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Ann Thorac Surg 1999;67:392-395
© 1999 The Society of Thoracic Surgeons

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Original Articles

Pump prime only aprotinin inhibits cardiopulmonary bypass-induced neutrophil CD11b up-regulation

^a Division of Cardiothoracic and Vascular Surgery, Department of Surgery, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska, USA

Accepted for publication June 26, 1998.

Address reprint requests to Dr Hill, Department of Anesthesiology, University of Nebraska Medical Center, 600 S 42nd St, Omaha, NE 68198-4455

	Abstract

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. The expression of neutrophil integrin CD11b is up-regulated after cardiopulmonary bypass (CPB) and is the neutrophil adhesive molecule of most importance in neutrophil–endothelial adherence. This neutrophil–endothelial adherence is responsible for post-CPB neutrophil-induced reperfusion injury. Low-dose aprotinin protocols inhibit the CPB-induced neutrophil CD11b up-regulation. This investigation was undertaken to evaluate the effects of pump prime only aprotinin (280 mg) on the CPB-induced up-regulation of this neutrophil integrin.

Methods. Twenty-two patients scheduled for elective myocardial revascularization were randomized into two groups: (1) control (n = 12), or (2) pump prime only aprotinin (280 mg) (n = 10). Neutrophils were isolated at baseline, 50 minutes of CPB, and 30 minutes after CPB and neutrophil CD11b expression was measured.

Results. The control group demonstrated a significant (p < 0.05) increase in neutrophil CD11b immunofluorescent staining at 50 minutes of CPB and at 30 minutes after CPB when compared to same group baseline and to the pump prime only aprotinin group at similar time intervals.

Conclusions. These results indicate that pump prime only aprotinin modulates the CPB-induced up-regulation of neutrophil CD11b integrin, an important indicator of the systemic inflammatory response to CPB. In addition to blunting of the CPB-induced up-regulation of this neutrophil integrin expression, this pump prime only dose of aprotinin is also reported to be effective at reducing post-CPB bleeding and transfusion requirements. This salutary effect of pump prime only aprotinin suggests that such low-dose regimens can be both therapeutically effective and cost effective.

	Introduction

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Neutrophil–endothelial adherence is a fundamental ("final common pathway") step in inflammation, including the inflammatory response during and after cardiopulmonary bypass (CPB) [1]. Adhesion molecules, produced by both vascular endothelium and circulating neutrophils, are required for this adherence [2]. Neutrophils express several adhesion molecules of the CD11/CD18 family, the most important for neutrophil–endothelial adherence is the CD11b integrin [3]. Neutrophil CD11b integrin is increased during and after CPB [1]. The importance of up-regulation of this integrin is illustrated by the reduced myocardial [4] and lung [5] injury after CPB by monoclonal antibody blockade of this neutrophil integrin [4] or by the pharmacologic inhibition [5] of the CPB-induced upregulation of CD11b expression, respectively.

Previous research demonstrated that low-dose aprotinin (140 mg loading dose, 35 mg/h infusion rate, and 140 mg in the pump prime) during CPB inhibits the up-regulation of neutrophil CD11b integrin expression [6], an antiinflammatory effect of aprotinin. Recent studies indicate that pump prime only aprotinin (280 mg) is as effective [7], or nearly so [8], as high-dose protocols (280 mg loading, 70 mg/h infusion rate, and 280 mg in the pump prime) and low-dose protocols in post-CPB reduction in bleeding and transfusion requirements. Hayashida and colleagues [9] found that even smaller doses (140 mg) of pump prime only aprotinin reduced blood loss and transfusion requirements after CPB as well as preventing fibrinolysis. The present study was undertaken to determine whether pump prime only aprotinin is sufficient to blunt CPB-induced neutrophil CD11b up-regulation.

	Material and methods

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
After Institutional Review Board approval and written informed consent, 22 patients scheduled for elective primary aortocoronary artery bypass grafting were included in a prospective randomized study. The patients were assigned into either a control group (n = 12) or a group that received pump prime only aprotinin (280 mg) therapy (n = 10). Any patient receiving preoperative glucocorticoid or nonsteroidal antiinflammatory therapy within the previous 2 weeks was excluded. Only patients with a preoperative ejection fraction more than 45% were studied. No exogenous blood product, including platelet concentrates, was administered to any study patient until after the final blood sample was obtained. No other antiinflammatory drug therapy, other than the pump prime only aprotinin in the 10 noncontrol patients, was used in conjunction with CPB in any patient.

