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Ann Thorac Surg 2004;77:1678-1683
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

A new poly-2-methoxyethylacrylate-coated cardiopulmonary bypass circuit possesses superior platelet preservation and inflammatory suppression efficacy

^a Department of Cardiovascular Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan

Accepted for publication October 8, 2003.

^* Address reprint requests to Dr Ikuta, Department of Cardiovascular Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
e-mail: nama{at}msic.med.osaka-cu.ac.jp

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
BACKGROUND: Poly-2-methoxyethylacrylate (PMEA) is a new coating material, and several studies have revealed that PMEA-coated cardiopulmonary bypass (CPB) circuits have good biocompatibility. This study sought to compare this biocompatibility with those of heparin-coated and noncoated circuits.

METHODS: Forty-five patients undergoing coronary artery bypass grafting were randomly assigned to PMEA-coated (group P, n = 15), heparin-coated (group H, n = 15), or noncoated (group N, n = 15) circuit groups. Clinical data and the following markers were analyzed: (1) platelet preservation by number of platelets; (2) complement (C) activation by C3a and C4a levels; (3) inflammatory response by interleukin-6 (IL-6) and interleukin-8 (IL-8) levels.

RESULTS: Platelet numbers were significantly preserved in group P compared with groups N and H. Postoperative blood loss did not differ among the groups. During CPB, C3a values were significantly lower in group H (536 ± 145 ng/mL) than in group P (1,458 ± 433 ng/mL, p < 0.01) and group N (1,815 ± 845 ng/mL, p < 0.01). The C4a values did not differ 60 minutes after CPB initiation among the groups. The IL-6 and IL-8 levels were significantly lower in group P and groupH than in group N.

CONCLUSIONS: The PMEA coating was superior to heparin coating and noncoating in preserving platelets, and was equivalent to heparin coating in terms of the perioperative clinical course and inhibition of inflammatory cytokines, but slightly inferior in reducing complement activation.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
The continuous interaction of blood with artificial surfaces during cardiopulmonary bypass (CPB) leads to substantial damage to cells and plasma proteins, the release of various inflammatory cytokines, and the activation of complements and coagulation-fibrinolysis systems [1], resulting in the potential dysfunction of several organs [2, 3]. To reduce such adverse effects of blood-tissue interactions, CPB systems need to be adapted to physiologic conditions. Heparin-coated circuits were developed to reduce systemic inflammatory reactions by lowering complement activation, decreasing neutrophil activation, and reducing plasma levels of inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8) [4–8]. Although heparin coatings are useful for CPB, the industrial procedure for applying heparin coatings to CPB devices is costly and adds considerably to the overall cost of CPB [9].

The search for improved materials for the surfaces of artificial organs is a bioengineering focus, the goal being to reduce systematic inflammation while increasing cost effectiveness. Poly-2-methoxyethylacrylate (PMEA), a relatively recent coating material for artificial membranes, appears to promise improved biocompatibility for artificial organs. In vitro and ex vivo studies of PMEA-coated circuits have clearly demonstrated the advantages of this technology [10, 11]. However, the efficacy of PMEA-coating for CPB circuits, compared with heparin-coated circuits, is not established. This study aimed to evaluate the biocompatibility of PMEA-coated circuits compared with conventional heparin-coated and noncoated circuits, focusing chiefly on platelet preservation and systemic inflammatory response.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Patients
The subjects consisted of 45 patients undergoing first-time elective coronary artery bypass grafting scheduled between April 2001 and February 2002. Subjects were randomly divided into three groups: the first group using PMEA-coated circuits (group P: n = 15), the second group using heparin-coated circuits (group H: n = 15), and the third group using noncoated circuits (group N: n = 15). Exclusion criteria included previous cardiac surgery, renal or liver dysfunction, and preoperative coagulopathy. Anticoagulation or antiplatelet therapy was discontinued 7 days before surgery in all patients. Informed consent for the study was obtained from all patients before surgery.

Anesthesia and cardiopulmonary bypass
Anesthesia was induced after premedication with morphine sulfate and scopolamine hydrobromide, then maintained with fentanyl, midazolam, and vecuronium bromide.

