The Systemic Inflammatory Response to Cardiac Surgery

Received from the Department of Anesthesia and Intensive Care, University College Hospital, Galway, Ireland; the Department of Anesthesia, Intensive Care and Pain Medicine, St. Vincent's University Hospital, Dublin, Ireland; and the Department of Anesthesia and Perioperative Medicine, University of Western Ontario, London, Ontario, Canada.THE purpose of this review is to evaluate recent developments in our understanding of the inflammatory response to cardiac surgery. Scientific knowledge in this field is continually expanding, potentially significant advances are regularly reported, and this area constitutes a major interface of clinical and basic scientific research. The review is divided into four major sections. The first section describes the pathophysiology of the inflammatory response to cardiac surgery. Factors that influence the extent of the inflammatory response, including the immunomodulatory effects of drugs commonly administered perioperatively, are discussed in the second section. The third section examines the evidence that the inflammatory response contributes to adverse perioperative events, in particular organ dysfunction, while the final section evaluates potential therapeutic strategies to control this response. The review concludes with a summary of potential future research directions and key deficiencies in our knowledge regarding the inflammatory response to cardiac surgery.Inflammation is the body's response to tissue injury and is a rapid, highly amplified, controlled humoral and cellular response. 1While the term “sepsis” has classically been utilized to imply a clinical response to infection, a similar response may arise in the absence of infection. 2In fact, patients who appear to have sepsis but have negative microbial cultures have similar morbidity and mortality rates to the respective culture-positive populations. 3This has led to the understanding that this process is a generalized, nonspecific inflammatory response to injury and prompted a diagnostic reclassification of these events into a pathophysiologic continuum by the American College of Chest Physicians–Society of Critical Care Medicine Consensus Conference Committee in 1991 (table 1). 2The term “systemic inflammatory response syndrome” (SIRS) has been proposed to describe the entry point to this continuum, an entity that overlaps with normal postoperative physiology. 2SIRS is a nonspecific, generalized inflammatory process, independent of the causative factors, and is of importance for several reasons. It is a sensitive if nonspecific indicator of injury. The classification of severity of SIRS into uncomplicated SIRS, sepsis, severe sepsis, and septic shock based on the existence of documented infection or hypotension has prognostic significance. 3A frequent complication of SIRS is the development of organ dysfunction, including acute lung injury, shock, renal failure, and multiple organ dysfunction syndrome (MODS). Finally, long-term survival in patients developing SIRS may also be adversely affected. This is well documented in the context of sepsis, with the risk of death increased for up to 5 yr after the septic episode. 4Cardiac surgery provokes a vigorous inflammatory response, which has important clinical implications. In the report from the Society of Thoracic Surgeons National Database, 20% (22,000 patients) of “low-risk” patients developed postoperative complications. 5The incidence of MODS following cardiopulmonary bypass (CPB) was 11%, with a mortality rate of 41% in these patients in another study. 6Acquired multiple organ dysfunction is the best predictor of mortality in cardiac surgical patients who require prolonged postoperative mechanical ventilation. 6Many aspects of a patient's risk of serious perioperative complications are perceived as being relatively fixed (genotype, preoperative health status, surgical difficulty, etc. ), but the degree to which these may be improved (e.g. , hemodynamic optimization using pharmacologic or mechanical support) is still under assessment. The contribution of the inflammatory response to patient outcome is potentially remediable and therefore deserves attention.Factors influencing incidence, severity, and clinical outcome of the inflammatory response, and in particular the reasons why certain patients develop life-threatening perioperative complications, are currently not well understood. Three separate perspectives contribute to our understanding of the link between the inflammatory response and adverse clinical sequelae. First, the complex interaction of humoral proinflammatory and antiinflammatory molecules may influence the clinical presentation and course of SIRS, with the balance of proinflammatory and antiinflammatory cytokines determining the clinical course following cardiac surgery. 7Alternatively, changes in the time course, magnitude, or patterns of cytokine release following CPB may contribute to abnormalities in the inflammatory response to cardiac surgery.Second, a “multiple-hit” scenario may be seen, whereby serious sequelae develop after cardiac surgery as a result of adverse events, such as infection or ongoing organ hypoperfusion. 