On the morning of operation, each patient was given morphine sulfate (0.1 mg/kg) and scopolamine (0.2 to 0.4 mg) intramuscularly before admission to the operating room. On arrival to the operating room, a radial artery catheter, a right internal jugular vein pulmonary artery catheter, and large-bore intravenous catheters were placed. Standard anesthetic treatment consisting of fentanyl (75 to 100 µg/kg) as a short intravenous infusion and pancuronium (0.1 to 0.2 mg/kg) was used. Cardiopulmonary bypass was completed with a centrifugal pump (Medtronic Bio-Medicus, Inc, Eden Prairie, MN), hollow-fiber membrane oxygenator (Baxter Healthcare Corp, Irvine, CA) with arterial line filtration, and mild hypothermia (32°C core temperature). Perfusion flow rate and mean arterial pressure during CPB were maintained between 2.2 and 2.4 L · min^-1 · m^-2 and 60 to 80 mm Hg, respectively. Myocardial preservation was achieved through both antegrade and retrograde administration of cold hyperkalemic blood (8:1 blood-to-crystalloid mixture) cardioplegic solution. A terminal dose of normothermic continuous cardioplegic solution was administered approximately 15 minutes before reperfusion. Anticoagulation in both groups was obtained by the administration of bovine lung heparin (300 IU/kg), and kaolin-based activated clotting times were maintained at 480 seconds or greater in both groups by the addition of heparin when necessary. At the termination of CPB, protamine was administered in a ratio of 1.3 mg for every 100 U of total heparin administration, and the efficacy was confirmed by the return of the activated clotting time to baseline values.

Heparinized whole blood (20 mL) was drawn: (1) at baseline (after placement of the arterial and intravenous catheters but before anesthetic drug administration), (2) after 50 minutes of CPB, and (3) 30 minutes after termination of CPB. No patient received blood products during periods 1 to 3.

The blood samples were immediately taken to the laboratory. Laboratory personnel were blinded as to which arm of the study each patient was assigned. Dextran (Pharmacia, Uppsala, Sweden) was added to each sample of whole blood (1:2 dilution), and the sample inverted several times and subjected to 1 g velocity sedimentation for 1 hour. The samples were maintained at room temperature throughout the entire experimental protocol. The leukocyte-containing layer was removed and the neutrophils separated by Ficoll-Hypaque (Sigma Chemical Co, St. Louis, MO) density centrifugation [10]. In the unwashed sample, integrin expression was detected with the use of a double antibody technique. Ten microliters of the first antibody, anti-CD11b antibody (Becton-Dickinson, San Jose, CA) or the isotype control was added and the sample incubated for 30 minutes at room temperature. After samples were washed, 10 µL of the second antibody, a fluorescein isothiocyanate conjugate of goat antimouse immunoglobulin (Becton-Dickinson), was added to the suspension and incubated for 30 minutes. The fluorescein-conjugated second antibody allows for a fluorescence-activated cell sorter (FACScan, Becton-Dickinson) to quantify the surface expression of the neutrophil CD11b surface integrin as described by Ledbetter and Herzenberg [11]. Flow cytometry data analysis (FACScan) was performed with Lysis II software (Becton-Dickinson); the data were expressed as mean channel fluorescence intensity minus background fluorescence on a linear scale. Mean channel fluorescence intensity values were then used to evaluate differences between measurement periods and the two groups. A repeated-measures analysis of variance was performed to distinguish within-group differences over time, and t tests were done to evaluate differences at the same time periods between groups. A p value of 0.05 or less was required for significance.

	Results

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
There were no significant differences between the two groups with regard to age, weight, or duration of CPB (Table 1).

View larger version (16K): [in this window] [in a new window]   Fig 1. Mean channel fluorescence intensity (mean ± standard error of the mean) of CD11b neutrophil integrin for the control and pump prime only aprotinin groups at baseline, after 50 minutes duration of CPB, and 30 minutes after CPB termination. *p < 0.05, when compared to same group baseline, +p < 0.05, when compared to pump prime only aprotinin at the same time period.

	Comment

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The institution of CPB results in a systemic inflammatory response characterized by production and release of proinflammatory cytokines, including tumor necrosis factor- (TNF-) and the interleukins 1, 6, and 8 (IL-1, 6, and 8) [1]. Up-regulation of neutrophil surface adhesion molecules and resultant increased adherence of these inflammatory cells to the vascular endothelium is a well-known effect of these proinflammatory cytokines [2, 3]. The neutrophils display several surface adhesion molecules (or integrins) of the CD11/CD18 family; the most important for neutrophil–endothelial adherence is the CD11b integrin [2, 3]. Reduction of neutrophil integrin expression and function reduces myocardial and lung reperfusion injury after CPB [4, 5] and leukocyte depletion during CPB reduces lung [12] and myocardial [13] reperfusion injury after CPB. Therefore, reduction of neutrophil CD11b integrin during and after CPB results in less neutrophil mediated organ dysfunction [4, 5, 14].

