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Ann Thorac Surg 1997;63:50-56
© 1997 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Heparin Coating With Aprotinin Reduces Blood Activation During Coronary Artery Operations

Department of Thoracic and Cardiovascular Surgery, Hôpital Henri Mondor, Créteil, France, and Department of Cardiac Surgery, Free University Hospital, and Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Department of Plasma Protein Physiology, Amsterdam, the Netherlands

Accepted for publication July 10, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

 
Background. This study was performed to evaluate whether the combination of heparin-coated extracorporeal circuits (ECC) and aprotinin treatment reduce blood activation during coronary artery operations.

Methods. Sixty patients were prospectively divided into two groups (heparin-coated ECC and uncoated ECC groups), which were comparable in terms of age, sex, left ventricular function, preoperative aspirin use and consequent intraoperative aprotinin use, number of grafts, duration of aortic cross-clamping, and duration of cardiopulmonary bypass. Blood activation was assessed at different times during cardiopulmonary bypass by determination of complement activation (C3 and C4 activation products C3b/c and C4b/c and terminal complement complex), leukocyte activation (elastase), coagulation (scission peptide fibrinopeptide 1+2), and fibrinolysis (D-dimers).

Results. Univariate analysis showed that heparin-coated ECC, under conditions of standard heparinization, did not reduce perioperative blood loss and need for transfusion. Heparin coating, however, reduced maximum values of C3b/c (446 ± 212 nmol/L versus 632 ± 264 nmol/L with uncoated ECC; p = 0.0037) and maximum C4b/c values (92 ± 48 nmol/L versus 172 ± 148 nmol/L with uncoated ECC; p = 0.0069). Levels of terminal complement complex, elastase, fibrinopeptide 1+2, and D-dimers were not significantly modified by the use of heparin-coated ECC. Multivariate analysis showed that the intergroup differences in maximum C3b/c and C4b/c values were more pronounced in women in part with high baseline values of C3b/c. We also found that aprotinin contributed to the reduction of maximum values of fibrinopeptide 1+2 and D-dimers, whereas heparin coating had no significant influence on these parameters.

Conclusions. We found no evidence of combined properties of heparin-coated ECC and aprotinin in reducing complement activation, coagulation, and fibrinolysis. We therefore recommend use of both together to achieve maximal reduction of blood activation during cardiopulmonary bypass for coronary artery operations.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

 
Despite improvements in coronary artery surgery over the last three decades, the whole-body inflammatory response that occurs after cardiopulmonary bypass (CPB) contributes to the postoperative organ dysfunction [1–3]. Recent research has demonstrated that complement activation and leukocyte release products play a key role in organ dysfunction. Bleeding disorders are considered to be mediated by contact phase activation and the subsequent thrombin and plasmin generation [2, 4]. The contact phase activation is also rapidly followed by complement activation [5, 6] as reflected by generation of C3 activation products and terminal complement complex (TCC) C5b-9 throughout the duration of CPB. These mediators of inflammation have been associated with the incidence of postoperative cardiac, pulmonary, and renal dysfunction [6–8]. Several investigators have demonstrated that heparin surface coating ofthe extracorporeal circuit (ECC) results particularly in significant reduction of complement activation and, subsequently, of the postoperative inflammatory response [9–1111]. In recent years, heparin-coated circuits have become commercially available, and their relatively low price makes them attractive for routine use in cardiac operations.

In addition, the use of aprotinin also reduces contact phase activation, preserves platelet hemostatic function, and decreases blood loss and blood requirements during CPB[12–16]. Several cardiac centers in Europe routinely use aprotinin for this purpose, particularly when excess bleeding problems are expected as with the preoperative use of acetylsalicylic acid [15, 16].

Therefore, combined properties of heparin-coated ECC and aprotinin could be expected when they are used together in patients undergoing coronary artery operations. The aim of this study was to evaluate whether the combination of heparin-coated ECC and aprotinin treatment reduces blood activation during coronary artery operations.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

 
Design of the Study
Sixty patients undergoing elective coronary artery bypass grafting using ECC were randomly allocated to either heparin-coated circuits or uncoated circuits. Physicians and trial nurses involved in the postoperative care were blinded to the randomization. Inclusion criteria were left ventricular end-diastolic pressure less than 30 mm Hg or ejection fraction of 0.30 or greater. Exclusion criteria included valvular operations or ventricular aneurysm operations, impaired organ function (apart from myocardial ischemia), preoperative coagulopathy, diabetus mellitus, active inflammatory disease, or antiinflammatory drugs (except acetylsalicylic acid). Aprotinin (2 x 10⁶ KIU [280 mg] in the prime) was administered if acetylsalicylic acid administration was not stopped within 8 days before the operation.