1,8The combination results in the conversion of an inherently self-limiting, tightly controlled homeostatic response to an uncontrolled destructive process resulting in organ dysfunction. 1,8,9Potential mechanistic insights into the pathophysiologic basis for multiple hits include the ability of CPB to “prime” neutrophils, causing pulmonary leukosequestration, 10and enhanced cytotoxin release following a subsequent insult. 10Third, it has been suggested that there may be a fundamental misconception about the inflammatory response. The proinflammatory state, SIRS, may be only one aspect of a multifaceted response. The converse has been termed the compensatory antiinflammatory response syndrome. 11CPB-induced generalized immunosuppression may play an important role in the development of infectious complications. 12Cumulatively, these responses represent the body's attempt to reestablish homeostasis and may clinically manifest as predominantly proinflammatory (SIRS), antiinflammatory (compensatory antiinflammatory response syndrome), or an intermediate mixed response. 11As perioperative physicians, anesthesiologists contribute to the management of the patient when adverse sequelae of CPB may pose a significant threat. Anesthesiologists are well positioned to minimize the risk of adverse sequelae resulting from the inflammatory response to CPB by reducing perioperative risk factors. Many drugs administered during the perioperative period, particularly for the purposes of anesthesia and sedation, possess potentially important immunomodulatory effects. Anesthesiologists may be best placed to properly evaluate and eventually implement therapeutic strategies, particularly as many potentially useful therapies seem poised to enter the clinical arena. Finally, a thorough knowledge of all aspects of the inflammatory response to CPB is mandatory if the anesthesiologist is to realize the goal of minimizing perioperative risk.Nonspecific activators of the inflammatory response include surgical trauma, blood loss or transfusion, and hypothermia. In addition, CPB may specifically activate the inflammatory response via at least three distinct mechanisms (fig. 1). One mechanism involves direct “contact activation” of the immune system following exposure of blood to the foreign surfaces of the CPB circuit. A second mechanism involves ischemia–reperfusion injury to the brain, 13,14heart, 14,15lungs, 16kidney 17,18and liver 19as a result of aortic cross-clamping. Restoration of perfusion on release of the aortic cross-clamp is associated with activation of key indices of the inflammatory response. 20,21Endotoxemia may indirectly activate the inflammatory cascade. Splanchnic hypoperfusion, a common finding during and following CPB, 22may damage the mucosal barrier, allowing gut translocation of endotoxin. 23,24Systemic endotoxin concentrations correlate closely with the degree of cardiovascular dysfunction following CPB, 25,26while low preoperative serum immunoglobulin M antiendotoxin core antibody concentrations predict poor outcome. 27However, the importance of endotoxin in stimulating the inflammatory response to cardiac surgery remains in doubt, with conflicting evidence regarding the importance of gut translocation. 26,28In fact, endotoxin may be a contaminant of fluids, such as cardioplegia and circuit priming fluid, routinely used during CPB. 29The sole study to examine the incidence and time sequence of splanchnic hypoperfusion (as measured by intramucosal pH), gut permeability, and endotoxemia during CPB found no association between mucosal acidosis and either endotoxemia or intestinal permeability. 30Complement is activated during extracorporeal circulation, reperfusion of ischemic tissues, and heparin neutralization with protamine. 31Exposure of blood to the foreign surface of the extracorporeal circuit results in direct “contact” activation of the complement cascade, predominantly via the alternate pathway (fig. 2). 20,32,33The blood–gas interface of the CPB circuit may also play a role in complement activation. 34The formation of heparin–protamine complexes activates the complement cascade mainly via the classic (C4a) pathway. 32,35In the first 5 days following cardiac surgery, a second delayed increase in complement activation products is seen. 36This delayed activation of complement appears to be mediated by C reactive protein in response to heparin–protamine complexes. 36The central role of complement in the inflammatory response to cardiac surgery has been demonstrated by the effects of complement-specific inhibitors. Soluble human complement receptor type 1 attenuates lung and myocardial injury, 37while blockade of C3a formation prevents activation of neutrophils, monocytes and platelets in models of CPB. 38Anti-C5a monoclonal antibodies attenuate CPB-mediated pulmonary, 39myocardial, 40mesenteric, 41and microvascular 39,40dysfunction. Specific blockade of the alternative pathway of complement activation by monoclonal antibodies to properdin causes near complete inhibition of C3a and C5b-9 formation and dramatically reduces platelet and neutrophil activation. 