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Ann Thorac Surg 2003;75:S715-S720
© 2003 The Society of Thoracic Surgeons

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II: Surgical myocardial protection

Inflammatory response to cardiopulmonary bypass

^a Department of Anesthesiology, Emory University School of Medicine, Division of Cardiothoracic Anesthesiology and Critical Care, Emory Healthcare, Atlanta, Georgia, USA

* Address reprint requests to Dr Levy, Department of Anesthesiology, Emory University Hospital, 1364 Clifton Rd, NE, Atlanta, GA 30322, USA.
e-mail: jerrold_levy{at}emoryhealthcare.org

Presented at the 3^rd International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, June 2–6, 2002.

Abstract

Inflammation in cardiac surgical patients is produced by complex humoral and cellular interactions with numerous pathways including activation, generation, or expression of thrombin, complement, cytokines, neutrophils, adhesion molecules, mast cells, and multiple inflammatory mediators. Because of the redundancy of the inflammatory cascades, profound amplification occurs to produce multiorgan system dysfunction that can manifest as coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency, and neurocognitive defects. Coagulation and inflammation are also closely linked through networks of both humoral and cellular components including proteases of the clotting and fibrinolytic cascades, including tissue factor. Vascular endothelial cells also mediate inflammation and the cross talk between coagulation and inflammation. Novel antiinflammatory agents inhibit these processes by several mechanisms such as preventing proteolysis of the protease-activated receptor (aprotinin), inhibiting complement-mediated injury (pexelizumab), or inhibiting contact activation (kallikrein inhibitors). Surgery alone also activates specific hemostatic responses, activation of immune mechanisms, and inflammatory response mediated by the release of various cytokines and chemokines. Novel agents are under investigation to further improve outcomes in cardiac surgical patients.

Inflammation is a protective response of vascularized tissue that functions as part of normal host surveillance mechanisms to destroy or quarantine both harmful agents and damaged tissue [1–4]. The hallmark of an inflammatory response is the complex humoral and cellular interaction with numerous pathways contributing to inflammation including activation, generation, or expression of thrombin, complement, cytokines, neutrophils, adhesion molecules, and multiple inflammatory mediators [5, 6]. Because of the redundancy of the inflammatory cascades, profound amplification occurs to produce multiorgan system dysfunction. Clinically we may see these inflammatory manifestations as coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency, and neurocognitive defects [7]. Further, the inflammatory response that occurs during cardiopulmonary bypass (CPB) has been often referred to as a systemic inflammatory response syndrome (SIRS) similar to sepsis and part of the rationale for off-pump coronary artery bypass (OPCAB) grafting is to avoid the inflammatory effects of CPB [8, 9]. Although several reviews have discussed inflammation and CPB, this review will focus on some of the novel aspects of inflammation and review some of the additional cells that may be involved, including potential therapeutic approaches to prevention.

Coagulation and inflammation

Doctor Levy discloses that he has received research support and is a consultant to Bayer, Genzyme, Dyax, and Alexion.

 

The activation of coagulation and inflammation is closely linked through a network of both humoral and cellularcomponents including proteases of the clotting and fibrinolytic cascades (especially tissue factor) [4, 9–12]. Inflammation-induced thrombin generation can occur through tissue factor (TF) because TF is expressed on cytokine-activated mononuclear cells, which mediate a pivotal role in the host defense responses. Coagulation is activated as a central element of a both local but also a systemic response to inflammation [13, 14]. Several of the key coagulation components and their products have proinflammatory effects including thrombin and factor Xa. Thrombin also has direct chemoattractant activity for polymorphonuclear leukocytes and monocytes and is a potent activator of mast cells [15–17]. Vascular endothelial cells perform a pivotal role in mediating responses to systemic inflammation and the cross talk between coagulation and inflammation [18, 19]. Endothelial cells respond to the cytokines expressed and released by activated leukocytes but can also release cytokines themselves [20–22]. Furthermore, endothelial cells are able to express adhesion molecules and growth factors that may not only promote the inflammatory response further but also affect the coagulation response.

