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Ann Thorac Surg 1998;65:1342-1347
© 1998 The Society of Thoracic Surgeons

Cardiopulmonary Bypass Circuit Treated With Surface-Modifying Additives: A Clinical Evaluation of Blood Compatibility

^a Department of Cardiothoracic Surgery, Thorax Center, University Hospital Groningen, Groningen, the Netherlands

Accepted for publication December 26, 1997.

Address reprint requests to Dr van Oeveren, Blood Interaction Research, Dept. of Cardiothoracic Surgery, University Hospital Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands

	Abstract

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Background. The cardiopulmonary bypass (CPB) circuit induces blood activation and a systemic inflammatory response in cardiac surgical patients. The CPB circuit treated with surface-modifying additive (SMA) has been found to reduce blood activation by in vitro and ex vivo experiments. This study evaluates the surface thrombogenicity and complement activation of SMA circuits during clinical CPB.

Methods. Twenty patients undergoing coronary artery bypass grafting were randomly divided into two groups. In the SMA group (n = 10), all blood-contacting surfaces in the CPB circuit were treated or coated with SMA, whereas in the control group (n = 10) patients were perfused with an identical circuit without treatment.

Results. During CPB, platelet count and ß-thromboglobulin were found similar in both the SMA and the control groups. Prothrombin activation indicated by fragment F1+2 was found less in the SMA group (p < 0.05). After CPB, platelet deposition on the CPB circuit was significantly less (p < 0.05) in the SMA group than in the control group as assessed by the labeled monoclonal antibody against platelet glycoprotein IIIa. Complement activation identified by C3a and terminal complex C5b-9 did not differ between the two groups, but C4a generation was less in the SMA group (p < 0.05). Leukocyte activation identified by elastase and cytokine release indicated by interleukin-8 were found uniformly in both groups. Postoperatively, chest tube drainage, blood transfusion, duration of ventilatory support, as well as the intensive care unit and hospital stay were not significantly different between the two groups.

Conclusions. These preliminary clinical results suggest that SMA inhibits platelet interaction with the biomaterial surface of the CPB circuit. Complement activation assessed by the terminal complement complex is not influenced by SMA. The clinical benefit of this surface-modifying technique has yet to be assessed in a larger population of patients undergoing cardiac operations.

	Introduction

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Patients undergoing a cardiac operation with cardiopulmonary bypass (CPB) are still confronted with a systemic blood activation caused by the contact of blood with the CPB circuit [1–3]. This blood–surface interaction induces a whole body inflammatory response and increases postoperative morbidity such as bleeding complication and organ dysfunction [4, 5].

In the past, a number of studies have shown that this blood–surface interaction can be reduced partly by coating the surface with heparin [6–9]. Recently, a surface-modification technique called surface-modifying additive (SMA) has been introduced [10–12]. The SMA technology is based on a family of polysiloxane-containing copolymers that can be either blended with base polymer resins before processing or coated to blood-contacting surfaces [10]. Initial investigations have demonstrated that SMA-treated biomaterial surface reduces blood activation during in vitro and ex vivo experiments [10–12]. In this study, we examine whether the SMA-treated CPB circuit improves the blood compatibility by modifying the surface thrombogenicity and complement activation during clinical CPB in cardiac surgical patients.

	Material and methods

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Patients
This clinical evaluation was carried out on 20 patients who underwent elective coronary artery bypass grafting. These patients had no evidence of severe heart failure or renal or hepatic dysfunction, had no history of bleeding diathesis, and had not used platelet-inhibiting drugs within 3 days before the operation. Written informed consent was obtained from each patient before operation and the study protocol was approved by the medical ethics committee of the University Hospital in Groningen. Patients’ demographic data in both groups are summarized in Table 1.

