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Ann Thorac Surg 1998;65:66-69
© 1998 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Aprotinin Enhances the Endogenous Release of Interleukin-10 After Cardiac Operations

Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska, USA

Accepted for publication July 2, 1997.

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

	Abstract

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Background. Cardiopulmonary bypass (CPB) is characterized by the systemic release of proinflammatory cytokines, such as tumor necrosis factor- and the interleukins 1 and 6, as well as endogenous antiinflammatory cytokines, including interleukin-10 (IL-10). Glucocorticoids reduce tumor necrosis factor- plasma concentrations while enhancing IL-10 plasma concentrations after CPB. Aprotinin, a serine protease inhibitor used primarily to reduce blood loss after CPB, reduces CPB-induced proinflammatory cytokine tumor necrosis factor- release similarly to glucocorticoids. This study evaluates the effect of full-dose aprotinin on the plasma concentrations of IL-10 after CPB.

Methods. Twenty adults were randomized into a control (group C, n = 10) and a full-dose aprotinin-treated group (group A, n = 10). Plasma levels of IL-10 were measured by enzyme-linked immunosorbent assay technique at baseline (before anesthetic induction), and at 1 and 24 hours after CPB termination.

Results. A significant (p < 0.05) increase of IL-10 occurred in both groups at 1 and 24 hours after termination of CPB when compared with the same group at baseline. In group A, the increase in IL-10 was significantly greater than in group C (p < 0.05) at 24 hours after CPB.

Conclusions. These results demonstrate an endogenous antiinflammatory response generated after CPB, characterized by IL-10 release, that is enhanced by aprotinin therapy. This study demonstrates a unique antiinflammatory activity of aprotinin that may be of clinical significance.

	Introduction

Top Abstract Introduction Material and Methods Results Comment References

 
Cardiopulmonary bypass (CPB) is characterized by systemic endotoxemia (1) followed by cytokine generation, including the proinflammatory cytokines tumor necrosis factor- (TNF) and the interleukins 1 (IL-1) and 6 (IL-6) [1]. Endotoxin also induces the cellular (monocyte) release of interleukin-10 (IL-10) [2], which is considered an antiinflammatory cytokine. For example, IL-10 inhibits endotoxin-activated monocyte proinflammatory (TNF, IL-1, and IL-6) and antiinflammatory (IL-10) cytokine production at the transcriptional level [2]. The proinflammatory cytokines TNF and IL-1 upregulate neutrophil and endothelial adhesive molecule expression [1], including the primary endothelial adhesive ligand (receptor) for neutrophils, intercellular adhesion molecule-1 (ICAM-1), thereby enhancing neutrophil–endothelial adherence. Enhanced neutrophil–endothelial adherence is thought to be responsible for inducing lung and myocardial reperfusion injury after CPB [1]. Interleukin-10 downregulates ICAM-1 expression in vitro [3], and reduces lung reperfusion injury in a rat model [4]. Thus reports of increased IL-10 plasma levels after CPB [5] may indicate an endogenous antiinflammatory response to CPB.

Administration of a glucocorticoid before CPB not only reduces TNF levels during and after CPB [1], but also enhances the endogenous release of IL-10 [5]. Aprotinin, used primarily to reduce bleeding after CPB, is also known to reduce TNF plasma levels during and after CPB [1]. This study was performed to evaluate whether aprotinin, like glucocorticoids, enhances endogenous IL-10 release after CPB in human subjects.

	Material and Methods

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After obtaining Institutional Review Board approval and patient’s informed consent, 20 adult patients scheduled for first-time myocardial revascularization operations were randomized according to a computer-generated sequence and assigned equally to one of two groups: (1) a control group (group C), and (2) a group that received aprotinin, 280 mg (2 x 10⁶ KIU) intravenously as a loading dose, 280 mg (2 x 10⁶ KIU) as a "pump prime," and 70 mg (5 x 10⁵ KIU) per hour constant intravenous infusion until chest closure (full-dose aprotinin, group A). Any patients with indications of an active infection, or who were receiving a glucocorticoid or a nonsteroidal antiinflammatory drug were excluded.

On the morning of the 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, a radial artery catheter, a right internal jugular vein pulmonary artery catheter, and large-bore intravenous lines were placed. Standard anesthesia 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 (Biomedicus, Inc., Eden Prairie, MN), hollow-fiber membrane oxygenator (Baxter Health Care, 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) cardioplegia. A terminal dose of normothermic continuous cardioplegia was administered approximately 15 minutes before reperfusion. Anticoagulation 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 confirmed by the return of the activated clotting time to baseline values. No shed mediastinal blood was reinfused in any study patient.

Ten milliliters of heparinized arterial blood was drawn at three time periods: (1) baseline (after placement of the arterial and intravenous catheters but before anesthetic drug administration); (2) 1 hour after termination of CPB; and (3) 24 hours after termination of CPB.

The blood samples were immediately taken to the laboratory. Arterial blood for IL-10 levels was collected in sterile 20-mL syringes and spun at 2,000 g for 15 minutes, and the plasma was separated, frozen at -80°C, and batched. Interleukin-10 was quantified by using a "sandwich" enzyme-linked immunosorbent assay using specific monoclonal antibodies (Quantikine HS, R&D Systems, Minneapolis, MN) after plasma thawing and extraction as described previously [6]. Laboratory personnel responsible for assay determinations were blinded as to which group each patient was assigned. Sensitivity (minimal detectable dose) for IL-10 is less than 1.5 pg/mL, with a normal human plasma concentration of less than 7.8 pg/mL. All results are reported as mean ± standard error of the mean. A repeated-measures analysis of variance was done to distinguish within-group differences over time, and Student’s t tests were done to evaluated differences at the same time periods between groups; p values of 0.05 or less were considered significant.