42Recombinant soluble complement receptor 1, 43C3-binding cyclic synthetic peptide, 44and antihuman C5 monoclonal antibody 45all prevent up-regulation of adhesion molecules necessary for neutrophils to bind to the CPB circuit and vascular endothelium, a necessary step in the injury process. Finally, increased plasma concentrations of C5b-9, a terminal complex of complement proteins C5 to C9, are seen during CPB (fig. 2). Selective blockade of C5b-9 formation by antihuman C8 monoclonal antibody inhibits platelet but not leukocyte activation in a model of simulated extracorporeal circulation. 46The degree of complement activation in patients undergoing CPB has clinical significance. The degree of postoperative pulmonary shunt correlates with activation of the classic pathway by protamine–heparin complexes. 47Postoperative levels of C4d–C-reactive protein, a specific marker for C-reactive protein–mediated activation of complement, correlate with the incidence of postoperative arrhythmia following coronary artery bypass graft (CABG). 35,36Postoperative C3a concentrations may predict the probability of cardiac, pulmonary, renal, and hemostatic dysfunction 48and the likelihood of developing MODS in children. 33Strategies that improve CPB circuit biocompatibility reduce indices of complement activation and may decrease postoperative morbidity, particularly in high-risk patients. 49Anti-C5a antibody, which reduces sC5b-9 formation, significantly reduces myocardial injury, blood loss, and postoperative cognitive deficits in patients undergoing CPB. 50Cytokines are soluble proteins and polypeptides that act as paracrine messengers of the immune system and are produced by a large variety of cell types, including activated monocytes, tissue macrophages, lymphocytes, and endothelial cells (fig. 3). Individual cytokines may exert either proinflammatory or antiinflammatory effects. Cytokines are essential for immunologic and physiologic homeostasis, are normally subject to tight homeostatic control, and are produced in response to a variety of physiologic and pathologic stimuli.Proinflammatory cytokines play a pivotal role in stimulating the inflammatory process, with plasma concentrations of specific cytokines, such as interleukin-1β (IL-1β) and interleukin-6 (IL-6), predictive of outcome in certain critically ill patient subgroups (table 2). 51Tumor necrosis factor α (TNF-α) and IL-1β are elevated early following cardiac surgery, with IL-6 and IL-8 peaking later. 52,53While a direct cause-and-effect relation has not been demonstrated, elevations of proinflammatory cytokines have been strongly associated with adverse outcome following cardiac surgery. Patients who develop SIRS demonstrate significant elevations in cytokine concentrations compared to patients with an uncomplicated course following cardiac surgery. 54Within the subgroup of cardiac surgical patients who develop SIRS, nonsurvivors had dramatically higher IL-8 and IL-18 concentrations compared to survivors. 54In addition, serum concentrations of IL-6 correlate with mortality following pediatric cardiac surgery. 55The proinflammatory cytokine response to cardiac surgery is balanced by a phased antiinflammatory cytokine response, with soluble cytokine receptors, cytokine receptor antagonists, and antiinflammatory cytokines also produced in large quantities (table 3). 52Key antiinflammatory cytokines include interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1ra), TNF soluble receptors 1 and 2 (TNFsr 1 and 2), and transforming growth factor β. IL-10 is a potent inhibitor of the production of TNF-α, IL-1β, IL-6, and IL-8. 56While the specific role of other antiinflammatory mediators remains undefined, it has been suggested the clinical prognosis following CPB may depend on the balance between proinflammatory and antiinflammatory cytokines. 7Nitric oxide (NO) is a ubiquitous biologic mediator that acts as a physiologic regulator and can be responsible for tissue damage. Physiologic regulatory functions include endothelial-mediated vasodilation in both the systemic and pulmonary circulations, potentially significant immunomodulatory functions, as well as protean roles in nociception, memory, and erectile function. 57NO may have several protective roles in the inflammatory response. NO-induced vasodilation may prevent accumulation of injurious mediators at the endothelium (fig. 3). NO may scavenge free radicals and prevent up-regulation of neutrophil CD11/CD18 adhesion molecules. 58Supplementation of cardioplegia and perfusate with an NO precursor (arginine) or NO donor (SPM-5185) has beneficial effects on postreperfusion neutrophil accumulation, endothelial function, and myocardial performance following experimental myocardial ischemia, 59possibly by inhibiting neutrophil adherence and cytotoxicity. The release of NO during CPB appears to be dependent on the type of bypass flow, with attenuation of basal NO release during nonpulsatile flow leading to end-organ functional capillary closure as a result of diminished vessel wall shear stress. 