In group P, commercially available PMEA-coated circuit sets including an oxygenator (Terumo CAPIOX with X coating and CAPIOX RX25; Terumo Corporation, Tokyo, Japan) were used. The CPB circuit consisted of a hollow-fiber membrane oxygenator (CX-RX25), a hard-shell venous reservoir (CX-RR40), an arterial filter (CX-AF125X [all three components made by Terumo]), and a centrifugal pump (CX-SP4538, Terumo) In group H, all components were coated with covalently bonded heparin (Carmeda Bioactive Surface; Medtronic Cardiac Surgery, Minneapolis, MN). In group N, all components used were similar to those of group H, but with noncoated surfaces. The CPB circuits in groups H and N consisted of a hollow-fiber membrane oxygenator (CBMAX-PRF and MAX-PRF), a soft-shell venous reservoir (models CB1386 and 1386), a cardiotomy reservoir (models CB1351 and 1351), a 40 µmol/L arterial filter (models CBM-40 and M-40 [all four components made by Medtronic]), and a centrifugal pump (Bio-pump models CB BP-80 and BP-80, Medtronic [all CB prefixed models for group H, and the others for group N, respectively]). The circuits were primed with a mixture of 1,300 mL of lactated Ringer's solution, 250 mL of human serum albumin (250 mg/mL), 200 mL of mannitol (200 mg/mL), and 100 mL of sodium bicarbonate (84 mg/mL). Standard ascending aortic cannulation and right atrial cannulation were performed.

Before aortic cannulation, all patients received a 300 U/kg dose of bovine heparin. Activated clotting time (ACT) was measured using a Hemochron 801 (International Technidyne, Edison, NJ). The ACT was maintained at 400 seconds or above by the administration of heparin during CPB, as required. While the patient was fully heparinized, a cardiotomy suction device was used to return pericardial blood. At all other times during the operation, a cell-saving device (Hemonetics Cell-Saving Device 5 model 2005; Hemonetics, Braintree, MA) was used.

During CPB, a nonpulsatile flow of 2.4 L min^–1 m^–2 body surface area was maintained under moderate systemic hypothermia (rectal temperature, 32°C). During CPB, mean arterial pressures were maintained in the range from 50 to 80 mm Hg, and the hematocrit value was maintained at above 16%, with blood transfusions when necessary. The left ventricle was vented by cannulation through the right superior pulmonary vein. Cold blood cardioplegic solution was administered in antegrade and retrograde fashion during aortic clamping. After termination of CPB, heparin was neutralized with an equivalent dose of protamine sulfate. If necessary, additional protamine was administered to reestablish the preoperative ACT.

Data collection and measurements
Intraoperative variables including the duration of aortic cross clamping, the duration of CPB, initial and total doses of heparin, and the protamine dose were recorded, as was the amount of postoperative blood loss during the first 3, 6, and 12 hours through mediastinal and pleural chest tubes.

Blood samples were obtained at the following six points in both groups: before the induction of anesthesia (Pre); 60 minutes after the initiation of CPB (CPB 60); 10 minutes after aortic declamping (Declamp); 5 and 60 minutes after protamine administration (Post 5 and Post 60); and 180 minutes after termination of CPB (Post 180). Hematocrit and platelet counts were measured with an automatic cell counter (MAXM-Retic, Beckman Coulter, CA). Plasma was separated from blood cells by centrifugation at 3000g for 10 minutes and stored at –80°C until analysis. The C3a and C4a levels were measured by radio immunoassay. The IL-6 and IL-8 levels were measured by enzyme linked immunosorbent assay. The values obtained during CPB and until 60 minutes after protamine administration were collected for hemodilution and normalized to the hematocrit before the operation.

Statistical analysis
Data were analyzed using standard computer software (Statview 5.0 and Super ANOVA 1.11; Abacus Concepts, Berkeley, CA). All results are reported as mean values ± standard deviation. The repeated measure analysis of variance (ANOVA) was performed to evaluate differences among three groups. If significant differences were found, the Wilcoxon rank-sum test was applied to comparisons within groups and the Mann-Whitney U test was used for comparisons between groups. A p value of less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Perioperative patient data are summarized in Table 1. Although the operative procedures were not completely the same in all patients, no significant differences among the three groups were observed in age, sex, operation time, CPB time, cross-clamp time, the number of distal anastmosis, or the amount of intraoperative and postoperative blood loss. No incidence of perioperative myocardial infarction, cerebral infarction, thromboembolism, or other complications was observed in any patient.

View larger version (16K): [in this window] [in a new window]   Fig 1. Changes in platelet counts during the six time periods monitored in this study. Comparing the three groups, platelets were significantly preserved in group P (circles) at Declamp, Post 5, Post 60, and Post 180 compared with those in group N (diamonds) and group H (triangles). *p less than 0.05, **p less than 0.01 (group P versus groups N and H). (Pre = before anesthesia induction; CPB60 = 60 minutes after cardiopulmonary bypass [CPB] initiation; Declamp = 10 minutes after aortic declamping; Post5 = 5 minutes after protamine administration; Post60 = 60 minutes after protamine administration; Post180 = 180 minutes after CPB termination.)

