Ann Thorac Surg 2000;69:115-120
© 2000 The Society of Thoracic Surgeons
Original Articles
Biocompatibility of silicone-coated oxygenator in cardiopulmonary bypass
Akira Shimamoto, MDa,
Shinji Kanemitsu, MDa,
Kazuya Fujinaga, MDa,
Motoshi Takao, MD, PhDa,
Koji Onoda, MD, PhDa,
Takatsugu Shimono, MD, PhDa,
Kuniyoshi Tanaka, MD, PhDa,
Hideto Shimpo, MD, PhDa,
Isao Yada, MD, PhDa
a Department of Thoracic and Cardiovascular Surgery, Mie University School of Medicine, Tsu, Japan
Address reprint requests to Dr Shimamoto, Department of Thoracic and Cardiovascular Surgery, Mie University School of Medicine, 2-174, Edobashi, Tsu, Mie 514-8507, Japan
e-mail: jj6jdv{at}clin.medic.mie-u.ac.jp
 |
Abstract
|
|---|
Background. This study was designed to analyze the biocompatibility of silicone-coated oxygenators using inflammatory response as the outcome measure, and to investigate whether the silicone-coated oxygenators perform better in terms of postoperative organ dysfunction.
Methods. The 32 patients who underwent cardiopulmonary bypass (CPB) were divided into 3 groups: group A (n = 10), heparin-coated circuit with silicone-coated oxygenator; group B (n = 11), whole heparin-coated circuit; and group C (n = 11), whole untreated circuit. The plasma concentrations of the proinflammatory markers, made of inflammatory cytokines (tumor necrosis factor-
, interleukin-1ß, interleukin-6, interleukin-8), terminal complement complex (C5b-9), and polymorphonuclear elastase (PMN-E), were measured by enzyme-linked immunosorbant assay.
Results. All proinflammatory markers were significantly lower in groups A and B than in group C, especially C5b-9 and PMN-E concentrations, which were significantly lower in group A than in group B. The alveolar-arterial oxygen gradients (A-aDO2) and the respiratory index were significantly better in group A than in group C. In group B, however, only the A-aDO2 was significantly better than in group C. The duration of intubation and the length of stay in the intensive care unit stay were significantly shorter in groups A and B than in group C.
Conclusions. Silicone-coated oxygenators are biocompatible and prevent postoperative organ dysfunction.
|
Introduction
|
|---|
Cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response attributable to the release of various inflammatory cytokines and the activation of the complement or coagulofibrinolytic systems [1, 2]. It has been suggested that the development of organ failure is caused by neutrophil-endothelium interactions with adhesion molecules which are upregulated by this systemic inflammatory response [3]. We previously reported that heparin-coated circuits suppress the release of inflammatory cytokines following CPB, and prevent postoperative organ dysfunction. Recently, many reports have suggested that silicone-coated oxygenators have improved durability and biocompatibility [4–6]. We measured the changes in inflammatory cytokine (tumor necrosis factor- [TNF-], interleukin [IL]-1ß, IL-6, and IL-8), terminal complement complex (C5b-9), and polymorphonuclear elastase (PMN-E) concentrations following CPB to analyze the biocompatibility of the silicone-coated oxygenator with respect to its effect on the systemic inflammatory response.
|
Patients and methods
|
|---|
Between March 1995 and March 1997, 32 patients undergoing elective coronary artery bypass grafting (CABG) with CPB were randomized prospectively into 3 groups (groups A, B, and C). Informed consent was obtained from all patients prior to operation. The study was approved by the Mie University Hospital. Group A consisted of 10 patients in whom the silicone-coated oxygenator (Mera Excelung Binding Prime HPO-25H-C; Senko Medical Instrument Mfg, Tokyo, Japan) was used. Group B consisted of 11 patients in whom a heparin-coated oxygenator (Univox Gold; Baxter Healthcare Corp, Irvine, CA) was used. In both groups, except for the oxygenator, the same CPB circuit treated with surface-bonded heparin (Duraflo; Baxter Healthcare Corp), consisting of a soft-shell venous reservoir, an arterial filter, a cardiotomy reservoir, and polyvinyl chloride tubing system excluding the oxygenator, was used. Group C (control group) included 11 patients in whom conventional noncoated circuits were used.
