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.

The Systemic Inflammatory Response

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). 2 

Table 1. Criteria for Diagnosis of SIRS, Sepsis, and MODS 2 

SIRS = systemic inflammatory response syndrome; MODS = multiple organ dysfunction syndrome.

Table 1. Criteria for Diagnosis of SIRS, Sepsis, and MODS 2
Table 1. Criteria for Diagnosis of SIRS, Sepsis, and MODS 2

The 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. 4 

The Inflammatory Response to Cardiac Surgery

Cardiac 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. 10 

Third, 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. 11 

Relevance to the Anesthesiologist

As 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.

Pathophysiology of the Inflammatory Response to Cardiac Surgery

Factors That Activate the Inflammatory Response

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. 20,21 

Fig. 1. Schematic diagram of the sequence of events by which cardiopulmonary bypass (CPB) may lead to the development of systemic inflammatory response syndrome (SIRS).

Fig. 1. Schematic diagram of the sequence of events by which cardiopulmonary bypass (CPB) may lead to the development of systemic inflammatory response syndrome (SIRS).

Endotoxemia 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. 30 

Key Components of the Inflammatory Response

The Complement Cascade.

Complement 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. 36 

Fig. 2. Schematic diagram of the complement cascade. Two major pathways of complement activation operate in plasma: the classic pathway requires Ag-Ab complexes for activation, while the alternative pathway can be directly activated, e.g. , by contact activation endotoxin or ischemia and reperfusion injury. C-reactive protein (CRP) may also activate complement, mainly via  the classic pathway. Both pathways then proceed through the sequential activation or binding of proteins termed components or factors, resulting in the assembly of a series of components. These assemblies are capable of activating the key component C3. C3a is a potent anaphylatotoxin, while C3b activates the final common pathway, leading to the formation of C5a, an anaphylatotoxin, and the terminal membrane attack complex. The terminal complex is capable of inserting itself into cell membrane lipid bilayers, allowing passage of water and ions, resulting in cell lysis. C4d-CRP, formed following CRP mediated activation of the cascade, is an index of the contribution of CRP to activation of the complement cascade.

Fig. 2. Schematic diagram of the complement cascade. Two major pathways of complement activation operate in plasma: the classic pathway requires Ag-Ab complexes for activation, while the alternative pathway can be directly activated, e.g. , by contact activation endotoxin or ischemia and reperfusion injury. C-reactive protein (CRP) may also activate complement, mainly via  the classic pathway. Both pathways then proceed through the sequential activation or binding of proteins termed components or factors, resulting in the assembly of a series of components. These assemblies are capable of activating the key component C3. C3a is a potent anaphylatotoxin, while C3b activates the final common pathway, leading to the formation of C5a, an anaphylatotoxin, and the terminal membrane attack complex. The terminal complex is capable of inserting itself into cell membrane lipid bilayers, allowing passage of water and ions, resulting in cell lysis. C4d-CRP, formed following CRP mediated activation of the cascade, is an index of the contribution of CRP to activation of the complement cascade.

The 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. 46 

The 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. 50 

The Cytokine Cascade.

Cytokines 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.

Fig. 3. This schematic diagram depicts the role of the endothelium in the regulation of vascular tone and illustrates important early events known to occur in systemic inflammatory response syndrome (SIRS) at the level of the endothelium. The endothelium regulates local vascular tone and adapts organ blood flow to metabolic needs, by altering the balance of 4 key mediators: nitric oxide (NO), prostacyclin (PGI2), thromboxane (TXA2), and endothelin (ET). Endotoxin (lipopolysaccharide [LPS]) binds to macrophages to release cytokines, which bind to and activate the endothelium. This increases production of these vasoactive agents, in particular NO, by up-regulating the inducible form of NO synthase (iNOS). This alters the dynamic balance of these 4 vasoactive agents over time and appears to play a central role in the hemodynamic sequelae of SIRS. cNOS = constitutive form of NOS; COX-1 = cyclooxygenase 1; COX-2 = cyclooxygenase 2; PLA2= phospholipase 2; AA = arachidonic acid; l-ARG = l-arginine; pro-ET = proendothelin; ECE = endothelin-converting enzyme.

