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Ann Thorac Surg 1995;59:100-105
© 1995 The Society of Thoracic Surgeons

Circulating Adhesion Molecules in Cardiac Operations: Influence of High-Dose Aprotinin

Departments of Anesthesiology and Intensive Care Medicine and Cardiovascular Surgery, Justus-Liebig-University Giessen, Giessen, Germany

Accepted for publication June 30, 1994.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Cardiac operations using cardiopulmonary bypass (CPB) are associated with a systemic inflammatory response most likely attributable to the release of various inflammatory mediators and activation of complement or coagulation cascade. In addition, (circulating) adhesion molecules, such as endothelial leukocyte adhesion molecule (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1), appear to be of central importance in the CPB-related inflammatory process. In this situation, antiproteases, such as aprotinin, may help to prevent damage of endothelial integrity. In a prospective study, 40 consecutive patients undergoing elective cardiac operation were randomly divided into two groups (with 20 patients in each group): in group 1 ``high-dose'' aprotinin was used (2 million IU of aprotinin before CPB, 500,000 IU/h until end of operation, 2 million IU added to the prime) (with aprotinin), and in group 2 no aprotinin was given (without aprotinin). Circulating adhesion molecules (cICAM-1, cELAM-1, and cVCAM-1) were measured from arterial blood samples using ELISA after induction of anesthesia (baseline), during CPB, at the end of the operation, 5 hours after CPB, and on the first postoperative day. The two groups were comparable concerning their biometric profile and CPB data. Baseline values of circulating adhesion molecules were within normal range and similar in both groups. During CPB, hemodilution resulted in a decrease in all circulating adhesion molecules. On the first postoperative day, cICAM-1 (with aprotinin, 215 ± 32 ng/mL; without aprotinin, 230 ± 40 ng/mL) and cELAM-1 (with aprotinin, 28 ± 6 ng/mL; without aprotinin, 31 ± 6 ng/mL) returned to baseline values. Only cVCAM-1 plasma levels were increased beyond baseline values at this data point (with aprotinin, 576 ± 41 ng/mL; without aprotinin, 588 ± 31 ng/mL) without exceeding normal range. None of the patients suffered from high fever (temperature more than 38.5°C), organ dysfunction, or needed prolonged intensive care therapy. It can be concluded that circulating adhesion molecules cICAM-1, cELAM-1, and cVCAM-1 were not markedly changed in our patients undergoing elective cardiac operations, which indicates only a limited endothelial damage or inflammatory response, respectively. Proteinase inhibitor aprotinin did not influence plasma levels of circulating adhesion molecules in this situation.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
C ardiopulmonary bypass (CPB) is associated with a generalized inflammatory response [1, 2]. Release of various inflammatory mediators has been implicated in the pathogenesis of ``postperfusion syndrome'' including cytokines (eg, tumor necrosis factor and interleukins), arachidonate metabolites, platelet-activating factor, and others [1–5]. In addition to the actions of these inflammatory mediators, the interaction between white cells and the endothelium of the microcirculation appears to be of particular interest [6]. One initial step in tissue injury is adherence of neutrophil cells to the vascular endothelium [7]. Specific adhesion molecules, such as endothelial leukocyte adhesion molecule (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1), are expressed on the surface of various cell formations that result in binding of neutrophils [8, 9]Au: have renumbered all references; 8 was skipped. By this binding, a complex pathophysiologic process is activated, which results in marked microvascular injury and thus tissue damage [1, 10, 11]. Release of oxygen free radicals and proteases are believed to be the main reasons for the neutrophil-related damage of the endothelial integrity [6, 12]. Some of these adhesion molecules are present also in the circulating blood in soluble forms, and they are believed to be markers of the extent of inflammatory disease [13, 14]. Their definite significance or function, however, are not fully elucidated.

In recent years, several attempts have been initiated to prevent CPB-related organ failure. This includes use of leukocyte filtering, inhibitors of release of various endogenous inflammatory mediators, receptor antagonists of these mediators, immunomodulation, and monoclonal antibodies to prevent endothelial adhesion [5]. Most of these attempts, however, have been used only in an experimental setting. Antiproteases, such as aprotinin, were reported to be a promising therapeutic approach to avoid inflammatory-related organ dysfunction in the critically ill patients either by its influence on the mediator cascade, its direct effects on white blood cells, or by its (direct) effects on bacteria [2, 15]. Thus, the present study was designed to investigate whether aprotinin, which is used in several centers for different reasons, influences circulating (soluble) adhesion molecules in adults undergoing cardiac operation using CPB.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Patients and Grouping
Forty consecutive patients undergoing elective cardiac operations were studied prospectively. Informed consent was obtained from each patient according to the protocol of the Human Ethic Committee of the hospital. Patients with renal and liver insufficiency were excluded from participating in the study. Therapy with aspirin (100 mg/day) was stopped 7 days before the day of operation.