	Anesthesia, Extracorporeal Circulation, and Postoperative Care

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

 
Anesthesic drugs used were phenoperidine and droperidol. The extracorporeal circuit consisted of a roller pump (Sarns 9000; 3M Health Care Group, Ann Arbor, MI), closed venous reservoir, hollow fiber oxygenator (Univox; Baxter, Irvine, CA), cardiotomy reservoir (Baxter BCR 3500), and arterial line filter (Baxter AF-1040). All components of the circuits in the heparin-coated group were treated with ionically bonded heparin (Duraflo II; Baxter). The extracorporeal circuit was primed with 1,200 mL of Ringer's lactate solution with 5,000 IU heparin, 60 mL of 8.4% sodium bicarbonate, and 1 g of potassium chloride. Heparin (300 IU/kg) was injected directly into the right atrium before cannulation. Immediately before the start of CPB and depending on the hemodynamic state, 500 to 1,000 mL of blood was collected for immediate post-CPB autotransfusion. Cardiopulmonary bypass was performed with core cooling to 28°C and nonpulsatile flow of 2.4 L•min^-1•m^-2. After aortic cross-clamping, myocardial protection was achieved with cold antegrade crystalloid cardioplegia (Assistance Publique-Hôpitaux de Paris solution, 1,000 mL at 4°C). Anticoagulation during bypass was controlled by monitoring the activated clotting time (Hemotec, Inc, Englewood, CO); additional heparin was administered if the activated clotting time was less than 400 seconds (600 seconds in aprotinin patients). If additional volume was required, macromolecular solution, human albumin solution (4%), or both were added to the circuit. Transfusion of packed red blood cells was performed when the hematocrit was less than 25%. Fresh frozen plasma and platelets were transfused if there was excessive postoperative bleeding with a prothrombin rate less than 40% or a platelet count less than 80,000 x 10⁶/L. During bypass, all intrapericardial blood was collected in the reservoir and retransfused through the aortic cannula. After cessation of CPB, protamine (1 mg/100 IU heparin) was administered intravenously, followed by the infusion of unmodified pump blood. All the patients were operated on according to a standardized surgical protocol: distal anastomosis first, proximal anastomosis after release of the aortic cross-clamp.

Patients were discharged from the intensive care unit when they were extubated with no need for continuous monitoring or intravenous inotropic drugs, and after removal of the chest tubes. Donor blood transfusion, volume of blood loss, and vasoactive medication were measured from induction of anesthesia until 18 hours after arrival in the intensive care unit.

	Blood Sampling and Measurements

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

 
Samples were taken in tubes containing trisodium citrate (fibrinopeptide 1+2, D-dimer, polymorphonuclear neutrophil [PMN] elastase) or EDTA (complement activation) and immediately immersed in crushed ice. After centrifugation at 3,000 g for 20 minutes at 4°C, the platelet-poor plasma was aliquoted into Eppendorf tubes and stored at -80°C until measurements. Arterial blood samples were collected after induction of anesthesia, after heparinization, at 10 minutes after the start of CPB, before release of the aortic cross-clamp, 10 minutes after release of the aortic cross-clamp, after the stop of CPB before administration of protamine sulfate, and after administration of protamine sulfate.

Thrombin generation was measured by plasma concentrations of the prothrombin scission peptide fibrinopeptide 1+2 (enzyme-linked immunosorbent assay [ELISA]; Behring Werke, Marburg, Germany), and fibrinolysis by fibrin degradation product D-dimer (ELISA; Diagnostica, Boehringer Mannheim, Germany). Polymorphonuclear neutrophil activation was measured by the release of elastase in the plasma. Elastase was measured by the activating immunization method with a automated homogenous enzyme immunoassay (Merck Diagnostica, Darmstadt, Germany) in a Hitachi 717 selective analyzer (Boehringer, Mannheim, Germany). The activation of complement was assessed by measuring C3 activation products (C3b, iC3b, C3c), C4 activation products (C4b, iC4b, C4c), and TCC [17–19].