The anesthesia and CPB techniques were standardized. After premedication, general anesthesia was induced and maintained with a high dose of fentanyl (0.1 mg/kg), nitrous oxide, and vecuronium bromide. The extracorporeal circuit and the oxygenator were primed with 1.6 L of 20% D-manitol (5 mL/kg), 6% hydroxyethyl starch (5 mL/kg), and Ringer’s lactate solution without blood. Nonpulsatile extracorporeal circulation was initiated at a perfusion index of 2.4 L/min/m2 body surface area using a roller pump (Mera MSH-15: Senko Medical Instrument Mfg, Tokyo, Japan or Gambro HL-10: Jostra Medizintechnik GmbH & Co KG, Hirrlingen, Germany). After administration of an initial prebypass bolus dose of heparin (300 IU/kg), whole blood activated clotting time was maintained at greater than 400 seconds for the entire duration of CPB with intermittent intravenous heparin administration. The operative procedures were performed under moderate whole body hypothermia, with the rectal temperature maintained between 28° and 32°C. Myocardial protection was provided by injecting cold blood cardioplegic solution (4°C) supplemented with ice slush for topical hypothermia every 20 minutes. After CPB, protamine sulfate (4.5 mg/kg) was administered.
Blood was withdrawn from an indwelling arterial cannula into a sterile tube containing EDTA (VACUTAINER 367661; Becton Dickinson VACUTAINER System, Rutherford, NJ) at the following times: before CPB; 5 minutes and 1 hour after the start of CPB; immediately after CPB; 1 hour, and 3 hours after the termination of CPB; and on the first postoperative days. Plasma samples were separated immediately by centrifugation (3000 rpm) for 15 minutes at 4°C. They were then stored at -80°C until measured with an enzyme-linked immunosorbent assay (ELISA) kit (TNF- and IL-1ß: BioSource Europe S.A., Nivelles, Belgium; IL-6 and IL-8: TFB Inc, Tokyo, Japan; C5b-9: Quidel, San Diego, CA; PMN-E: E Merck, Darmstadt, Germany). The limits of sensitivity were 0.6 pg/mL (TNF-), 6.3 pg/mL (IL-1ß), 3.8 pg/mL (IL-6), 1.1 pg/mL (IL-8), 16 ng/mL (C5b-9), and 20 ng/mL (PMN-E). All results reported means from duplicate measurements. Plasma levels of inflammatory cytokines were corrected for hemodilution.
All parameters are expressed as the mean values ± the standard deviation. Repeated measures of the analysis of variance were performed to examine group differences over time. The student’s t-test was performed to evaluate differences at the same times between groups. A p value of less than 0.05 was considered significant.
|
Results
|
|---|
There were no statistically significant differences between the groups with respect to age, sex, operative time, CPB time, or aortic cross-clamp time (Table 1). There were no deaths or postoperative complications in this series.
Cytokines
Tumor necrosis factor-
In all groups, the TNF- increased 1 hour after the start of CPB, reaching a peak 1 hour after the termination of CPB (Fig 1). Thereafter, the concentrations swiftly declined, and in groups A and B had decreased to levels similar to those measured before CPB by the first postoperative day. Concentrations were significantly lower in groups A and B than in group C at all times beginning 1 hour after the start of CPB (p < 0.01). There were no significant differences between groups A and B at any time.
Interleukin-1ß
In all groups, the IL-1ß concentrations increased and reached a peak at the end of CPB (Fig 2). Thereafter, the concentrations swiftly declined. On the first postoperative day, they had decreased to levels similar to those measured before CPB. The levels were significantly lower in groups A and B than in group C at the end of CPB, and 1 and 3 hours after the termination of CPB (p < 0.05). There were no significant differences between groups A and B at any time.