The patients were randomized prospectively into two groups. In group 1 (n = 20), high-dose aprotinin was used (2 million IU of aprotinin before CPB, 500,000 IU/h until end of operation, 2 million IU added to the prime) (with aprotinin); and in group 2 (n = 20), no aprotinin was given (without aprotinin; control group).

Anesthesia and Cardiopulmonary Bypass
Induction and maintenance of anesthesia were standardized and consisted of weight-related dosages of fentanyl, midazolam, and pancuronium bromide. All patients were ventilated mechanically for at least 5 hours after the end of CPB.

Five minutes before CPB, 300 IU/kg of bovine heparin was administered to achieve anticoagulation. Activated clotting time (using kaolin as activator) was monitored using a Hemochron system (Hemochron, International Technidyne Corp, Edison, NJ). When necessary, 150 IU/kg of heparin was added to keep the activated clotting time always more than 400 seconds during CPB. CPB was performed with a capillary oxygenator (Monolyth, Sorin, Turino, Italy). The circuit was primed with 1,000 mL of Ringer's solution, 1,000 mL of dextrose 5%, and 250 mL of albumin 5%. A flow of 2.4 L • min^-1 • m^-2 was maintained within the entire CPB. Bretschneider's cardioplegic solution was infused for myocardial preservation. Within 20 minutes after the start of CPB, the perfusate was concentrated using a hemofiltration device (HF-80; Fresenius, Bad Homburg, Germany) to adjust hemoglobin between 8 and 10 g/dL. When necessary to guarantee filling of the circuit, Ringer`s solution was added. When the hemoglobin value dropped to less than 7 g/dL, packed red blood cells were added to the perfusate. After separation from CPB, the residual blood of the circuit was salvaged by the hemofiltration device, and the autologous blood was retransfused until the end of the operation. To antagonize heparin effects, protamine sulfate was given in a 1:1 ratio to the initially administered heparin dose.

To maintain stable hemodynamics in the postoperative period, albumin 5% was infused (when pulmonary capillary wedge pressure was less than 10 mm Hg and cardiac index was less than 2.25 L • min^-1 • m^-2. Packed red blood cells were given when hemoglobin was less than 9 g/dL. Shed mediastinal blood was not collected and retransfused during the postoperative period. All volume therapy, catecholaminergic support (epinephrine, dobutamine, norepinephrine), and vasodilator therapy (nitroglycerine, calcium-channel blockers) were indicated by physicians who were not involved in the study and who were blinded to the grouping.

Measured Parameters and Data Points
Blood was withdrawn from an indwelling arterial cannula into an EDTA-containing tube. After collection, the blood was immediately centrifuged (15 minutes, 600 g) and the plasma samples were stored at -70° C. Within 4 weeks after blood sampling, samples, circulating intercellular adhesion molecule-1 (cICAM-1; normal mean value, 210 ng/mL; ± 2 standard deviations [SD] range, 115 to 305 ng/mL), endothelial leukocyte adhesion molecule-1 (cELAM-1; normal mean value, 47 ng/mL; ± 1 SD range, 28 to 66 ng/mL), vascular cell adhesion molecule-1 (cVCAM-1; normal mean value, 553 ng/mL; ± 1 SD range, 395 to 715 ng/mL), and were measured using commercial enzyme-linked immunosorbent assays (ELISA; British Bio-technology Products, Abingdon, UK). The assays are based on simultaneous reactions of the adhesion molecule to two monoclonal antibodies directed against different epitopes on the adhesion molecule (ICAM, ELAM, VCAM). All assays are standardized against a purified form of recombinant ICAM, ELAM, or VCAM, respectively. Sensitivity (minimal detectable dose) for cELAM-1 is less than 1.0 ng/mL, for cVCAM-1 less than 2.0 ng/mL, and for cICAM-1 less than 0.35 ng/mL. All results from ELISA represent the means from duplicate measurements. Plasma levels of circulating adhesion molecules were not corrected for hemodilution because the actual plasma concentrations were of interest. Measurements were carried out after induction of anesthesia (baseline values), 20 minutes after start of CPB (after hemoconcentration by hemofiltration), at the end of the operation, 5 hours after the end of CPB, and on the first postoperative day. In addition, standard laboratory (hemoglobin, neutrophil count, blood gas analysis) and relevant clinical parameters were monitored at the same data points.