60,61This release of NO is considered to be physiologic, produced by endothelial constitutive NO synthase (cNOS), 60,62and its release appears to be a function of both the frequency and amplitude of the pulsatile flow. 63The role of NO in the inflammatory response is complex, however, and NO has several potentially deleterious actions. Cytokine-induced decrements of myocardial function appear to be related to increases in myocardial inducible NO synthase (iNOS), 64which is up-regulated by CPB. 65Prevention of myocardial iNOS up-regulation may reduce hemodynamic instability post-CPB, 65while NOS inhibition can reverse refractory hypotension in established shock. NO is a highly reactive free radical and combines with a variety of molecules in vivo . While the free radical scavenging role of NO is generally protective, 66NO may combine with the free radical superoxide to form peroxynitrite, a more reactive and injurious free radical. 66,67Finally, NO appears to be a powerful direct cellular toxin, inactivating enzymes involved in glycolysis, the Krebs cycle, and the electron transport chain 67and reducing intracellular adenosine triphosphate and antioxidant concentrations, hence predisposing to cell death.The timing, source, and quantities of NO produced may be the key to dissecting these apparently paradoxical roles. NO is produced constitutively in small (picomolar) quantities by cNOS isoforms, such as the vascular endothelial isoform (ecNOS). ecNOS plays a pivotal role in the physiologic regulation of basal vascular tone, blood flow capillary integrity, and leukocyte and platelet adhesiveness to the endothelium. 57The activity of ecNOS appears to be inhibited in the earliest phases of the inflammatory response, allowing both unopposed vasoconstrictive influences and increased leukocyte and platelet adhesion to the endothelium. However, within 4–8 h, iNOS is produced in a wide variety of tissues, including vascular smooth muscle, hepatocytes, and Kupffer cells, 67,68and produces NO at much higher (nanomolar) quantities. Cytokines, particularly IL-1β, play a pivotal role in the process of NO-induced inflammatory dilatation. 69The proinflammatory response, once fully developed, represents a high-output NO state. 67In fact, exhaled NO following initiation of CPB may represent an index of severity of the inflammatory response, 70although this has been disputed. 71The coagulation–fibrinolytic cascades and the inflammatory response, while in many respects separate processes, are closely interconnected, with activation of coagulation a key component of the acute inflammatory response and vice versa . In this context, inflammation and coagulation should perhaps be considered different facets of the same host response to injury.The coagulation system has traditionally been divided (for conceptual and practical purposes) into the intrinsic and extrinsic pathways, both of which lead to a final common pathway, and result, via thrombin generation, in the formation of an insoluble fibrin clot. Activation of coagulation after CPB had been thought to be predominantly due to activation of the intrinsic pathway via the contact system. In this paradigm, plasma factor XII was pivotal to this process, becoming adsorbed and activated on contact with the CPB circuit. However, patients with congenital deficiency of factor XII still generate thrombin following CPB. 72This suggests that the extrinsic pathway, which requires expression and activation of tissue factor, perhaps in response to inflammatory stimuli and oxidative or shear stress, may also be involved. 73Hemostasis is mediated by a balance of procoagulant and anticoagulant forces, which normally coexist in a delicate balance. The coagulation cascade consists of inactive circulating precursors, which are sequentially activated via enzymatic cleavage, yielding an active serine protease that hydrolyses the next factor in the cascade. Thrombin, the end product, catalyzes the formation of insoluble fibrin from fibrinogen, which form the strands that bind the platelet plug. This process is normally controlled and limited to discrete sites of injury by modulators, including plasminogen activators, thrombomodulin, proteins C and S, and serine protease inhibitors such as antithrombin III. 74The fibrinolytic cascade, activated during coagulation, results in the formation of plasmin, which splits fibrinogen and fibrin, remodelling the formed clot and later removing the thrombus when the endothelium heals.Several specific points regarding the complex interrelation between coagulation and inflammation, in the context of CPB, deserve attention. The endothelium is intricately involved in both processes (see Endothelium). Proinflammatory cytokines play a key role in initiating the coagulation process locally at sites of inflammation, by activation of the endothelium, induction of the expression of tissue factor, the expression of leukocyte adhesion molecules on the cell and stimulating production of factors. with of expression and of the fibrinolytic and protein C anticoagulant pathways, the balance between procoagulant and anticoagulant resulting in a