	Results

Top Abstract Introduction Material and Methods Results Comment References

 
No significant differences were noted between either group in age (years), weight (kilograms), CPB duration (minutes) or aortic cross-clamp time (minutes), although group C received significantly (p < 0.05) greater packed red blood cell unit infusions compared with group A (Table 1).

View larger version (18K): [in this window] [in a new window]   Interleukin-10 (IL-10) plasma levels (pg/mL) (mean ± standard error of the mean [SEM]) at baseline (time period 1), 1 hour (time period 2), and 24 hours (time period 3) after cardiopulmonary bypass in groups A and C. (*p < 0.05, compared with the same group at baseline; p < 0.05, compared with group C at the same time period.)

	Comment

Top Abstract Introduction Material and Methods Results Comment References

Interleukin-10 is considered an inhibitory (or antiinflammatory) cytokine; that is, IL-10 reduces the macrophage or monocyte release of the proinflammatory cytokines TNF, IL-1, and IL-6 [16], while enhancing the release of soluble TNF receptor (which functions to scavenge plasma TNF) [17]. Endotoxin is released systemically during CPB [1], and IL-10 is a potent inhibitor of endotoxin-induced neutrophil release of TNF and IL-1 by reducing their respective mRNA levels [2]. In addition to the inhibitory effects on proinflammatory cytokine release, IL-10 also inhibits the cytokine-induced expression of ICAM-1 [3], suggesting that IL-10 may reduce neutrophil–endothelial adherence after CPB. Of interest is the recent demonstration that glucocorticoids (dexamethasone and methylprednisolone) enhance CPB-induced IL-10 release [5], which may suggest a mechanism for the reported antiinflammatory effects of glucocorticoids after CPB [1][6][15].

Cardiopulmonary bypass is thought to cause lung and myocardial reperfusion injury by neutrophil-mediated oxidative injury [1]. Because IL-10 reduces the cytokine-induced expression of the primary endothelial receptor for neutrophil adherence, ICAM-1 [3], increased plasma levels of IL-10 may be advantageous after CPB. Because IL-1 induces IL-6 release [1], and IL-10 reduces IL-1 synthesis [2], enhanced IL-10 release after CPB by aprotinin therapy may partly explain the finding that aprotinin reduces IL-6 plasma levels after CPB [18]. This enhancement of IL-10 release after CPB by aprotinin may also partially explain the reduced incidence of myocardial reperfusion injury after CPB in a high-dose aprotinin-treated patient compared with an untreated control group [19].

Although patient profiles were similar (including total intensive care, intubation, and mechanical ventilation times), the control group (group C) received more blood products after CPB than the aprotinin-treated group. Although TNF, IL-1, and IL-6 concentrations are elevated in stored blood products [20], the direct induction of IL-10 by these proinflammatory cytokines has not been reported. Thus the administration of blood products should not alter the endogenous production and release of IL-10. The mechanism of the enhancement by aprotinin of IL-10 release after CPB in humans remains to be determined.

The effect of CPB on IL-10 plasma levels in the control group reported in this study is consistent with that measured by McBride and coworkers [21]. They reported comparable plasma levels measured at similar time periods (before anesthetic induction and 2 and 24 hours after CPB termination) and found, as in our control group, lower IL-10 levels at 24 hours compared with those measured shortly after CPB termination. Wan and associates [22] similarly found in adult subjects lower plasma IL-10 concentrations 24 hours after CPB compared with those measured at shorter time periods. In contrast, Seghaye and colleagues [23] reported that IL-10 plasma levels in infants increased significantly at 4 hours but peaked at 24 hours after CPB. Because only adults were included in our study protocol, IL-10 plasma levels were measured at 1 hour, a similar time interval used by others [21][22] to demonstrate a significant CPB-induced increase in IL-10 concentrations. To demonstrate an effect of aprotinin on the enhancement of IL-10 release after CPB, measurements were taken at 24 hours, a time interval at which IL-10 concentrations are known to be significantly less than at earlier time periods after CPB in adult subjects [21][22]. These reports [21][22] support our contention that aprotinin has a unique effect in enhancing the endogenous release of IL-10 that lasts well into the time period after CPB termination. The enhancement of endotoxin-induced IL-10 release is not unique to glucocorticoids [5] and aprotinin. The methylxanthines [24] and epinephrine [25] also enhance endotoxin-induced IL-10 production and release in murine and human sepsis models, respectively.

In summary, this study demonstrates an endogenous CPB-induced release of the antiinflammatory cytokine IL-10 that is enhanced by aprotinin therapy. This effect on the antiinflammatory cytokine IL-10 may explain some of the beneficial effects reported with aprotinin use during cardiac operations [1][19].

	References

Top Abstract Introduction Material and Methods Results Comment 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): Gary E. Hill Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hill, G. E. Articles by Pohorecki, R. Search for Related Content PubMed PubMed Citation Articles by Hill, G. E. Articles by Pohorecki, R.