View larger version (26K):
[in this window]
[in a new window]
|
Fig 2. Changes in plasma interleukin-1ß (IL-1ß) concentrations during and after cardiopulmonary bypass (CPB). (*p < 0.05 versus group C; group A = silicone-coated oxygenator; group B = heparin-coated oxygenator; group C = conventional circuit; POD = postoperative day.)
|
|
Interleukin-6
In all groups, the IL-6 concentrations increased after the end of CPB, remaining at high levels until the first postoperative day (Fig 3). A peak was noted at 3 hours after the termination of CPB. The levels were significantly lower in groups A and B than in group C at any time 1 hour after the termination of CPB (p < 0.01). There were no significant differences between groups A and B at any time.
View larger version (28K):
[in this window]
[in a new window]
|
Fig 3. Changes in plasma interleukin-6 (IL-6) concentrations during and after cardiopulmonary bypass (CPB). (* = p < 0.01 versus group C; group A = silicone-coated oxygenator; group B = heparin-coated oxygenator; group C = conventional circuit; POD = postoperative day.)
|
|
Interleukin-8
In all groups, the IL-8 concentrations increased after the end of CPB, remaining at high levels until 3 hours after the termination of CPB (Fig 4). A peak was noted at 3 hours after the termination of CPB. Thereafter, the concentrations swiftly declined. In groups A and B, they decreased to levels similar to those measured before CPB by the first postoperative day. The levels were significantly lower in groups A and B than in group C at any time after the end of CPB (p < 0.01). There were no significant differences between groups A and B at any time.
View larger version (28K):
[in this window]
[in a new window]
|
Fig 4. Changes in plasma interleukin-8 (IL-8) concentrations during and after cardiopulmonary bypass (CPB). (* = p < 0.01 versus group C; group A = silicone-coated oxygenator; group B = heparin-coated oxygenator; group C = conventional circuit; POD = postoperative day.)
|
|
Terminal complement complex
In all groups, the C5b-9 concentrations began to increase as the CPB was initiated, reaching a peak at the end of CPB in group C, and at 1 hour after termination of CPB in groups A and B (Fig 5). Thereafter, the concentrations swiftly declined. By the first postoperative day, they had decreased to levels similar to those measured before CPB. The levels were significantly lower in groups A and B than in group C at 1 hour after the start of CPB and immediately and 1 and 3 hours after the termination of CPB (p < 0.01). The concentrations were significantly lower in group A than in group B at 1 hour after the start of CPB, and immediately and 1 and 3 hours after the termination of CPB (p < 0.01).
View larger version (27K):
[in this window]
[in a new window]
|
Fig 5. Changes in plasma terminal complement complex (C5b-9) concentrations during and after cardiopulmonary bypass (CPB). (* = p < 0.01 versus group C; ** = p < 0.01 versus group B; group A = silicone-coated oxygenator; group B = heparin-coated oxygenator; group C = conventional circuit; POD = postoperative day.)
|
|
Polymorphonuclear elastase
In all groups, the PMN-E concentrations began to increase 1 hour after the start of CPB, reaching a peak at the end of the CPB (Fig 6). Thereafter, they remained at high levels until the first postoperative day. The levels were significantly lower in groups A and B than in group C at any time after 1 hour after the start of CPB (p < 0.01). The concentrations were significantly lower in group A than in group B at any time after 1 hour after the start of CPB (p < 0.05).
View larger version (28K):
[in this window]
[in a new window]
|
Fig 6. Changes in plasma polymorphonuclear elastase (PMN-E) concentrations during and after cardiopulmonary bypass (CPB). (* = p < 0.01 versus group C; ** = p < 0.05 versus group B; group A = silicone-coated oxygenator; group B = heparin-coated oxygenator; group C = conventional circuit; POD = postoperative day.)
|
|
Clinical outcomes
The alveolar-arterial oxygen gradients at the end of the operation (p < 0.01) and 4 hours after the operation (p < 0.05), and the respiratory index at the end of the operation (p < 0.05), were significantly better in group A than in group C. In group B, only the alveolar-arterial oxygen gradients were significantly better than in group C (p < 0.05). Moreover, the duration of intubation and intensive care unit stay were significantly shorter in groups A and B than in group C (p < 0.05) (Table 2).
