The complement system includes a large number of plasma proteins, and it is activated by the classic and the alternative pathways during CPB. The exposure of blood to extracorporeal circuits activates the alternative pathway, which leads to the formation of C3a and C5a, and reversal of heparin with protamine activates the classical pathway that produces C4 and C2. Thus, C4 and C2 activation does not occur in patients undergoing off-pump surgery without protamine administration. By activation of the complement system, a number of active products increase the vascular permeability, mast cells and basophils release histamine, and white blood cells release free oxygen radicals and lysosomal enzymes. The complement system can be activated by contact of blood with extravascular surfaces, probably by way of the Hageman factor. Complement activation has also been shown during hemodialysis during exposure of blood to the dialysis membrane.

The extent of complement activation during CPB correlates with the severity of the operation and the development of complications. However, most clinical problems do not occur until the first or second postoperative days. CRP, one of the acute-phase proteins, has strong potency to activate complement. But it is not clear whether CRP contributes to complement activation during or after CPB. The duration of the CPB does not affect the final C3a level, but protamine administration has a strong effect. Pretreatment of the patient with steroids may decrease complement activation but does not prevent it completely.

Pulmonary sequestration of the polymorphonuclear leukocytes and neutropenia during CPB has been shown to be related to complement system activation. Thus, activation of the complement system is involved in production of pulmonary edema. Once the complement system has been activated, pulmonary neutrophil migration occurs, neutrophil-mediated pulmonary endothelial injury begins, pulmonary vascular permeability increases, and reactive oxygen radicals may contribute to the adverse effects of CPB on pulmonary function.

Cytokines are a kind of protein produced by immune system cells. Myocardium, lungs and kidneys play a role in sequestrating proinflammatory cytokines. These cytokines may damage them in the presence of hypoperfusion [1]. They include interleukins (IL), tumor necrosis factor-α (TNFα), and transforming growth factor-β. They need to bind specific receptors to activate cells, and they can affect autocrine (effective in its own cell), paracrine (effective in the neighboring cells), and endocrine (effective in the remote cells). Proinflammatory cytokines are increased in pulmonary venous blood [2].

Interleukin–1: Its main role is a mediator in the inflammatory response. It has a chemotactic effect for macrophages and neutrophils. It also causes fever via central nervous system effects.

Interleukin–2: Mainly, this is produced from T-helper cells. Its most important role is proliferation of T-cells.

Interleukin–6: This is produced by macrophages, monocytes, fibroblasts, and endothelial cells. IL-6 is a proinflammatory cytokine. It has effects on proliferation of B-cells. Its most important effect is the coordination of the generalized systemic inflammatory response, and it is one of the acute phase reactants [3]. IL-6 has been accepted as the best proinflammatory cytokine predictor of LV systolic dysfunction and myocardial ischemia [4]. IL-6 levels rise in cardiac surgery with extracorporeal circulation [5].

Interleukin–8: This is produced by macrophages, monocytes, fibroblasts, and endothelial cells. It is an activator of neutrophils, and it has a chemotactic effect on neutrophils. IL-8 levels rise in cardiac operations with using CPB [5].

Tumor necrosis–alpha (TNF–α): This is mainly produced by activated macrophages. It is produced by activated monocytes and plays a very significant role in inflammation [6]. During CPB, its plasma levels have been shown to rise [7]. It is a powerful activator of neutrophils and phagocytes. It causes fever, hypoglycemia, and vasodilatation, and it stimulates the coagulation cascade. TNF-α can directly cause hypotension, coagulopathy, and renal dysfunction [8].

Platelet–activating factor (PAF): This is a phospholipid released from endothelial cells. It has strong vasoactive effects And causes the release of cytokines.

Leukotriene: This causes endothelial cell contraction and increases capillary leakage.

Thromboxane A ₂ : This is derived from macrophages and platelets. It has forcing effects on platelet aggregation and causes vasoconstriction and thrombosis.

These products increase permeability via its effect on membrane lipids, and they cause organ dysfunction. Hyperoxic CPB is widely used during cardiac operations, but it induces oxygen-derived free radicals. These products represent a potential risk for the myocardium and lungs [9, 10].

Endotoxins have very strong effects on the inflammatory cascade during cardiac surgery. It has been shown that there is a significant increase of endotoxin levels during CPB. Extracorporeal circulation, pulmonary arterial catheters, intravenous fluid administration, and blood transfusions are believed to be responsible for endotoxemia. The presence of circulating endotoxins is a major stimulus for producing TNF-α. In addition, endotoxins activate the complement system and cause the release of some cytokines. During CPB, splanchnic hypoperfusion can result in increased permeability of the gut mucosal barrier and consequently endotoxemia. Endotoxemia causes the release of inflammatory and antiinflammatory mediators [11].

Many investigations have shown that the amount of bradykinin increases during CPB. Because the lungs play a primary role in the elimination of bradykinin, reduced pulmonary ­circulation causes reduced bradykinin elimination during CPB. Bradykinin is a powerful vasodilator, and this effect has great importance in the body’s inflammatory response to CPB.

Exposure of blood to the extracorporeal circuit activates the contact system because the CPB circuit lacks endothelial cells. Although coagulation is largely inhibited by administering heparin during CPB, its activation cannot be ­completely prevented. Due to incomplete inhibition of the coagulation cascade by heparin, small amounts of fibrin are present during routine CPB. Because of this process, some of the coagulation factor levels are reduced by the end of CPB.

The coagulation system has two pathways: intrinsic (contact activation) and extrinsic. The intrinsic pathway is activated by the Hageman factor, and at the end of this pathway, thrombin is produced. The intrinsic pathway is mostly activated by tissue damage. The extrinsic pathway is activated by infection and systemic inflammation. Activation of the coagulation system is not only important for cloth formation, it is also important for the proinflammatory response.

The fibrinolytic cascade may be initiated by activation of the Hageman factor during CPB. Kallikrein is produced by activation of the Hageman factor, and it facilitates the conversion of plasminogen to plasmin.

During CPB, the lungs are the major site of synthesis, release, and degradation of the eicosanoids (products of the arachidonic acid cascade). Prostacyclin and prostaglandin E₂ production appears to be increased during CPB, and they can cause pulmonary vasodilation, while leukotriene-C4 and thromboxane tend to cause vasoconstriction. It is believed that thromboxane-A₂ is mostly produced by platelets, but its release occurs in the lungs. Platelet-activating factor (PAF) is another factor in the arachidonic acid cascade, and it is an important mediator of the inflammatory response. Leukotriene-B₄ is another product of this cascade and promotes plasma leakage and leukocyte adhesion; it is also increased after CPB.