Statistics
All parameters are expressed as mean values ± SD. One- and two-factorial analyses of variance including Scheffé's test were used for statistical interpretation. A relationship between two parameters was tested by analysis of covariance. A p value of less than 0.05 was considered significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Patients' characteristics, type of operation, and data from CPB were similar in both groups (Table 1)tab 1. Postoperative blood loss and use of homologous blood did not differ between the patient groups (Table 1).

View larger version (26K): [in this window] [in a new window]   Fig 1. . Plasma level of circulating intercellular adhesion molecule-1 (cICAM-1) (normal range, 200 to 300 ng/mL). (CPB = cardiopulmonary bypass; p.o. = postoperative day; *p < 0.05 different from baseline values.)

View larger version (26K): [in this window] [in a new window]   Fig 2. . Plasma level of circulating endothelial leukocyte adhesion molecule-1 (cELAM-1) (normal range, 30 to 60 ng/mL). (CPB = cardiopulmonary bypass; p.o. = postoperative day; *p < 0.05 different from baseline values.)

View larger version (26K): [in this window] [in a new window]   Fig 3. . Plasma level of circulating vascular cell adhesion molecule-1 (cVCAM-1) (normal range, 400 to 700 ng/mL). (CPB = cardiopulmonary bypass; p.o. = postoperative day; *p < 0.05 different from baseline values.)

None of the patients were reoperated on or needed prolonged intensive care therapy. All patients were transferred from the intensive care unit to a normal ward by the third day at the latest.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Cardiopulmonary bypass is reported to (more or less) injure the endothelium [1, 16]. The definite etiology of endothelial cell damage in this situation has not been fully elucidated. Direct effect of hypoxia attributable to microcirculatory abnormalities, release of proteinases from activated white cells, activation of mediator systems (eg, the complement system), and activation of platelets-all may contribute to endothelial function abnormalities. One important aspect for this damage appears to be the interactions between activated neutrophils with the endothelium and the cell-to-cell interactions [17]. The binding of neutrophils to the endothelial cells appears to play a central role in the pathogenesis of CPB-related systemic inflammatory response [1, 10, 11].

Three different families of adhesion receptors are known: (1) the immunoglobulin superfamily (eg, ICAM-1, VCAM-1); (2) the integrin family; and (3) the selectins (eg, ELAM-1, L-selectin-leukocyte endothelial cell adhesion molecule [LECAM], P-selectin-granule membrane protein 140 [GMP 140]) [8]. All adhesion molecules, ICAM-1, ELAM-1, and VCAM-1, are located on a variety of cells including the endothelial cells, which appear to be one of the most important locations [8]. Cell-surface interactions are mediated initially by members of the selectin family to (loosely) associate the leukocytes with the endothelium. Members of the integrin and immunoglobulin family are required to induce firm leukocyte adhesion [7–9]. VCAM-1 forms a receptor counterstructure pair with CD49d/CD29 on phagocytes; the CD11/CD18 complex on the neutrophil surface is the receptor ligand of endothelial ICAM-1 [8, 9, 13].

Endothelial-bound adhesion molecules are reported to be up-regulated in various situations: membrane-bound ICAM-1 was found to be elevated in patients suffering from transplant rejection [17]. VCAM-1 expression correlated with the presence of moderate transplant rejection [18], whereas ELAM-1 was not detected in this situation. ELAM-1 was shown to be a useful marker for endothelial activation [19]; unlike other endothelial activation markers, such as ICAM-1 and VCAM-1, ELAM-1 is not constitutively present in normal endothelium [11].

The appearance of soluble adhesion molecules in the circulating blood may result from inflammation-induced tissue damage and thus appears to be a marker of the extent of inflammatory disease, endothelial damage, and activation [8, 13]. Adhesion molecules are reported to play an important role in various inflammatory processes (eg, lupus erythematosus, rheumatoid arthritis, human immunodeficiency virus) [8–10]. Plasma levels of cICAM-1 in healthy individuals range from approximately 200 to 300 ng/mL [13]. In a recent study in cardiac operation patients, cICAM-1 plasma level was approximately 200 ng/mL before CPB and remained almost unchanged when a membrane oxygenator was used. In a group in which CPB was carried out with a bubble oxygenator, cICAM-1 significantly increased 24 hours after CPB (to approximately 290 ng/mL) [20], whereas time course of neutrophil CD11b/CD18 expression, complement activation, and elastase plasma levels were without differences between the bubble and membrane oxygenator groups. The increase in cICAM-1 in the patients undergoing bubble oxygenation was assumed to be attributable to a greater endothelial response to CPB. Furthermore, plasma level of circulating (soluble) ICAM-1 has been reported to be of prognostic value after heart transplantation [21].