View larger version (29K): [in this window] [in a new window]   Fig 2. Change in C3a and C4a levels during the six time periods monitored in this study. (A) Comparing groups P (circles), H (triangles), and N (diamonds), significant differences were revealed after CPB60. (B) Significant differences among groups P (circles), H (triangles), and N (diamonds) were observed at Post5 to Post180. *p less than 0.05, **p less than 0.01, p less than 0.001 (group H versus groups N and P). (Pre = before anesthesia induction; CPB60 = 60 minutes after cardiopulmonary bypass [CPB] initiation; Declamp = 10 minutes after aortic declamping; Post5 = 5 minutes after protamine administration; Post60 = 60 minutes after protamine administration; Post180 = 180 minutes after CPB termination.)

Interleukin-6
The values of IL-6 are presented in Figure 3, A. Compared with preoperative levels, IL-6 increased significantly after aortic declamping in all groups (group N: 3.7 ± 1.6 to 194.3 ± 70.7 pg/mL, p < 0.01; group H: 4.4 ± 1.1 to 217.5 ± 117.6 pg/mL, p < 0.01; and group P: 3.7 ± 1.1 to 160.1 ± 80.5 pg/mL, p < 0.01), and continued to increase thereafter. The time-dependent curve in group N was significantly higher than those in groups H and P. Significant intergroup differences were revealed at the three points after protamine administration. There were no differences observed between groups H and P at any points.

View larger version (26K): [in this window] [in a new window]   Fig 3. (A) Change in interleukin (IL)-6 level and (B) change in IL-8 levels during the six time periods monitored in this study. The IL-6 and IL-8 levels in group H (triangles) and group P (circles) were significantly reduced compared with those in group N (diamonds). There were no differences between groups H and P at any points. *p less than 0.05, **p less than 0.01, p less than 0.001 (group N versus groups H and P). (Pre = before anesthesia induction; CPB60 = 60 minutes after cardiopulmonary bypass [CPB] initiation; Declamp = 10 minutes after aortic declamping; Post5 = 5 minutes after protamine administration; Post60 = 60 minutes after protamine administration; Post180 = 180 minutes after CPB termination.)

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
Poly-2-methoxyethylacrylate is an alkoxyl polymer strain developed for use in CPB by polymerization of the monomer. The strain has a hydrophobic polyethylene backbone, and its residue is mildly hydrophilic, with no chemical functional groups such as –OH or –NH₂. Because the outer side of the PMEA molecule is chemically inert, its surface has little tendency to react with blood components [10, 12].

Reports [10, 12, 13] have demonstrated that compared with uncoated circuits, PMEA-coated circuits can decrease adsorption of platelets and several plasma proteins related to coagulation-fibrinolysis and complement activation during CPB. To rigorously evaluate the biocompatibility of the PMEA-coated circuits, we compared them with heparin-coated circuits, which are widely accepted as the most effective type of circuit for reducing systematic inflammatory responses, and with noncoated circuits as control. Our observations clearly showed that PMEA-coated circuits exhibit better platelet preservation than heparin-coated or noncoated circuits. However, suppression of complement activation in PMEA-coated circuits was less effective than in heparin-coated circuits. The levels of inflammatory cytokines in PMEA-coated circuits were equal to those in heparin-coated circuits, being significantly lower than those in noncoated circuits. Perioperative clinical courses were identical among the three groups. We interpret these results to indicate that the biocompatibility of PMEA-coating is in no way inferior to heparin coatings, and justify this interpretation below.

The present results—that platelet counts were significantly better preserved in PMEA-coated circuits compared with heparin-coated or noncoated circuits—indicate that PMEA-coatings are superior in their efficacy of reducing adsorbed platelets onto the surface. We speculate that PMEA-coating surfaces suppress platelet adhesion and aggregation by the following mechanism. At a molecular level, the surface structure affects protein adsorption. Both the amount of adsorbed protein and conformational change play major roles in platelet adhesion. Previous studies [10, 12, 13] have demonstrated that PMEA-coating surfaces inhibited protein adsorption and the denaturation of adsorbed protein. In particular, the fibrinogen, which is known to be a blood-clotting protein and a universal cofactor for platelet aggregation and adhesions, adsorbed onto the surface of PMEA is similar to native fibrinogen. Thus, the PMEA-coating can suppress adhesion and aggregation of platelets and preserve platelet counts.