|
Comment
|
|---|
The systemic inflammatory response to CPB is characterized by the activation of the complement, or coagulofibrinolytic systems, and the release of various inflammatory ctytokines, and has been associated with significant morbidity and mortality [1, 2]. This generalized reaction is complex, and eventually leads to leukocytes stimulation and adhesion to the microvasculature. Neutrophil activation also results in the generation of oxygen free radicals, and the release of powerful serine proteases causing significant injury to the endothelium in the capillary bed [3]. Whether this process represents reperfusion injury or contact activation of blood components, especially complement, remains unresolved [7–9].
Cytokines act as mediators of CPB-induced injury by promoting neutrophil-related damage to the microcirculation. Production of IL-1ß stimulates the synthesis of the cell adhesion molecules on endothelial cells, promoting neutrophil and monocyte adhesion [3]. TNF- promotes leukocyte adhesion in a manner similar to IL-1ß, which results in a marked activation of leukocytes resulting in degranulation [10]. Plasma TNF- and IL-1ß have been detected during CPB in some studies [11, 12], but not in others [13, 14]. In our study, circulating TNF- and IL-1ß were detected. The short half-life of TNF- and IL-1ß, the presence of soluble receptors, and differences in the methods of cytokine measurement used may explain the discrepancies between studies [13].
IL-6 is a major promoter of the acute phase response and serum levels of it have been shown to be a marker for the severity of tissue damage [15]. In the present study, IL-6 release was significantly lower in the silicone-coated and heparin-coated groups compared with the uncoated group. No significant differences were noted between the silicone-coated and heparin-coated groups. This implies the induction of a less severe acute-phase response, and suggests a lesser degree of tissue trauma in the silicone-coated and heparin-coated groups compared to the uncoated group.
IL-8 is an extremely potent chemoattractant for neutrophils. Inducing pulmonary or myocardial sequestration of neutrophils could contribute to endothelial injury and capillary leak after CPB [16, 17]. IL-8 is thought to regulate the degree of neutrophil-mediated injury, thus giving it a potentially major role in the tissue damage seen during CPB [16]. As with IL-6, there were no significant differences in IL-8 release between the silicone-coated and heparin-coated groups, although the release was significantly less than that in the uncoated group.
It has been recommended that the biocompatibility of extracorporeal circuits be assessed by the degree of complement activation, particularly C5b-9 [18]. In some studies, the lower C5b-9 concentration in the heparin-coated CPB might be accounted for by direct binding to the heparin-coated circuit [19]. The C5b-9, however, could not be bound to the silicone-coated surface. In our study, therefore, the significant decrease in the C5b-9 concentration in the silicone-coated group suggests that the silicone-coated oxygenator is more biocompatibile in terms of surface activation.
As in C5b-9, the release of PMN-E was significantly lower in the silicone-coated group compared with the heparin-coated group. Polymorphonuclear elastase is released from activated neutrophils induced by IL-8 or C5b-9 [16, 20]. In our study, however, this difference failed to achieve significance in terms of IL-8 release, though the release of C5b-9 and PMN-E was significantly less in the silicone-coated group than in the heparin-coated group. This finding may be due to the fact that ischemia-reperfusion, the main stimulus for IL-8 release, occurred equally in both groups.
Heparin bonding to bypass circuits has been found to reduce bleeding complications. Here, this process is reviewed with special attention to markers of inflammation and clinical outcome. Indicators of inflammation are decreased when using heparin-bonded circuits compared with conventional bypass circuits [13, 14]. The decrease in the levels of these response modifiers appears minimal, while clinical outcomes using this technology, other than bleeding complications, have not been studied to any great extent [21, 22]. However, our study demonstrated that the use of heparin-coated bypass circuits, which were limited in the Duraflo, significantly reduced not only plasma levels of inflammatory cytokines but also duration of intubation or intensive care unit stay.