Fig. 3. This schematic diagram depicts the role of the endothelium in the regulation of vascular tone and illustrates important early events known to occur in systemic inflammatory response syndrome (SIRS) at the level of the endothelium. The endothelium regulates local vascular tone and adapts organ blood flow to metabolic needs, by altering the balance of 4 key mediators: nitric oxide (NO), prostacyclin (PGI2), thromboxane (TXA2), and endothelin (ET). Endotoxin (lipopolysaccharide [LPS]) binds to macrophages to release cytokines, which bind to and activate the endothelium. This increases production of these vasoactive agents, in particular NO, by up-regulating the inducible form of NO synthase (iNOS). This alters the dynamic balance of these 4 vasoactive agents over time and appears to play a central role in the hemodynamic sequelae of SIRS. cNOS = constitutive form of NOS; COX-1 = cyclooxygenase 1; COX-2 = cyclooxygenase 2; PLA2= phospholipase 2; AA = arachidonic acid; l-ARG = l-arginine; pro-ET = proendothelin; ECE = endothelin-converting enzyme.

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. 55 

Table 2. Key Proinflammatory Cytokines in the Immune Response to Cardiac Surgery

TNF-α= tumor necrosis factor α; IL = interleukin; SIRS = systemic inflammatory response syndrome; iNOS = inducible nitric oxide synthase.

Table 2. Key Proinflammatory Cytokines in the Immune Response to Cardiac Surgery
Table 2. Key Proinflammatory Cytokines in the Immune Response to Cardiac Surgery

The 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. 7 

Table 3. Key Antiinflammatory Cytokines in the Immune Response to Cardiac Surgery

IL = interleukin; TNF-α= tumor necrosis factor α; HLA = human leukocyte antigen; CPB = cardiopulmonary bypass; TGF-β= transforming growth factor β; IL-1ra = interleukin 1 receptor antagonist; TNFsr = tumor necrosis factor soluble receptor.

Table 3. Key Antiinflammatory Cytokines in the Immune Response to Cardiac Surgery
Table 3. Key Antiinflammatory Cytokines in the Immune Response to Cardiac Surgery

Nitric Oxide.

Nitric 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. 63 

The 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. 71 

Coagulation–Fibrinolytic Cascades.

The 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. 73 

Hemostasis 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, eliciting the expression of leukocyte adhesion molecules on the intravascular cell surfaces, and stimulating production of platelet-activating factors. 75,76This, combined with down-regulation of thrombomodulin expression and of the fibrinolytic and protein C anticoagulant pathways, alters the balance between procoagulant and anticoagulant activities, resulting in a markedly procoagulant state. 75,76 

The coagulation system in turn impacts on the inflammatory response. Platelet activation at sites of tissue injury results in the release of multiple mediators that alter tissue integrity. Several key coagulation proteins, such as thrombin and factor Xa, have proinflammatory properties. Thrombin, formed following activation of the coagulation cascade, stimulates several cell chemotaxins and mitogens, which are responsible for the spreading of the lesion and the tissue repair process. 75,76 

Heparin and protamine, which are used to modulate coagulation in almost all patients undergoing cardiac surgery, may have important immunomodulatory effects. 32,77Heparin appears to possess important antiinflammatory effects. 77Protamine neutralization of heparin may result in multiple cardiovascular effects, including increased pulmonary artery pressures and decreased systolic and diastolic blood pressure, myocardial oxygen consumption, cardiac output, heart rate, and systemic vascular resistance. 78Although protamine by itself has adverse effects, the heparin–protamine complex is particularly deleterious. The heparin–protamine interaction activates the inflammatory response by several mechanisms, including complement activation, histamine release, thromboxane and nitric oxide production, and antibody formation. 78The release of thromboxane may result in severe pulmonary hypertension. 78In a minority of patients, severe anaphylactoid reactions may result from the heparin– protamine interaction.

The balance of procoagulants and anticoagulants is profoundly disturbed in CPB patients. Activation of procoagulants such as thrombin mandates administration of anticoagulant drugs prior to CPB to prevent blood from clotting instantly on contact with the extracorporeal circuit. In addition, the stimulation of fibrinolysis during CPB appears to contribute to the postoperative coagulopathy commonly seen in these patients. 79Widespread vascular injury following CPB may result in uncontrolled platelet activation, thrombin generation, and disseminated intravascular coagulation. 80The resulting widespread fibrin deposition in the microvasculature may occlude microcirculatory flow and cause end-organ damage, which may progress to MODS and death. 80 

The Endothelium.

