1. Cytokine Responses to CPB Seoul National University Hospital Department of Thoracic & Cardiovascular Surgery

2. Cardiopulmonary Bypass  Cytokine responses 1. Role of the endotoxin release 2. Role of complement activation 3. Role of ischemia-reperfusion and the relationship with myocardial injury 4. Role of IL-10 & organ source of cytokines 5. Importance of temperature

3. Proinflammatory Cytokines  Roles of cytokines 1. Alter myocardial contractility (postischemic depression) 2.Alter peripheral circulation (reducing vascular tone) 3. Direct damaging effect to other organs (multiorgan failure) 4. Immunologic alterations in postoperative period

4. Circulating Adhesion Molecules  Causes of increased levels 1. Surgical injury, infections Production of cytokine damages endothelium. 2. Cardiac operation using CPB Release of cytokine Activation of coagulation cascade 3. Magnitude in noncardiac operation Interleukin-6 TNF-a  4. Anesthesia influence endothelial function Release of interleukin-6, & interleukin-1-b

5. Cardiopulmonary Bypass  Effect on the monocytes The procedure of CPB resulted in significant reduction of HLA-DR expression on CD14 bright and CD14 dim monocytes, lasting for at least 3 hours postoperatively. Decreased HLA-DR expression on circulating monocytes has been reported after major trauma or surgical intervention, as well as during the course of sepsis, reflecting monocyte deactivation. In addition, a predictive value of HLA-DR expression has been shown, with low HLA-DR expression correlating with poor outcome

6. Inflammatory Response  Role of monocytes Monocytes play a key role by releasing a variety of proteases, cytotoxic proteins, and oxidants leading to tissue damage and by producing proinflammatory and anti-inflammatory cytokines that might amplify or suppress the inflammatory reaction. The CD14 molecule is one of the most characteristic surface antigens of the monocyte lineage. Functionally, CD14 is a receptor for the complex of lipopolysaccharide and its binding protein. On the basis of the intensity of CD14 expression, blood monocytes can be separated into 2 subpopulations.

7. Function of Monocytes  As antigen-presenting cells They bear the class II glycoproteins of the major histocompatibility complex gene complex: human leukocyte antigen (HLA) DR, HLA-DP, and HLA-DQ. HLA-DR expression on monocytes is increased by interferon and granulocyte-macrophage colony- stimulating factor, whereas tumor necrosis factor, endotoxin, interleukin (IL) 10, and glucocorticoids downregulate HLA-DR expression. Decreased HLA-DR antigen expression on blood monocytes has been shown after severe trauma or major operations in adults correlating with the presence or the development of major infection.

8. Function of Monocytes  Expression of adhesion molecules In addition to their major histocompatibility complex class II molecules, monocytes express multiple surface adhesion molecules, including CD11b/CD18 (Mac-1). CD11b/CD18 is critical for adhesion and transendothelial migration Expression of CD11b/CD18 on circulating neutrophils is decreased in critically ill patients with SIRS and after CPB. Monocytes have the ability to orient and move along a chemical gradient. Chemokines are important mediators of chemotactic and migratory behavior.

9. Adhesion Molecules 1. Immunoglobulin superfamily 1) Vascular cell adhesion molecule-1 [ VCAM-1] 2) Intercellular adhesion molecule [ICAM-1, ICAM-2, ICAM-3] 2. Integrin family Lymphocyte functioning associated antigen 3. Selectins 1) E-selectin, Endothelial-leukocyte adhesion molecule [ ELAM-1] 2) L-selectIn Leukocyte-endothelial cell adhesion molecule 3) P-selectin Granule membrane protein 140 [GMP140] 4. Soluble isoforms of some adhesion molecules Circulating adhesion molecule

10. The Role of Endotoxin 1. Cardiopulmonary bypass can trigger the release of endotoxin. 2. CPB impairs gut barrier function and lead to increase gut permeability. 3. The endotoxin can act as a powerful trigger for release of cytokines such as TNF.

11. Cardiopulmonary Bypass  Role of complement activation 1. Complement is activated during CPB. a) Blood-air interfaces b) Blood-material interaction c) Formation of heparin-protamine complex 2. Activation by alternate (after onset of CPB) or classic pathway (after administration of protamine). 3. The degree of activation depends on the degree of trauma & duration of CPB.

12. Antiinflammatory Cytokine 1. Interleukin-10 is known to inhibit directly release of pro-inflammatory cytokines. 2. Interleukin-10 is known to exert indirectly anti-inflammatory effects by triggering the release of IL-1 receptor antagonist, & TNF soluble receptors 1 and 2. 3. Production may be also enhanced by pro-inflammatoy cytokines such as TNF.

13. Cardiopulmonary Bypass  Cytokine response 1. Cytokine release can be triggered by many factors during CPB, ischemia-reperfusion may play most important role. 2. The levels of tumor necrosis factor, IL-6, and IL-8 are correlated with duration of ischemia and the myocardium is a major source. 3. IL-10 levels are correlated with duration of CPB and the liver is a main source. 4. Steroid pretreatment is an effective intervention to inhibit release of pro-inflammatory cytokines and enhance IL-10 production.

14. Cardiopulmonary Bypass  Anticytokine strategies 1. Hemofiltration or ultrafiltration 2. Heparin bonding of bypass circuit 3. Pharmacologic intervention 1) Steroid administration 2) Aprotinin administration

15. Cardiopulmonary Bypass  Effect of steroids 1. The steroid may suppress the overreactions to extracorporeal circuits of complement system, complement-mediated activation of neutrophils, and cytokines. 2. Ultimately, steroids may reduce the risk of the postperfusion lung syndrome and have favorable effects. 3. Both CPB and steroids, however, are known to generate immunocompromised states.(suppression of T-cell function) 4. The hemodynamic benefits of steriod are negligible, whereas glucose tolerance is worsened during CPB.

16. Cardiopulmonary Bypass  Steroid administration 1. Reduce complement activation 2. Prevent cytokine release 1) Reduce TNF production after reperfusion 2) Inhibit production of IL-6, IL-8 3) Increase the release of IL-10 3. Increase endotoxin release which might counterbalance some of their effect 4. Increase IL-4 production which prolong graft survival