Of the components of the bypass circuit, the membrane oxygenator results in the greatest activation. Recently, a new membrane oxygenator (Mera Excelung Binding Prime) composed of microporous polypropylene hollow fibers, was developed by Senko Medical Instrument Mfg (Tokyo, Japan). It costs almost the same as a heparin-coated oxygenator in Japan. The blood contact surface of the hollow fiber is coated with a 0.2 µm ultra-thin silicone layer (cyclosiloxane) based on IVOX (intravenacaval oxygenator) fiber technology (Cardiopulmonics, Inc, Salt Lake City, UT) [23]. Silicone has the best gas transfer properties for macromolecular compounds. However, the gas transfer ability of the silicone hollow fiber oxygenator is not adequate because of the thick homogenous membrane of the silicone fiber. Durability has been a problem with microporous polypropylene hollow fiber oxygenators with or without heparin coating because plasma leakage occurs with prolonged use. We have already evaluated gas transfer and hemolysis with the use of this new oxygenator on veno-arterial extracorporeal circulation in animals [4]. This new oxygenator is more durable than the previous generation of polypropylene hollow fiber oxygenators, and offers greater gas transfer capabilities than the previously developed silicone fiber oxygenators [5]. Theoretically, the silicone coating of the new oxygenator also could reduce the contact activation of blood-borne materials through two mechanisms. First, silicone itself has good biocompatibility. Gemmel and colleagues [24] have performed basic research to elucidate the biocompatibility of three different biomaterials (silicone, polyethylene, and polyvinyl alcohol hydrogel). They have concluded that silicone is more biocompatible for platelets than the other biomaterials. Secondly, the silicone coating completely prevents contact between blood and gas. The direct blood and gas interface activates the complement system. We have also reported that silicone-coated oxygenator biocompatibility for platelets, the coagulation and fibrinolytic systems, and granulocytes is at least as good as that of heparin-coated oxygenator [6]. We therefore designed this study to measure the clinical potential of a silicone-coated oxygenator to reduce proinflammatory markers during CPB.
Silicone-coated oxygenators suppress the release of proinflammatory markers as well or better than heparin-coated oxygenators. The preservation of postoperative respiratory function was equivalent with the silicone-coated and heparin-coated oxygenators. Moreover, silicone-coated oxygenators were associated with a short duration of intubation and a shorter length of stay in the intensive care unit compared to the control group. Silicone-coated oxygenators are biocompatibile, and prevent postoperative organ dysfunction.
We suggest that silicone-coated oxygenator which has better durability than heparin-coated oxygenator does is suitable for prolonged CPB and percutaneous cardiopulmonary support, and further evaluation of the performance of this oxygenator for prolonged use will be necessary.
|
Acknowledgments
|
|---|
The authors thank Hayato Nakagawa, Yoshinori Nishii, and Kohei Nishikawa (medical students at the Mie University School of Medicine) for their help with the data collection, as well as Fuji Rebio Inc, for their generous gift of C5b-9 ELISA kits.
|
References
|
|---|
-
Butler J., Rocker G.M., Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993;55:552-559.[Abstract]
-
Casey L.C. Role of cytokine in the pathogenesis of cardiopulmonary-induced multisystem organ failure. Ann Thorac Surg 1993;56:S92-S96.