	Statistical Analysis

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

 
Data were stored in a database (Open Access III; Software Products International, Inc, San Diego, CA) and analyzed with the SPSS software package (SPSS for Windows; SPSS Inc, Chicago, IL) [20]. Quantitative variables were expressed as mean ± standard deviation, and univariate analysis was performed using t test, Mann-Whitney test, or correlation when appropriate. Qualitative variables, expressed as percentages, were analyzed with the ² test or Fisher's exact test when appropriate. To investigate whether factors other than heparin coating could influence maximum levels of C3b/c, C4b/c, TCC, elastase, fibrinopeptide 1+2, and D-dimers, stepwise multiple regression was carried out. Significant variables determined from the univariate analysis were associated with heparin coating, aprotinin, and the following variables: baseline values, sex, preoperative use of aspirin, duration of CPB and aortic cross-clamping, reperfusion time defined by the difference calculated between duration of CPB and aortic cross-clamping, heparin dose, and protamine sulfate dose. A two-tailed p less than 0.05 was retained for statistical significance of this multivariate analysis.

	Results

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

 
Patient characteristics and surgical data are presented in Table 1. There were no differences in the postoperative course with regard to use of vasoactive medication after CPB (inotropic support by dopamine, dobutamine, or vasodilating agents), delay of extubation, and the occurrence of adverse events (death, organ dysfunctions, infections) with uncoated or heparin-coated ECC. Heparin-coated ECC did not reduce blood loss (727 ± 460 mL versus 695 ± 285 mL with uncoated ECC; not significant) or the need for transfusion of blood products (30% of patients versus 23% with uncoated ECC; not significant).

	Complement Activation

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

View larger version (16K): [in this window] [in a new window]   Fig 1. . Pattern of C3 activation products release in blood during cardiopulmonary bypass, (CPB). Data are presented as mean ± standard error of the mean. (HECC = heparin-coated extracorporeal circuit; preop = preoperative time; *p = 0.039; **p = 0.003.)

View larger version (16K): [in this window] [in a new window]   Fig 2. . Pattern of C4 activation products release in blood during cardiopulmonary bypass (CPB). Data are presented as mean ± standard error of the mean. (HECC = heparin-coated extracorporeal circuit; preop = preoperative time; *p = 0.008.)

View larger version (15K): [in this window] [in a new window]   Fig 3. . Pattern of terminal complement complex (TCC) release in blood during cardiopulmonary bypass (CPB). Data are presented as mean ± standard error of the mean. (AU = arbitrary units; HECC = heparin-coated extracorporeal circuit, preop = preoperative time.)

	Leukocyte Activation

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

View larger version (14K): [in this window] [in a new window]   Fig 4. . Pattern of polymorphonuclear neutrophil (PMN) elastase release in blood during cardiopulmonary bypass (CPB). Data are presented as mean ± standard error of the mean. (HECC = heparin-coated extracorporeal circuit; preop = preoperative time; X-off = aortic cross-clamp release.)

	Coagulation Activation

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

View larger version (15K): [in this window] [in a new window]   Fig 5. . Pattern of fibrinopeptide 1+2 release in blood during cardiopulmonary bypass (CPB). Data are presented as mean ± standard error of the mean. (HECC = heparin-coated extracorporeal circuit; preop = preoperative time; *p = 0.033.)

	Fibrinolytic Activation

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

View larger version (15K): [in this window] [in a new window]   Fig 6. . Pattern of D-dimers release in blood during cardiopulmonary bypass (CPB). Data are presented as mean ± standard error of the mean. (HECC = heparin-coated extracorporeal circuit; preop = preoperative time; *p < 0.001.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

After correction for several confounding variables, the reduction in complement activation with heparin-coated circuits was significant for C3 activation products but did not result in decreased TCC and PMN elastase release. C3 activation may be a more sensitive marker of complement activation cascade than TCC, as only a minor part will proceed into C5 activation [21]. However, the biological importance of complement activation is mainly associated with formation of C5a, the most biologically active agonist of the inflammatory reaction. Also, the leukocyte inflammatory mediators, indicated by PMN elastase, were not modified by heparin coating. This could indicate contribution to inflammation by other sources of blood activation occurring during CPB, as suggested by the relationship with CPB duration, like release of endotoxin [22]. The implication is that the gain from the reduction of complement activation by heparin-coated surfaces has to be accompanied by the reduction of activation of other sources and hence by modifying current perfusion techniques. These multifactorial sources of blood activation must logically require a multifactorial approach to reduction.