Thrombin

Thrombin plays a pivotal role in signaling inflammatory processes (Fig 1). After endothelial damage, as described above, tissue factor is expressed and through factor VIIa binding, thrombin is generated. Thrombin can induce a variety of cellular responses involved in inflammationand is also a very potent activator of endothelial cells, increasing the expression of P-selectin and causing neutrophil adherence, activation and subsequent (neutrophil-mediated) damage to the endothelium [21–23]. Thrombin receptor activation on leukocytes increases the release of chemotactic and inflammatory cytokines [21–25]. Thrombin also directly activates protease-activated receptors (PARs). Protease-activated receptors are G-protein–coupled receptors that use a novel mechanism of extracellular proteolytic cleavage that is translated into a transmembrane signal. The roles of PARs in thrombosis and inflammation have been reviewed elsewhere [26].

View larger version (96K): [in this window] [in a new window]   Fig 1. Pivotal role of thrombin in the mechanisms and effects of excessive hemostatic activation with cardiac surgery. The coagulation system, a complex web of interactions, is subdivided into three pathways: intrinsic or contact (enclosed by small dashed line), extrinsic or tissue factor (enclosed by a large dashed line), and common (enclosed by a solid line); the conversion of factor X to Xa is within all three pathways (enclosed by a solid thick line). Dashed lines designate release of protein cleavage by-products. Activated factors are designated using a small "a" whereas inactivated factors are designated using a small "i." (XII = factor XII; VII = factor VII; X = factor X; VIII = factor VIII; IX = factor IX; V = factor V; XIII = factor XIII; PT 1.2 = prothrombin fragment 1.2; Ca2+ = calcium ions; FPA = fibrinopeptide A; PL = phospholipid; PAP = plasmin-antiplasmin complexes; EC = endothelial cells; tPA:PAI1 = tPA-PAI1 complexes; fibrin (m) = fibrin monomer; fibrin (p) = fibrin polynomer; fibrin (L) = fibrin cross-linked polymer; PAI1 = plasminogen activator inhibitor; tPA = tissue plasminogen activator; D-dimer = polymerized fibrin degradation products.) *Designates endothelial cell related. Reprinted from Despotis GJ et al, Anesthesiology; 1999;91:1122–51, with permission.

Inflammation associated with ischemia reperfusion injury

The adverse effects of ischemia-reperfusion (I/R) injury range from reversible postischemic organ dysfunction to permanent tissue damage including myocellular necrosis [33–35]. Ischemia-reperfusion injury is associated with an acute inflammatory response that is mediated by cytokines, chemokines, and adhesion molecules that recruitment of neutrophils, monocytes, and other inflammatory cells that lead to damage of ischemic myocardium. TF and thrombin generation activation can occur after I/R injury that may be independent of fibrin deposition [35] Thrombin can contribute to local inflammation and tissue damage by activation of a family of protease-activated receptors [36, 37] that stimulate cells to express cytokines such as interleukin (IL)-1 and IL-6, chemokines such as IL-8 and monocyte chemotactic protein-1 (MCP-1), and adhesion molecules such as P-selectin, E-selectin, and ICAM-1 [21–22, 36–38].

Inflammatory cells

Multiple cells are involved in the inflammatory response. Neutrophils represent the major inflammatory cell of inflammatory responses during sepsis, system inflammatory responses, and cardiopulmonary bypass and their role has been reviewed extensively. Other cells including mast cells and basophils are also involved in acute inflammation and may also be involved in inflammatory responses in cardiac surgical patients.

Mast cells are tissue fixed inflammatory cells that have a ubiquitous distribution in the perivascular spaces of the circulation, including the heart, lung, and skin. When activated, mast cells release a "pharmacopoeia" of mediators that affect multiple cell types including vascular endothelial cells, inflammatory cells, and vascular smooth muscle [39]. Mast cells have been suggested to play important roles in a series of inflammatory and proliferative disorders. The release of mast cell mediators by multiple stimuli may play a pivotal role in host defense. Mast cell-derived mediators can produce multiple proinflammatory effects. Histamine enhances both fibroblast proliferation and collagen synthesis; tryptase and chymase can digest multiple cellular components; and cytokines such as tumor necrosis factor, IL-4, and growth factors have effects on multiple cell types [39]. Mast cells therefore may play a pivotal role in linking coagulation and inflammation [10–20]. A spectrum of molecular structures can degranulate mast cells by multiple complex pathways that may not be different than pathologic activation by IgE. Mast cells and basophils also play a pivotal role in inflammatory processes [40–42].