An increase in circulating adhesion molecules (eg, cICAM-1) either results from an increased expression by the endothelial cells or, more likely, from proteolytic cleavage of endothelial-bound adhesion molecules (eg, cICAM-1) [20]. Whether the circulation adhesion molecules have their own biologic function is a subject of on going controversy: cICAM-1 appears to retain the ability of endothelial-related ICAM-1 to bind specifically to lymphocyte function-associated antigen (LFA-1; also named CD11a/CD18), an adhesion molecule found on all white blood cells [13]. Thus, cICAM-1 may regulate cell adhesion by promoting deadhesion [13]. It has been suggested that soluble ICAM-1 may compete with membrane-bound ICAM-1 for leukocyte adhesion, thus preventing attachment (or even promoting detachment) of white blood cells and thus preventing neutrophil-induced tissue damage [13]. On the other hand, by adhering to vessel walls and by adhering to each other, phagocytes can produce vascular plugs, thus leading to the no-reflow phenomenon inducing issue ischemia [22].

In recent years, the serine protease-inhibitor aprotinin has been widely used in several centers to avoid CPB-related disturbances in hemostasis, thus reducing blood loss and need for homologous blood transfusion [23]. In the 1970s, aprotinin was given in (traumatic or pancreatic related) shock to prevent (posttraumatic) lung dysfunction by inhibiting activation of various deleterious cascades (eg, kinin-kallikrein system, coagulation system, neutrophil activation) [15, 23]. The complexity of the pathogenesis of CPB-related organ dysfunction may offer a large number of opportunities for pharmacologic interventions. By its complex (direct or indirect) actions on the mediator cascade (eg, elastase), white blood cells (lymphocytes and neutrophils), and endothelial cells [15, 23–25], the proteinase-inhibitor aprotinin may also affect an inflammatory response by modifying endothelial-adhesion molecules. Thus, it was the aim of this study to investigate whether aprotinin influences circulating adhesion molecules beneficially.

Plasma levels of all adhesion molecules in both groups remained within the range of healthy volunteers. The decrease of adhesion molecule concentration during CPB was most likely attributable to hemodilution in this period. Postoperatively, cICAM-1 and cELAM-1 returned to baseline values. Only cVCAM-1 plasma levels increased significantly on the first postoperative day, without, however, exceeding normal range. None of the patients suffered from fever, organ dysfunction (limited use of catecholaminergic support), or needed prolonged intensive care therapy. The fact that plasma levels of circulating adhesion molecules were not significantly altered by CPB in our elective cardiac operation patients may implicate that biocompatibility of the extracorporeal oxygenation equipment (use of membrane instead of bubble oxygenators) and the perfusion technique (use of normothermia instead of hypothermia) have improved markedly in recent years, thus limiting endothelial damage and inflammatory response. Moreover, duration of CPB was not extensive and we have studied only elective cardiac operation patients.

Adhesion molecules are gaining increasing interest as markers and index of inflammation in various pathophysiologic circumstances. Although CPB appears to be associated with whole body inflammatory response directed against material of the CPB equipment, the soluble adhesion molecules cICAM-1, cVCAM-1, and cELAM-1 in the circulating blood were not changed markedly by CPB in patients undergoing elective cardiac operations. Protease inhibitor aprotinin did not influence circulating adhesion molecules in this situation. Whether plasma levels of these soluble adhesion molecules are increased more pronouncedly in sicker patients or patients undergoing prolonged CPB procedure and whether aprotinin then has beneficial effects warrants further studies.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Address reprint requests to Dr Boldt, Department of Anesthesiology and Intensive Care Medicine, Justus-Liebig-University Giessen, Klinikstr 29, 35392 Giessen, Germany.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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This Article Abstract 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 Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boldt, J. Articles by Hempelmann, G. Search for Related Content PubMed PubMed Citation Articles by Boldt, J. Articles by Hempelmann, G.