-
Windsor A.C., Mullen P.G., Fowler A.A., Sugarman H.J. Role of the neutrophil in adult respiratory distress syndrome. Br J Surg 1993;80:10-17.[Medline]
-
Shimono T., Shomura Y., Tahara K., et al. Experimental evaluation of a newly developed ultrathin silicone layer coated hollow fiber oxgenator. ASAIO J 1996;42:M451-M454.[Medline]
-
Shimono T., Shomura Y., Hioki I., et al. Silicone-coated polypropylene hollow-fiber oxygenator. Ann Thorac Surg 1997;63:1730-1739.[Abstract/Free Full Text]
-
Shimono T., Shomura Y., Tani K., et al. Clinical evaluation of a silicone coated hollow fiber oxygenator. ASAIO J 1997;43:M735-M739.[Medline]
-
Downing S.W., Edmunds L.H. Release of vasoactive substances during cardiopulmonary bypass. Ann Thorac Surg 1992;54:1236-1243.[Abstract]
-
Pillai R., Bando K., Scheuler S., Zebley M., Reitz B.A., Baumgartner W.A. Leukocyte depletion results in excellent heart lung function after 12 hours of storage. Ann Thorac Surg 1990;50:211-214.[Abstract]
-
Kuratani T., Matsuda H., Sawa Y., Kaneko M., Nakano S., Kawashima Y. Experimental study in a rabbit model of ischemia-reperfusion lung injury during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1992;103:564-568.[Abstract]
-
Butler J., Chang G.L., Baigrie R.J., Pillai R., Westaby S., Rocker G.M. Cytokine responses to cardiopulmonary bypass with membrane and bubble oxygenation. Ann Thorac Surg 1992;53:833-838.[Abstract]
-
Jansen N.J.G., van Oeveren W., Gu Y.J., von Vliet M.H., Eijsman L.L., Wildevuur C.R.H. Endotoxin release and tumor necrosis factor formation during cardiopulmonary bypass. Ann Thorac Surg 1992;54:744-748.[Abstract]
-
Tonz M., Mihaljevic T., von Segesser L.K., et al. Normothermia versus hypothermia during cardiopulmonary bypass. Ann Thorac Surg 1995;59:137-143.[Abstract/Free Full Text]
-
Steinberg B.M., Grossi E.A., Schwartz D.S., et al. Heparin bonding of bypass circuits reduces cytokine release during cardiopulmonary bypass. Ann Thorac Surg 1995;60:525-529.[Abstract/Free Full Text]
-
Ashraf S., Butler J., Tian Y., et al. Inflammatory mediators in adults undergoing cardiopulmonary bypass. Ann Thorac Surg 1998;65:480-484.[Abstract/Free Full Text]
-
Damas P., Ledoux D., Nys M., et al. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 1992;215:356-362.[Medline]
-
Finn A., Naik S., Klein N., Levinsky R.J., Strobel S., Elliott M. Interleukin-8 release and neutrophil degranulation after pediatric cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;105:234-241.[Abstract]
-
Boyler E.M., Kovacich J.C., Hébert C.A., et al. Inhibition of interleukin-8 blocks myocardial ischemia-reperfusion injury. J Thorac Cardiovasc Surg 1998;116:114-121.[Abstract/Free Full Text]
-
Mollnes T.E., Videm V., Riesenfeld J., et al. Complement activation and biocompatibility. Clin Exp Immunol 1991;88(Suppl 1):21-26.
-
Videm V., Mollnes T.E., Garred P., Svennevig J.L. Biocompatibility of extracorporeal circulation. J Thorac Cardiovasc Surg 1991;101:654-660.[Abstract]
-
Wachtforgel Y.T., Kucich U., Greenplate J., et al. Human neutrophil degranulation during extracorporeal circulation. Blood 1987;69:324-330.[Abstract/Free Full Text]
-
Tehrani F., Oeinck K.H., Wolfsperger C., Hoh A., Fraedrich G. Heparin requirements and post-operative blood loss when using heparin coated ECC systems. ECC International 1995;7:80-96.
-
Francalancia N.A., Aeba R., Yousem S.A., Griffith B.P., Marrone G.C. Deleterious effects of cardiopulmonary bypass on early graft function after single lung allotransplantation. J Heart Lung Transplant 1994;13:49-507.
-
Bagley B., Bagley A., Henrie J., et al. Quantitative gas transfer into and out of circulating venous blood by means of an intravenacaval oxygenator. ASAIO Trans 1991;37:M413-M415.[Medline]
-
Gemmell C.H., Ramirez S.M., Yeo E.L., Sefton M.V. Platelet activation in whole blood by artificial surfaces. J Lab Clin Med 1995;125:276-287.[Medline]
Accepted for publication June 16, 1999.
Top
Abstract
Introduction