Cardiopulmonary bypass
The extracorporeal circuit consisted of roller pumps (Stöckert Instrumentation, Munich, Germany) and a microporous polypropylene membrane oxygenator (CML Duo, Cobe Laboratories Inc, Lakewood, CO). In the SMA group, all the blood-contacting components in the extracorporeal circuit, including oxygenator, venous reservoir, tubing, connectors, and cannula were treated with SMA. Neither cardiotomy reservoir nor an arterial line filter was used in the circuit, and all the cardiotomy suction blood was discarded according to the method described previously [13]. The extracorporeal circuit was primed with a pentastarch solution (HEAS 2.5%; Fresenius, Bad Homburg, Germany). Standard hemodilution technique was used including a dilution of the circulating blood volume to a hematocrit of approximately 20% to 25%. During bypass the pump flow was set at 2.4 L · m^-2 · min^-1 and patients were cooled to a nasopharyngeal temperature of 28°C. Before the last anastomosis was finished, patients were rewarmed to 37°C. The mean arterial pressure was maintained at 50 to 60 mm Hg during bypass. Anticoagulation during bypass was monitored with the activated clotting time (Hemochron 800; International Technidyne Corp, Edison, NJ). Additional heparin was administered if the activated clotting time was shorter than 400 seconds. Heparin was neutralized by means of protamine chloride infusion (3 mg/kg) after the completion of cardiopulmonary bypass.

Blood compatibility parameters
Blood samples were taken from the indwelling radial artery catheter after heparinization but before the start of CPB, 5 minutes and 30 minutes after the start of CPB, 5 minutes after release of the aortic cross-clamp, and at the end of CPB. Platelets, leukocytes, and sample hematocrit were measured by an electronic automatic cell counter (Cell-Dyn 610; Sequoia-Turner Corp, Mountain View, CA) in samples anticoagulated with citrate. For biochemical assays, plasma was obtained by centrifuging whole blood at 1,000 g for 10 minutes and was stored at -80°C until further determinations. Platelet degranulation was indicated by ß-thromboglobulin, which was determined by radioimmunoassay (Kodak Clinical Diagnostics Ltd, Amersham, UK). Prothrombin activation was indicated by fragment F1+2, which was determined by enzyme linked immunoassay (Behringwerke AG, Marburg, Germany). Complement release products C3a and C4a were determined by radioimmunoassay (Amersham International Inc, Amersham, UK), whereas the terminal complement complex C5b-9 was determined by enzyme linked immunosorbent assay (Quidel, San Diego, CA). Leukocyte elastase was quantitated in complex with ₁-proteinase inhibitor (Merck, Darmstadt, Germany) by enzyme-linked immunosorbent assay. Interleukin-8 as cytokine marker was also determined by enzyme-linked immunosorbent assay (Innogenetics, Zwijnwaarde, Belgium).

Platelet binding on cardiopulmonary bypass circuit
After the termination of CPB, both parts of the arterial and venous tubing were gently flushed with saline solution, and collected for determination of platelet binding. Platelet binding was quantified by Eu-labeled antibody directed to the platelet GPIIIa receptor (M753, Dakopatts, Glostrup, Denmark) bound to the tubing surface. A control antibody directed against mouse antigen with similar amount of label was used as a reference. Also, aspecific antibody binding was tested on both nonused SMA and control tubing. After exposure to the antibody the tubing was washed with saline solution and filled with enhancement solution to release the Eu-label for counting in a fluorometer (Delfia, LKB Wallac, Turku, Finland).

Statistics
Clinical data are expressed as mean and standard deviation and the data of blood tests are expressed as mean and standard error of the mean. All values of blood tests during CPB were corrected for hemodilution by hematocrit. Statistical tests were performed with the StatView software (Brain-power Inc., Calabasas, CA). Student’s t test or Mann-Whitney test was used for analysis of difference between the two groups. A p value less than 0.05 was considered statistically significant.

	Results

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Patients
All operations were uneventful with an average bypass time of 69 ± 10 minutes in the SMA group and 67 ± 16 minutes in the control group (Table 1). In the SMA group, 2 patients had to be reoperated on within a few hours after the first operation because of surgical bleeding and spasm of the arterial graft, respectively. There was no statistical difference between the two groups regarding the postoperative chest tube drainage, red blood cell transfusion, duration of postoperative ventilatory support, and hospital stay (Table 2).

View larger version (14K): [in this window] [in a new window]   Fig 1. Platelets (A), ß-thromboglobulin (B), and prothrombin fragment F1+2 (C) expressed as percentage of initial (%) in both the surface-modifying additive (SMA) and control groups. (CPB = cardiopulmonary bypass; X-off = release of the aortic cross-clamp; *p < 0.05 for comparison between the two groups.)