Basophils share several notable features with the polymorphonuclear leukocytes but are distinctly different cell types. Both mast cells and basophils contain dense metachromatic cytoplasmic granules that contain stored inflammatory mediators including histamine and other potent chemical mediators that have been implicated in a wide variety of inflammatory processes [1]; they also constitutively express plasma membrane receptors that bind with IgE antibodies [45, 46]. Mature basophils are differentiated circulating polymorphonuclear leukocytes that can infiltrate tissues during inflammatory processes [45]. Mature mast cells are fixed in the perivascular areas of certain tissues (eg, skin, heart, lung, intestine).

Cardiopulmonary bypass and systemic inflammatory response syndrome

Cardiopulmonary bypass has often been compared with the pathophysiologic changes occurring in sepsis or systemic inflammatory response syndrome (SIRS) [47, 48] Disseminated intravascular coagulation (DIC) results after SIRS and can occur following cardiopulmonary bypass. In DIC, overactivation of thrombin or clotting or both leads to bleeding complications due to depletion of coagulation proteins, platelets, and endothelial dysfunction to produce microvascular dysfunction and a thrombotic state. DIC is characterized by decreased platelet counts, low fibrinogen, elevated PT and PTT, and elevated D-dimer levels, changes that can also occur in the pharmacologically naive patient who undergoes CPB [49, 50]. Acquired ATIII deficiency in the perioperative cardiac surgical period may be related to the preoperative use of heparin, the effects of hemodilution, and CPB-related consumption. ATIII levels as low as 40% to 50% activity, which are similar to levels observed with heterozygous hereditary deficiency, are commonly seen during CPB [51, 52]. Because the data in DIC suggest ATIII may play a major role in reducing inflammation and end-organ dysfunction, we have further expanded this consideration to cardiac surgical patients and are investigating whether ATIII represents a important therapeutic intervention that alone or in conjunction with other therapies may further reduce the inflammatory sequelae [53, 54].

Complement/neutrophil activation

Polymorphonuclear leukocyte (neutrophil) activation can occur following complement activation by immunologic (antibody mediated: IgM, IgG-antigen activation) or nonimmunologic (heparin-protamine, endotoxin) pathways [1]. C5a interacts with specific high-affinity receptors on white blood cells and platelets, initiating leukocyte chemotaxis, aggregation, and activation. Investigators have implicated polymorphonuclear leukocyte activation in producing the clinical manifestations of transfusion reactions, pulmonary vasoconstriction following protamine reactions, and transfusion related acute lung injury (TRALI). New anticomplement strategies using a monoclonal antibody (Pexelizumab) against C5a represent a promising modality of antiinflammatory therapy [55].

Therapeutic approaches to the inflammatory response

Therapeutic strategies can be directed at modulating multiple aspects of the inflammatory response including coagulation, contact activation, cytokines, neutrophils, intracellular molecular targets, and surface protein strategies (eg, adhesion molecules) [57–60]. Aprotinin is a serine protease inhibitor derived from bovine lung that inhibits trypsin, chymotrypsin, plasmin, tissue plasminogen activator, and kallikrein. The precise mechanism of action of aprotinin in reducing blood loss and transfusion requirement is not clear but there appears to be a dose dependency in its antiinflammatory effects. Reduction of allogeneic blood transfusions are also important as part of antiinflammatory strategies and aprotinin has been shown to consistently reduce bleeding and the need for transfusions. Although corticosteroids have been studied as antiinflammatory agents, controlled, placebo-controlled studies have not demonstrated efficacy in cardiac surgical patients although these agents are indicated in patients with asthma and reactive airway disease [57, 58]. Aprotinin has a different mechanism of action and may attenuate other aspects of the inflammatory response to CPB, including inhibiting neutrophil adhesion and activation. Aprotinin has been demonstrated to be highly effective in reducing bleeding and transfusion requirements in high-risk patients undergoing repeat median sternotomy or in patients who are taking aspirin. Results from multicenter studies of aprotinin show there is no greater risk of early graft thrombosis, myocardial infarction (MI), or renal failure in aprotinin-treated patients [59–61]. From the study of aprotinin in repeat coronary artery surgery, the incidence of stroke was significantly lower among aprotinin-treated patients [59].