procoagulant state. coagulation system in on the inflammatory response. activation at sites of tissue injury results in the release of multiple mediators that tissue key coagulation such as thrombin and factor have proinflammatory Thrombin, formed following activation of the coagulation cascade, several cell and which are responsible for the of the and the tissue process. and which are used to coagulation in all patients undergoing cardiac surgery, may have important immunomodulatory effects. appears to possess important antiinflammatory effects. neutralization of heparin may result in multiple cardiovascular including increased pulmonary artery and and blood myocardial cardiac and systemic vascular by has adverse the heparin–protamine complex is particularly The heparin–protamine interaction activates the inflammatory response by several including complement and oxide and antibody release of may result in severe pulmonary a of severe may result from the balance of and is in CPB patients. Activation of such as thrombin of anticoagulant drugs to CPB to prevent blood from on contact with the extracorporeal circuit. In addition, the of during CPB appears to contribute to the postoperative commonly seen in these patients. vascular injury following CPB may result in uncontrolled platelet thrombin generation, and resulting fibrin in the may flow and end-organ which may to MODS and vascular endothelium is a in cellular and organ function a barrier, as was once It is involved in a variety of physiologic and pathologic processes and has as the central of many of the biologic events that the perioperative course of the cardiac surgical The endothelium vascular and permeability, coagulation and and the of into of inflammation, the expression of surface proteins and of soluble inflammatory response to CPB is by a of endothelial activation and endothelial dysfunction. including and IL-1β, bind to specific receptors on the endothelium, initiating pathways, which in activate a specific of within the of the endothelial termed activation The factor plays a pivotal role in the process. it from the protein to the endothelial cell with specific and the of the basal resulting in the of the activation process results in the of including adhesion molecules (e.g. , adhesion and cytokines (e.g. , for endothelial cell a process that and at on the activated endothelial cell plays a pivotal role in the inflammatory and coagulation by proteins central to the activation of coagulation and cell adhesion expression the interaction between the neutrophil and the endothelial cell (see The resulting in neutrophil and This the endothelium, causing capillary and injury results in the expression of tissue factor, by IL-1β and TNF-α, which activates the extrinsic pathway of coagulation may result in addition, protein a key regulator of is in inflammatory by TNF-α, the balance a procoagulant state. endothelium plays a central role in the of following CPB. regulation of vascular (fig. is mediated via a variety of and such as factor, and increase in pulmonary vascular following CPB is to NO release from pulmonary endothelium is by NO complex between endothelial function, inflammation, and in the of adverse cardiovascular in NO appear to these particular the inflammatory response to cardiac surgery may increase the risk of a postoperative cardiac Proinflammatory cytokines and endotoxin can and the endothelium may its ability to to circulating or of demonstrate that IL-1β, TNF-α, and endotoxin prolonged but of endothelial termed cytokines production of NO and a of the and effects of NO may myocardial perfusion to unopposed and may the association between an acute inflammatory and a increase in the risk of a cardiovascular addition, endothelial dysfunction may the long-term of cardiac surgery, particularly by to the development of at graft sites as a result of by the of of including paradoxical responses , are in the earliest of coronary artery clinical demonstrate that this is associated with an increased rate of cardiovascular dysfunction activates the inflammatory response, and platelets to the which may the formation of process is particularly at sites of blood flow such as at graft is by the of dysfunction in patients is in large due to a of this which have been demonstrated to endothelial function, in by of endothelial function results in improved myocardial myocardial ischemia, and of process of adhesion is an essential component of the inflammatory response leading to endothelial damage and is well distinct phases of and adhesion (fig. the the leukocyte at with the in the of the In the first the neutrophil is to the state, in which it the endothelium. is mediated by the expression of a of adhesion molecules as and are on the endothelium, and is on the are involved in the formation of between the endothelium and the which the of the leukocyte the blood vessel on activation of the complement cascade following contact with the extracorporeal circulation, is a potent of is in and the plasma by after endothelial cell activation. may the in the pulmonary circulation, which following initiation of CPB. process of