The vascular endothelium is a dynamic participant in cellular and organ function rather than a static barrier, as was once believed. It is intimately involved in a variety of physiologic and pathologic processes and has emerged as the central focus of many of the biologic events that affect the perioperative course of the cardiac surgical patient. The endothelium controls vascular tone and permeability, regulates coagulation and thrombosis, and directs the passage of leukocytes into areas of inflammation, through the expression of surface proteins and secretion of soluble mediators.

The inflammatory response to CPB is characterized by a state of widespread endothelial activation and diffuse endothelial dysfunction. 70Inflammatory mediators, including TNF-α and IL-1β, bind to specific receptors on the endothelium, initiating diverse signal transduction pathways, which in turn activate a specific set of genes within the nucleus of the endothelial cell, termed activation genes. The transcription factor NF-κB plays a pivotal role in the signal transduction process. When activated, it dissociates from the cytosolic inhibitory protein IκB, translocates to the endothelial cell nucleus, binds with specific DNA sequences, and alters the conformation of the basal transcriptional apparatus, resulting in the transcription of the activation genes. 81This process results in the translation of proteins, including adhesion molecules (e.g. , E-selectin, intercellular adhesion molecule-1) and cytokines (e.g. , IL-8), required for endothelial cell activation, a process that takes approximately 4 h and peaks at 8–24 h depending on the gene. 73 

The activated endothelial cell plays a pivotal role in linking the inflammatory and coagulation systems, by expressing proteins central to the activation of coagulation and inflammation. 73,76Endothelial cell adhesion molecule expression mediates the interaction between the neutrophil and the endothelial cell (see The Cellular Immune Response), resulting in neutrophil adhesion, activation, and degranulation. This further damages the endothelium, causing diffuse capillary leak and edema formation. 73,82Endothelial injury results in the expression of tissue factor, augmented by IL-1β and TNF-α, which activates the extrinsic pathway of coagulation 76and may result in disseminated intravascular coagulation. 75In addition, protein C, a key inhibitory regulator of hemostasis, is antagonized in inflammatory states, most probably by TNF-α, further shifting the balance toward a procoagulant state. 76 

Vascular endothelium plays a central role in the pathogenesis of microcirculatory derangement following CPB. Endothelial regulation of local vascular tone (fig. 3) is mediated via  a variety of endothelium-derived relaxing and contracting factors such as NO, prostacyclin, endothelium-derived hyperpolarizing factor, endothelin, and thromboxane A2. 83The increase in pulmonary vascular resistance following CPB is attributed to reduced NO release from dysfunctional pulmonary endothelium 70and is reversed by NO supplementation. 84 

A complex interplay exists between impaired endothelial function, inflammation, and atherosclerosis in the pathogenesis of adverse cardiovascular events. 85,86Alterations in NO generation appear to underpin these interrelationships. 86Of particular concern, the inflammatory response to cardiac surgery may increase the risk of a postoperative cardiac event. Proinflammatory cytokines and endotoxin can impair endothelium-dependent dilatation, and the endothelium may lose its ability to respond to circulating hormones or autacoids. 69,86Studies of forearm vasoregulation demonstrate that IL-1β, TNF-α, and endotoxin 87,88cause prolonged but reversible impairment of endothelial relaxation, termed “endothelial stunning.”88,89Proinflammatory cytokines inhibit production of NO and a vasodilator antiplatelet prostanoid. 87Loss of the vasodilator and antithrombotic effects of NO may alter myocardial perfusion 88and expose preexisting atheroma to unopposed vasospastic and prothrombotic influences. 86This may explain the association between an acute inflammatory episode and a transient increase in the risk of a cardiovascular event. 89 