Previous investigations have demonstrated that the magnitude of the systemic inflammatory response to CPB depends on several dependent variables. Preoperative left ventricular ejection fraction less than 45% is associated with a greater inflammatory response during and after CPB as measured by the generation and systemic release of IL-6 [15]. Also, the total duration of CPB, but not aortic cross-clamp time, is directly correlated with the inflammatory response (also determined by IL-6 plasma levels) [16]. Therefore, to properly evaluate the effect of pump prime only aprotinin on CPB-induced inflammation as determined by neutrophil CD11b expression, matching of the two study groups for these variables that impact on the magnitude of CPB-induced inflammation is mandatory. Patients selected for inclusion in this study protocol all had left ventricular ejection fraction levels more than 45% and similar durations of CPB. Blood product infusions, including platelet concentrates, contain elevated concentrations of proinflammatory cytokines [17] and thus may impact on neutrophil adhesion molecule expression. Therefore, the demonstration that pump prime only aprotinin prevents the up-regulation of neutrophil CD11b expression in the treatment group of two similarly matched groups of patients is consistent with previous reports that demonstrated low-dose aprotinin therapy also prevents CPB-induced up-regulation of this neutrophil integrin [6]. Both groups received similar dosing of heparin before the institution of CPB. The demonstration that heparin has no effect on proinflammatory cytokine-induced neutrophil–endothelial adherence [18] shows that heparin has no effects on neutrophil adhesion molecule expression and therefore, will have no impact on the findings reported in this study.

Aprotinin (a protease inhibitor), when used as a high, low, or pump prime only dosing protocols effectively reduces bleeding and transfusion requirements after CPB [7, 8]. Even smaller (140 mg) pump prime only aprotinin is effective in the reduction of bleeding and transfusion requirements after CPB [9]. Levy and colleagues [19] demonstrated that 140 mg of aprotinin resulted in a plasma concentration in excess of 50 KIU/mL, the concentration required to inhibit plasmin. Several studies indicate that low [1, 6] and high-dose aprotinin have antiinflammatory effects during and after CPB. Wendel and colleagues [20] reported that a high-dose aprotinin protocol resulted in reduced myocardial ischemic episodes after CPB as determined by lower troponin T and creatine kinase-MB levels. Consistent with the data reported by Wendel and colleagues [20], Sawa and associates [21] demonstrated nafamostat (a protease inhibitor) reduced IL-6 and IL-8 plasma levels after CPB, and that by reducing these CPB-induced inflammatory mediators, myocardial reperfusion injury was also attenuated. Other human studies report aprotinin reduces myocardial infarction size secondary to coronary artery occlusion [22] while reducing lung injury during hypovolemic shock and the sepsis syndrome [23]. Lemmer and colleagues [7] found a significantly (16% versus 9%, p = 0.045) increased incidence of after CPB myocardial infarction in a pump prime only aprotinin group when compared to a placebo-treated group. In contrast, Levy and associates [8] found no difference in the incidence of perioperative myocardial infarction after repeat coronary artery bypass grafting in a pump prime only aprotinin group when compared to placebo, low-, and high-dose aprotinin groups. Therefore, additional studies will be required to determine the exact role and safety of pump prime only aprotinin therapy in cardiac operation.

Aprotinin prevents neutrophil degranulation and subsequent neutrophil elastase release during CPB, indicating aprotinin inhibits CPB-induced neutrophil activation [24]. In addition, aprotinin, when used as a cardioprotective agent when added to a cardioplegic solution, caused a significant increase in the preservation of myocardial cellular ADP and ATP levels while also inhibiting myocyte lysosomal enzyme release [25]. These reports are consistent with the concept that aprotinin demonstrates antiinflammatory effects when administered in several pathophysiologic conditions including during and after CPB.

Because TNF- up-regulates surface expression of the neutrophil CD11b integrin [2, 3], the demonstration by Kim and colleagues [26] that aprotinin inhibits endotoxin-stimulated macrophage production of TNF- may explain the mechanism of the aprotinin-induced inhibition of CPB-induced neutrophil CD11b integrin up-regulation. Systemic endotoxemia occurs immediately with the institution of CPB [1]; endotoxin is the primary stimulus for TNF- production and release by inflammatory (primarily macrophage) cells [1–3]. The report by Kim and associates [26] demonstrating aprotinin inhibits endotoxin-induced TNF- release is consistent with the finding that aprotinin (low-dose protocol) also blunts TNF- release during CPB [6].

In summary, this report demonstrates that pump prime only aprotinin (280 mg) blunts CPB-induced up-regulation of the neutrophil CD11b integrin. Because increased neutrophil CD11b expression is reported to be a major determinant in CPB-induced inflammation [1, 4, 5], these data indicate that therefore, this "mini" dose aprotinin may be effective in reducing this inflammatory response. Because pump prime only aprotinin is effective in reducing both bleeding and transfusion requirements after CPB and modulating the inflammatory response to CPB, higher doses of aprotinin may be unnecessary.

	Acknowledgments

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
In memory of Anselmo Alonso, MD, 1958–1998.

	Footnotes

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
^* Deceased.

	References

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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