at 2 hours after CPB, as it was in our patients. Those authors were not concerned about thrombin formation. They regarded the phenomenon as being part of the normalization of the hemostatic mechanisms that occurs after operations and the finding was comparable to the thrombin formation that occurs after the use of ordinary circuits and heparin-coated circuits with full systemic heparinization [2, 15].
The fact that thrombin is produced during CPB means that heparin is not an ideal anticoagulant. The optimal dose of heparin is determined as empirically as possible. On the basis of the plasma fibrinopeptide A concentrations measured in monkeys, Young and associates [17] have suggested that a heparin concentration resulting in an ACT greater than 400 seconds provides adequate anticoagulation during CPB. When heparin-coated equipment has been used, the ACT values have been reduced to 200 to 250 seconds with low systemic heparinization [9, 11]. In this study the heparin concentrations were also such that the ACTs were no less than 200 seconds. The mean ACT during CPB was 314 seconds (range, 233–426 seconds) in the coated group. The fact that the concentration of prothrombin fragment 1 + 2 and the plasma levels of D-dimer were higher in the heparin-coated group than in the control group after CPB could indicate inadequate anticoagulation.
Because of the relatively small number of patients in our study, it did not have the power to detect differences in the outcome of patients. However, the occurrence of two strokes in patients in whom heparin-coated circuits and reduced systemic heparinization were used, albeit not statistically significant, is disturbing and also raises questions about the adequacy of anticoagulation in this group. The neurologic variables in patients undergoing myocardial revascularization with either heparin-coated or uncoated circuits have been compared in two studies. Pradham and colleagues [18] found no difference in the incidence of retinal microembolization, and Stump and associates [19] found no difference in the cerebral blood flow during CPB or in the neurologic or neurophysiologic outcomes in their patients after CPB. Traditional systemic anticoagulation protocols for the coated and uncoated extracorporeal circuits were used in both studies. It has been demonstrated that heparin-coated CPB equipment remains fully functional for hours and even days when low or no systemic heparinization is used, but only if the flow is continuous [4]. Unlike full systemic heparinization, which in general prevents significant coagulation of stagnant blood, it cannot be taken for granted that this happens when systemic heparinization is reduced. There is one report of intracardiac thrombus formation during CPB in which low systemic heparinization was used [20].
Heparin-coated circuits may prove advantageous in reducing the inflammatory response associated with CPB and open heart operations. Low systemic heparinization may also be indicated in patients in whom the risk of systemic anticoagulation is high (ie, trauma, extracorporeal lung assist, resuscitation from accidental hypothermia, neurosurgical procedures, bilateral lung transplantation, protamine reactions). However, the reduction in systemic heparinization is associated with thrombin formation, which may predispose to the development of fibrin microemboli and intravascular and CPB circuit clotting. Therefore, it may still be prudent to use generous systemic heparinization despite the improved biocompatibility offered by the heparin coating of extracorporeal circuits.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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