In addition, endothelial dysfunction may limit the long-term success of cardiac surgery, particularly CABG, by contributing to the development of narrowing at graft anastomotic sites as a result of medial hyperplasia 85and by accelerating the progression of atherosclerosis. Abnormalities of endothelium-dependent vasodilation, including paradoxical vasoconstrictor responses to, e.g. , exercise, are often observed in the earliest stages of coronary artery disease. 85Long-term follow-up clinical studies demonstrate that this is associated with an increased rate of cardiovascular events. 90Endothelial dysfunction activates the inflammatory response, recruiting leukocytes and platelets to the arterial wall, which may initiate the formation of atherosclerotic plaque. 85,89This process is particularly likely at sites of disturbed blood flow such as occur at graft anastomoses 91and is markedly potentiated by the presence of hypercholesterolemia. Endothelial dysfunction in hypercholesterolemic patients is in large part due to a reduced bioavailability of NO. 92In this regard, statins, which lower cholesterol, have been demonstrated to rapidly restore endothelial function, in part by directly up-regulating eNOS. 85This restoration of endothelial function results in improved myocardial perfusion, reduced myocardial ischemia, and reversal of atherosclerosis. 85 

The Cellular Immune Response.

The process of neutrophil–endothelial adhesion is an essential component of the inflammatory response leading to widespread endothelial damage and is now well understood, involving distinct phases of primary and secondary adhesion (fig. 4). 82In the noninflamed state the leukocyte travels at around 1,000 μm/s, along with the erythrocytes, in the center of the postcapillary venule. In the first phase, primary adhesion, the freely moving neutrophil is converted to the “rolling” state, in which it tumbles slowly (around 30 μm/s) along the endothelium. 82This is mediated by the expression of a family of adhesion molecules known as selectins. P- and E-selectin are expressed on the endothelium, and L-selectin is expressed on the neutrophils. These are involved in the formation of loose bonds between the endothelium and the neutrophil, which slows down the passage of the leukocyte along the blood vessel wall. C5a, released on activation of the complement cascade following contact with the extracorporeal circulation, is a potent stimulant of P-selectin expression. 93P-selectin is stored preformed in cytoplasmic vacuoles (the Weibel Palade Bodies) and rapidly reaches the plasma membrane by exocytosis after endothelial cell activation. 94This may underlie the sudden leukosequestration in the pulmonary circulation, which occurs following initiation of CPB. 93This process of primary adhesion is later maintained by E-selectin, which must be produced de novo  by the activated endothelium. 73 

Fig. 4. This schematic diagram illustrates the neutrophil–endothelium interaction. Each neutrophil illustrates a key event, as it proceeds from from left to right along the capillary. Briefly, neutrophils become tightly adherent to the endothelium in a 3-stage process. In the first stage, the freely moving neutrophil is converted to the “rolling” state, in which it moves slowly along the endothelium. The neutrophil loosely interacts with the endothelium via  the expression of selectins on both the neutrophil and endothelial cell membranes. In the second stage, the expression of integrins on neutrophil and endothelium results in a tighter binding to the capillary wall. In the third stage, the neutrophil becomes tightly adherent to the endothelium and transmigrates out of the circulation, triggering activation and degranulation and further endothelial injury.

Fig. 4. This schematic diagram illustrates the neutrophil–endothelium interaction. Each neutrophil illustrates a key event, as it proceeds from from left to right along the capillary. Briefly, neutrophils become tightly adherent to the endothelium in a 3-stage process. In the first stage, the freely moving neutrophil is converted to the “rolling” state, in which it moves slowly along the endothelium. The neutrophil loosely interacts with the endothelium via  the expression of selectins on both the neutrophil and endothelial cell membranes. In the second stage, the expression of integrins on neutrophil and endothelium results in a tighter binding to the capillary wall. In the third stage, the neutrophil becomes tightly adherent to the endothelium and transmigrates out of the circulation, triggering activation and degranulation and further endothelial injury.