Aprotinin and protease-activated receptors

Aprotinin is generally regarded to be an effective hemostatic agent; however, aprotinin has been suggested to be simultaneously hemostatic and antithrombotic [61]. Poullis and associates [61, 62] reported that aprotinin achieves these two apparently disparate properties by selectively blocking the proteolytically activated thrombin receptor on platelets, the protease-activated receptor 1 (PAR1), while leaving other mechanisms of platelet aggregation unaffected. Aprotinin also appears to affect novel antiinflammatory targets. Aprotinin has been shown to exert an antiinflammatory effect by preventing the capacity of leukocytes to transmigrate through vascular endothelium [63, 64]. Aprotinin also inhibits intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, but not E-selectin, expression on tumor necrosis factor-–activated endothelial cells and that transendothelial migration (leukocyte extravasation) by neutrophils is also specifically suppressed under these conditions. Aprotinin inhibits thrombin-induced platelet activation by preventing proteolysis of the PAR1 receptor [62–64]. These findings argue against aprotinin being prothrombotic and suggest instead that aprotinin may have significant antithrombotic effects.

Off-pump surgery and inflammation

The rational for OPCAB in part is to reduce the inflammatory response associated with CPB. However, multiple factors are responsible for the inflammatory injury in addition to CPB that include surgical trauma, ischemia/reperfusion injury, and thrombin activation. Surgery alone activates specific hemostatic responses, activation of immune mechanisms, and inflammatory response mediated by the release of various cytokines and chemokines [65]. Comparing OPCAB with on-pump coronary artery bypass grafting (CABG) with respect to inflammatory response and hemostatic derangement is difficult: several potentially confounding factors like patient risk profile, protocol of heparin/protamine administration, different anesthesiologic techniques, threshold for blood transfusions complicate interpretation of the studies because transfusion alone can increase inflammatory mediators. Although a review of the literature suggests overall limitation of the inflammatory response in OPCAB surgery [66–81], there may not always be a direct correlation between different inflammatory markers and physiologic consequences. As complement activation is concerned, conflicting data exist. Serum levels of IL-6 have been shown to be similar in on-pump and off-pump patients [66]. This supports the concept that surgical injury per se (eg, sternotomy) triggers release of this reactant of the acute-phase response. However, IL-8 seems to be more directly related to CPB and limited available studies demonstrate consistently lower postoperative levels of this cytokine after off-pump surgery [67]. This observation may have important clinical implications, as IL-8 is not only involved in the regulation of neutrophil trafficking but also seems to participate in myocardial ischemic injury. In concert, lower levels of troponin I levels after off-pump interventions has been detected. Nevertheless it becomes very difficult to determine whether a reduced cytokine response may be directly translated into changes in clinical outcomes. Furthermore absolute perioperative values of inflammatory markers are probably less important than the balance between proinflammatory and antiinflammatory cytokines [1]. Since inflammatory and hemostatic cascades are also affected in OPCAB pharmacologic modulation may be justified as it is in on-pump CABG.

Summary and the future

Pivotal questions relating to antiinflammatory strategies include understanding the specific benefits of antiinflammatory therapies. Considerable time and money have been spent measuring mediator activation and assessing the effects of specific antagonists to many of the mediators involved but the improvement in end-organ injury has not been determined. At present we can measure a large number of inflammatory mediators with a variety of commercially available immunoassays. The other interesting question is on-pump versus off-pump surgery and whether it makes a difference in outcomes. The challenge for the future will be to identify a pharmacologic agent or other technique that will arrest the inflammatory cascade to prevent end-organ injury. The role of specific mediators and their potential antagonists plays a never-ending role in our potential to block and decrease inflammatory injury, coagulation, and ultimately improve patients’ outcomes. Future research will be directed at finding the unique pharmacologic and biologic agents or combinations that may effectively attenuate these pathologic responses [43, 44, 56].

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