The increase in C4 activation products after protamine administration was significantly less in patients treated with heparin-coated than uncoated circuits, even after the patients were disconnected from CPB. It is known [23] that the heparin-protamine complex activates the classic pathway of complement to a significant level. This post-CPB activation was significantly less in patients who were treated with heparin-coated circuits. This cannot be explained by differences in the heparin-protamine complexes (the likely cause of classic pathway activation). If heparin coating has a sparing effect on the systemic heparin consumption, as previously suggested [24], we would expect higher rather than lower degrees of activation. This could imply that complement factors may be adsorbed to the heparin-coated surfaces, thus preventing the activation of the classic pathway by the heparin-protamine complex shortly after bypass. This is still open for debate.

Because aprotinin reduces blood loss, especially in aspirin-treated patients [15, 16], aspirin-treated patients received it during the operation. Aprotinin use was not randomized in this study, but we observed that the distribution of aspirin-treated patients, and thus subsequent aprotinin use, was similar in heparin-coated and uncoated groups. The multivariate analysis suggests that only heparin coating could account for the reduction of the complement activation, despite the use of aprotinin.

Tabuchi and colleagues [25] found fulminant fibrinolysis and clotting activation in blood in the pericardial cavity, where tissue factor and tissue plasminogen activator are present. They suggested that thrombin generation, followed by fibrinolysis, was stimulated more strongly by tissue factor pathway activation (extrinsic pathway of coagulation) than through factor XII activation (intrinsic pathway). Our results are consistent with this observation. The multivariate analysis of maximum values of fibrinopeptide 1+2 emphasized the influence of the reperfusion time. The model indicates that a shorter reperfusion time implies the lowest fibrinopeptide 1+2 release. Thus, thrombin generation seems to be more explained by reperfusion time, as previously suspected by Tabuchi and colleagues [25]. The pericardial cavity seems therefore to be an important thrombogenic site during CPB. This activation of the extrinsic pathway of blood coagulation during reperfusion may explain why, despite the use of heparin-coated ECC during CPB, the activation of the clotting system is not completely suppressed.

The mechanism of aprotinin to improve hemostasis during CPB is multifactorial. In particular, aprotinin inhibits fibrinolysis [26]. Also, aprotinin has been reported to synergistically enhance anticoagulation by heparin through the inhibition of the kallikrein system [27]. The statistical weight, however, of the reperfusion time in the stepwise regression model of maximum values of fibrinopeptide 1+2 is much higher than aprotinin use, which indicates that aprotinin has little effect on thrombin formation and suggests that thrombin is mainly generated through the extrinsic pathway of coagulation.

We found no evidence of combined properties of heparin-coated ECC and aprotinin in reducing complement activation, coagulation, and fibrinolysis. Each of these systems has different clinical implications. Consequently, a reduction in morbidity and mortality, especially in high-risk patients, requires complete inhibition of the various pathways of blood activation. We therefore recommend use of heparin-coated ECC and aprotinin together to achieve maximal reduction of blood activation during CPB for coronary artery operations. The current first generation of commercially available heparin coating has only just opened the era of improved biocompatibility of blood contact surfaces. With the various biochemical assays currently available, the specific pathways of plasmatic activation can be identified and more rational improvements can be attempted. However, as observed previously, there are multiple factors of blood activation, and therefore improvements in perfusion techniques are also required.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

 
The clinical studies were performed in Hôpital Henri Mondor, whereas the biochemical studies were evaluated in the institutions of Amsterdam. We thank Dr Tom-Erik Mollnes for the TCC assay, Dr Ed H. Slaats (Department of Clinical Chemistry, Onze Lieve Vrouwe Gasthuis, Amsterdam) for the PMN elastase assay, Dr Augueste Sturk and René J. Berckmans (Department of Clinical Chemistry, University Hospital Leiden) for the fibrinopeptide 1+2 ELISA and D-dimer ELISA, Anke J. M. Eerenberg and Gerard van Mierlo for the C3b/c C4b/c ELISAs, and Dr Wallid C. Dihmis for his help in reviewing the manuscript.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

 
Address reprint requests to Dr Loisance, Department of Thoracic and Cardiovascular Surgery, Hôpital Henri Mondor, 51 Ave du Mal de Lattre de Tassigny, 94010 Créteil Cedex, France.

	References

Top Footnotes Abstract Introduction Material and Methods Anesthesia, Extracorporeal... Blood Sampling and Measurements Statistical Analysis Results Complement Activation Leukocyte Activation Coagulation Activation Fibrinolytic Activation Comment Acknowledgments References

 

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