Secondary or tight adhesion of the neutrophil to the endothelium requires the action of the integrin family of cell surface receptor molecules. These macromolecules consist of two different protein chains (α and β) that are noncovalently associated and are expressed on the cell surface. One subfamily of integrins, which share the same β chain (CD18), is expressed only on leukocytes. CD11a/CD18 and CD11b/CD18 are expressed abundantly by neutrophils, the former at relatively constant concentrations, while expression of the latter is greatly enhanced by cytokines, such as IL-8 and C5a. 73,82,95The activated integrins bind to adhesive molecules expressed on the endothelial surface, in particular, intercellular adhesion molecule-1. CD11a/CD18 may also bind to a related adhesion molecule, intercellular adhesion molecule-2, and CD11b/CD18 may adhere to elements of the extracellular matrix, such as fibrinogen. 82The neutrophil becomes tightly adherent to the endothelium, flattens out, and eventually transmigrates out of the circulation. 82,96Adherence via  CD11b/CD18 appears to prime the neutrophil to degranulate and undergo the respiratory burst. 82The primed neutrophils release cytotoxic proteases, such as elastase and myeloperoxidase, and reactive oxygen species, 96,97resulting in damage to the vascular endothelium and surrounding tissues. This complex process of coordination of the function of adhesive molecules and regulation of the migration of neutrophils is modulated by chemokines, in particular, platelet activating factor, IL-8, and C5a. 82,98Therefore, in the absence of secondary insults, such as shock or infection, endothelial cells return to their resting state and lose their adhesive properties following return of cytokine and C5a concentrations to normal. This limits the inflammatory response in most patients undergoing cardiac surgery. 73 

The cellular immune system is central to the inflammatory response following cardiac surgery. Increased spontaneous activation of both granulocytes and macrophages is observed following CPB. 99Hyperstimulation of naïve monocytes and granulocytes occurs following exposure to plasma from CPB patients. 100CPB activates monocytes and macrophages via  increased monocyte chemoattractant factor production, 101and up-regulation of macrophage adhesion molecule expression and cytokine production. 102Increased concentrations of leukocyte adhesion molecules (selectins and integrins) have been demonstrated following CPB. 95During CPB, the neutrophils are primed for enhanced free radical generation, as evidenced by an enhanced oxidative burst response seen up to 24 h after CPB 97and demonstration of the release of intracellular lysosomal granular contents post-CPB. 96Elevated circulating neutrophil counts and increased neutrophil aggregability, superoxide generation, and elastase release occur up to 24 h after surgery, 103with impaired oxidative function at 48 h postoperatively. 104This suggests a biphasic abnormality with potential early tissue cytotoxicity followed later by neutrophil dysfunction. In addition, reticuloendothelial Kupffer cells demonstrate greatly increased phagosomes following CPB, 105which may cause a relative “overuse” type of impairment of phagocytic activity. 105,106 

The clinical importance of leukocytes in the inflammatory response to CPB is underscored by several findings. Pulmonary neutrophil sequestration has been demonstrated following CPB and is associated with evidence of severe histologic lung injury. 107,108Inhibition of neutrophil CD11/CD18 expression 109or function 110improves myocardial function following cardiac surgery. Blockade of neutrophil adhesion 111decreases pulmonary injury after CPB. Finally, strategies that deplete circulating leukocytes can attenuate organ injury and may improve patient outcome following CPB (see Therapeutic Strategies). 112 

Factors Influencing the Extent of the Inflammatory Response to Cardiac Surgery

Preoperative Factors

Preexisting disorders may influence the inflammatory response to cardiac surgery. Disordered cytokine balance may be a pathophysiologic feature of ischemic heart disease. 113Patients with preoperative left ventricular dysfunction undergoing CPB appear to have a greater degree of proinflammatory cytokine release, which is associated with impaired hemodynamics and a higher incidence of perioperative complications. 114CPB appears to cause greater oxidative stress in patients with diabetes, and there are qualitative differences in the inflammatory response in diabetic patients. 115Poorly controlled diabetes impairs the inflammatory response. 116 

The perioperative course of proinflammatory and antiinflammatory cytokine release in adult patients undergoing CABG does not differ with age. 117 

Perioperative Hemodynamic Factors

Perioperative hemodynamic instability predicts morbidity and mortality following CPB, 118–120with low cardiac output syndrome the most common event leading to patient death. 121Strong clinical and experimental evidence links postoperative splanchnic hypoperfusion to the development of complications such as acute respiratory distress syndrome. 16Experimental splanchnic ischemia–reperfusion induces lung recruitment and sequestration of neutrophils, 122increased pulmonary iNOS expression, 123and free radical injury. 124Cytokines, particularly TNF-α, also appear central to this process. 125,126In addition, translocation of toxins and microbial flora may occur following ischemic compromise of the integrity of the mucosal barrier.