Postoperative blood loss did not differ among the three groups in this study, although platelets were better preserved in PMEA-coated circuits. We speculate that this finding is partly due to the natural advantage in preserved platelet counts with the use of heparin-coated circuits, partly due to the favorable effects of heparin-coated circuits on the coagulation-fibrinolysis system [14], and partly due to the relatively small sample size of this study. We suggest that the better preservation of platelets may offer an advantage for patients in whom CPB time is prolonged.

The results that the time-dependent curve of complement in group H was significantly lower than that in group P indicates that heparin coating is superior in suppressing complement activation. We believe this is the first study to directly compare complement activation in vivo between PMEA-coated and heparin-coated circuits. Saito and colleagues [13] have reported that the percentages of CD35-positive monocytes, cell surface markers of complement activation, were significantly lower in PMEA-coated circuits than those in uncoated circuits during CPB in swine models. Ninomiya and colleagues [15] have demonstrated that the PMEA-coated circuits exhibited better suppression of C3a in the clinical use. In this study, values of C3a during CPB were smaller in group P than those in group N. Therefore, it may be concluded that PMEA-coating is superior to uncoated circuits in efficacy of reducing complement activation, but inferior to heparin coatings.

Complement activation is widely used as an index of blood trauma and systemic inflammatory response, particularly during CPB [2]. Increases in C3a indicate an activation of the alternative pathway, while increases in both C3a and C4a indicate an activation of the classic pathway [16]. Along with other investigators, we have demonstrated that the alternative pathway is the main pathway activated during CPB, and that the classic pathway is mainly activated by protamine administration [17, 18]. In this study, C3a during CPB increased significantly in group P compared with that in group H, while C4a during CPB did not differ. Heparin itself can inhibit the alternative pathway by factor H binding to C3b [19]. However, heparin-coated CPB under low dose heparinization did not affect the inhibition of the alternative pathway, as reported previously [20]. In light of these observations, the reduction of complement activation appears to be due to the use of heparin-coated circuits, not to the action of heparin. Thus, the present results appear to indicate that heparin coatings have a superior efficacy in reducing complement activation in contact of blood.

The observations from this study that the time-dependent curves of IL-6 and IL-8 did not differ between groups H and P indicate that the PMEA coating is equal to the heparin coating in preventing the cytokine releases during and after CPB. In this study, IL-6 and IL-8, measured as proinflammatory cytokines, did not differ between groups H and P, although C3a was significantly higher in PMEA-coated circuits. as an example of mediators that participate in the mediation of immunoendocrine interactions; cytokines are necessary for optimal function of both T and B lymphocytes. Although cytokine release is induced by the complement, it can be induced by many other factors, including ischemia-reperfusion, the release of endotoxins, and lymphocyte activation. We speculate, therefore, that PMEA-coated circuits globally reduce the activation of inflammatory cytokines in a manner equivalent to heparin-coated circuits.

There are several limitations of this prospective study. First, the relatively small number of patients for accurately evaluating the biocompatibility of the new coating. Second, although postoperative blood loss was compared in this study, we did not evaluate platelet viability and function, or the activation of coagulation-fibrinolysis systems. Third, IL-6 and IL-8 are not specific markers of inflammation. However, these cytokines have been widely accepted for proinflammatory substances [21]. Fourth, the terminal complement complex was not measured in the present study. Complement 3a, C4a, and C5b-9 have been generally measured as indicators for monitoring the alternative, the classic, and the common pathway of complement activation [22]. The complement sequence leads to terminal complement complex activation, as shown by the significant increase in C5b-9 levels [23]. Thus we suggest that C3a is a crucial variable, which is induced mainly by blood contacting with artificial surfaces during CPB.

In conclusion, PMEA coatings appear to exhibit superior preservation of platelets compared with heparin coatings, and might offer equivalent performance in inhibiting inflammatory cytokines and the perioperative clinical course. Although PMEA coatings might be inferior to heparin coatings in suppressing complement activation, PMEA-coated can exhibit better suppression of the complement than uncoated circuits. Finally, the PMEA coating process is simpler and costs less than that for heparin, as reported by Wendel and Ziemer [9]. We concluded that the clinical utility of the PMEA-coated circuits is nearly equivalent to that of heparin-coated ones.

	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): Toshihiko Shibata Koji Hattori Shigefumi Suehiro Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ikuta, T. Articles by Suehiro, S. Search for Related Content PubMed PubMed Citation Articles by Ikuta, T. Articles by Suehiro, S. Related Collections Extracorporeal circulation