View larger version (13K): [in this window] [in a new window]   Fig 2. Platelet glycoprotein IIIa (GPIIIa) binding on either the arterial or venous tubing of the extracorporeal circuit. Significantly less GPIIIa was bound on surface-modifying additive (SMA)-treated tubings after the circuit had been used for cardiopulmonary bypass (*p < 0.05 for comparison between groups.)

View larger version (13K): [in this window] [in a new window]   Fig 3. Complement C3a (A), C4a (B), and the terminal complement complex C5b-9 (C) expressed as percentage of initial (%) in both the surface-modifying additive (SMA) and control groups. (CPB = cardiopulmonary bypass; X-off = release of the aortic cross-clamp; *p < 0.05 for comparison between the two groups.)

	Comment

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Determination of platelet membrane glycoprotein IIIa antigen bound to biomaterial surface has been reported to reflect platelet deposition to the extracorporeal circuit [14, 15]. When platelets become activated, glycoprotein IIIa together with glycoprotein IIb serves as receptor for platelet interaction with other platelets or with thrombogenic surfaces through adhesive proteins [16]. On the surface of the extracorporeal circuit, glycoprotein IIIa was found together with other plasma proteins after the circuit was exposed to human blood in a simulated extracorporeal circuit [14]. In the current study after exposure to clinical CPB, we observed that the surface binding of glycoprotein IIIa antigen was significantly reduced in the CPB circuit that was treated with SMA. This was particularly obvious on the tubing located at the arterial side, suggesting that the antithrombogenic effect of SMA is most effective under high flow circumstances [12].

The mechanism of antithrombogenicity of the SMA circuit seems to be mainly based on the effect of limiting platelet interaction with the surface and subsequently reducing platelet activation. This is in contrast to the heparin-coated material, which still allows platelet binding. Furthermore, in comparison with heparin coating, the SMA-treated surface is supposed to have a longer half-life than the heparin-coated surface, because the former is not sensitive to biological degradation. This assumption is supported by the recent results obtained on vascular access grafts [17] and on long-term observations on ventricular assist device using this technology [18].

Complement activation is known to occur in cardiac surgical patients and to be caused by blood contact with the foreign surfaces in the CPB circuit [1, 3]. Previously, we and other investigators [6, 7, 9] have demonstrated that patients perfused with a heparin-coated CPB circuit had a reduced complement activation during coronary artery bypass grafting. In the current study, complement activation represented by C3a and C5b-9 was found similar in both the SMA and control groups during the entire period of CPB. However, C4a generation was significantly less in the SMA group, particularly during the late period of CPB, suggesting that SMA may have modified complement activation through the classic pathway in these patients. The mechanism by which the SMA treatment inhibits the classic complement pathway remains uncertain, particularly by the fact that it appeared during the late part of CPB. In general, the alternative pathway is considered to be the main complement pathway activated by the CPB circuit [19, 20], although a decrease in C4 and an increase in C4a during CPB indicating classic pathway complement activation was also found during CPB with untreated circuits [21, 22]. Protamine is regarded as the main trigger activating the classic complement pathway [23]. However, in this study the difference of C4a appeared before protamine administration. Nevertheless, the clinical impact of this difference in C4a seems minor because a more harmful complement activation product, the terminal complement complex C5b-9 [24], was not reduced by SMA.

Although data from this study indicate that the SMA treatment modified the surface thrombogenicity of the CPB circuit, the patient’s hemostatic status remained unchanged. Probably the beneficial effect of a more biocompatible circuit does not appear to be significantly related to the improvement of clinical hemostasis when evaluated in a relatively low number of patients having a relatively short duration of CPB. Furthermore, all patients enrolled in this study received dexamethasone preoperatively. Dexamethasone may have affected the body inflammatory response uniformly in patients perfused either with the SMA circuit or with the control circuit, so that their clinical outcome after operation was without difference.

We conclude that SMA treatment tends to inhibit platelet interaction with the biomaterial surface of CPB circuit. Complement activation assessed by the terminal complement complex is not influenced by SMA. Further study on a larger patient population is necessary to evaluate whether this surface-modifying technique contributes to the improvement of clinical outcome in cardiac surgical patients.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Y. John Gu Piet W. Boonstra Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gu, Y. J. Articles by van Oeveren, W. Search for Related Content PubMed PubMed Citation Articles by Gu, Y. J. Articles by van Oeveren, W.