Gastric mucosal pH, as measured by gastric tonometry, provides an index of splanchnic perfusion. 127Gastric mucosal acidosis indicates inadequate oxygenation of splanchnic tissue and is common following weaning from CPB, even in the absence of gross hemodynamic instability. 128It is a highly sensitive predictor for complications, 129independent of clinical risk stratification, even during uneventful cardiac surgery with low expected mortality. 130Therapeutic strategies to maintain hemodynamic stability and minimize postoperative splanchnic ischemia may reduce postoperative complications.

Anesthetic Techniques

Thoracic Epidural Anesthesia.

Thoracic epidural anesthesia combined with general anesthesia for CABG decreased the perioperative stress response, as measured by plasma epinephrine, and may decrease postoperative myocardial and pulmonary injury. 131However, thoracic epidural anesthesia does not significantly alter the cytokine response to CPB. 132 

Lung Management during Cardiopulmonary Bypass.

Apnea during CPB may lead to activation of lysosomal enzymes in the pulmonary circulation, which in turn are correlated with the degree of postoperative acute lung injury (ALI). 133This may be attenuated by a vital capacity maneuver performed before termination of the bypass 134; however, continuous positive airway pressure applied during CPB appears ineffective. 135 

Anesthetic Agents and Adjuvant Drugs

Many of the drugs used to produce anesthesia and maintain postoperative sedation and analgesia possess immunomodulatory effects (table 4). The clinical implications of such effects, particularly in the context of CPB, remain unknown, with most data in this area to date confined to in vitro  experiments. Nevertheless, developments in this emerging field are worthy of consideration in the light of their future therapeutic potential.

Table 4. Antiinflammatory Effects of Anesthetic Drugs Used during Cardiac Surgery

IL = interleukin; IL-1ra = interleukin 1 receptor antagonist; CPB = cardiopulmonary bypass; CRH = corticotrophin-releasing hormone; ACTH = adrenocorticotrophin hormone; TNF-α= tumor necrosis factor α.

Table 4. Antiinflammatory Effects of Anesthetic Drugs Used during Cardiac Surgery
Table 4. Antiinflammatory Effects of Anesthetic Drugs Used during Cardiac Surgery

Propofol may enhance the antiinflammatory response to surgery by several mechanisms. Propofol may preserve hepatosplanchnic blood flow during CPB, thereby aiding maintenance of the mucosal barrier. 136It alters the balance between proinflammatory and antiinflammatory cytokines, increasing production of the antiinflammatory cytokine IL-10 and IL-1ra, 137while decreasing neutrophil IL-8 secretion, 138and scavenges reactive oxygen species. 139Low concentrations of propofol reduce neutrophil uptake in the coronary circulation following myocardial ischemia and reperfusion. 140However, this effect is abolished at higher propofol concentrations; this may be due to the propofol solvent Intralipid (Kabi Pharmacia, Uppsala, Sweden). 140Propofol impairs several aspects of monocyte and neutrophil function, including the respiratory burst, 141,142polarization, 143chemotaxis, 144–146phagocytosis, 141and oxygen radical generation. 147Certain immunomodulatory effects of propofol, such as suppression of respiratory burst of neutrophils by propofol, may be caused by the solvent Intralipid, 148while other actions, such as its ability toscavenge free radicals, appears to be a property of propofol itself. 137 

Sodium thiopental impairs the neutrophil respiratory burst, 142polarization, chemotaxis, adherence, phagocytosis and killing, 144–146and coronary uptake of neutrophils following myocardial ischemia and reperfusion. 140At therapeutic concentrations, thiopental also inhibits the monocyte respiratory burst. 141In high concentrations thiopental affects Escherichia coli  clearance in vitro  and neutrophil and monocyte phagocytosis. 141The effect of thiopental on the respiratory burst of neutrophils appears less pronounced compared to propofol. 148 

Ketamine attenuates the increase of serum IL-6 concentrations during and following CPB 149and reduces coronary uptake of neutrophils following myocardial ischemia and reperfusion. 140Ketamine affects E. coli  clearance and neutrophil and monocyte phagocytosis in vitro , although only in high concentrations. 141Methohexitone has only minimal effects on the respiratory burst of neutrophils in vitro . 142,148 

Opioids have multiple effects on the immune system, mediated indirectly via  the central nervous system or through direct interactions with the cellular immune system. 150,151While the precise cellular mechanisms underlying the immunomodulatory effects of opioids are largely unknown, emerging evidence indicates that opioids share many properties with cytokines. 151,152Ultrahigh affinity novel δ, μ, and κ opioid receptors have been demonstrated on inflammatory cells. 151Granulocytes contain both opioid peptide selective δ 2 receptors (which stimulate chemotaxis) and opiate alkaloid-selective, opioid peptide-insensitive receptors (which inhibit cytokine-induced activation and chemotaxis). 151 

Morphine down-regulates the activity of lymphocytes, granulocytes, and macrophages, and suppresses the antibody response. 153Microinjection of morphine into the lateral ventricle of the rat induces pronounced, dose-dependent reductions in lymphocyte proliferation to T- and B-cell mitogens, natural killer cell cytotoxicity, and the production of IL-2 and interferon-γ. 150Morphine also increases the secretion of CRH, ACTH, and glucocorticoids, i.e. , substances with inhibitory effects on the immune system. Certain immunomodulatory actions of morphine, including NO release and inhibition of cell adhesion, appear to be mediated specifically via  the μ3 receptor. 154 

Fentanyl increases concentrations of IL-1ra in in vitro  monocyte cultures. 155In an isolated blood primed CPB circuit, fentanyl increased CD11b, augmented the reduction in lymphocyte HLA-DR expression, and attenuated the increase seen in monocyte HLA-DR expression. 52However, fentanyl, unlike morphine, appears to lack the ability to bind to the μ3 receptor, diminishing its ability to down-regulate the inflammatory response to CPB. 154 

Midazolam, the best studied benzodiazepine, has little influence on host defense mechanisms. Midazolam decreases neutrophil IL-8 secretion in response to lipopolysaccharide but does not alter IL-8 production. 138Midazolam reduces postischemic uptake of neutrophils in the coronary circulation following myocardial ischemia and reperfusion. 140Midazolam, at clinically relevant concentrations in vitro , does not attenuate neutrophil polarization 143and has minimal effects on the neutrophil respiratory burst, 148neutrophil phagocytosis, 148and clearance of E. coli . 148 

Sevoflurane, isoflurane, and enflurane decrease proinflammatory cytokine (IL-1β, TNF-α) release by human peripheral mononuclear cells in vitro . 156Isoflurane decreases alveolar macrophage phagocytosis and microbicidal function to a greater extent compared with propofol. 157Halothane, isoflurane, and enflurane attenuate free radical–mediated myocardial injury. 158,159Isoflurane and halothane (but not sevoflurane) appear to attenuate hydroxyl radical production in the ischemic rat heart. 160Sevoflurane and isoflurane and halothane reduce neutrophil 161and platelet 162,163uptake in the coronary circulation and preserve cardiac function following myocardial ischemia and reperfusion. 162–164This effect is mediated at least in part via  reduced neutrophil expression of the adhesion molecule CD11b. 164 

Clonidine appears to exert antiinflammatory actions in such diverse areas as acute pain models, 165in extrinsic asthma, 166and angiotensin-converting enzyme inhibitor–induced inflammation. 167It appears that the antiinflammatory action of clonidine is a property of α2adrenoceptor activation. 168Furthermore, α2adrenoceptor agonists may regulate cytokine production via  stimulation of α2receptors on macrophages to augment TNF-α release in response to endotoxin. 169While use of clonidine during CABG does not appear to influence the perioperative stress response, 131its immunomodulatory effects in the context of CPB remain to be characterized.

Surgical Factors

Proinflammatory cytokine concentrations in patients undergoing heart transplantation are greater than in CABG patients. 12Possible explanations include the fact that these patients have severe ventricular dysfunction, a condition known to increase cytokine concentrations after cardiac surgery, 114or to the longer ischemia time required to perform this procedure. 12The later course of cytokine concentrations after heart transplantation may be further influenced by immunosuppressive therapy. 12Patients undergoing valve surgery appear to have similar immunologic response profiles to CABG patients. 170In general, indices of inflammation appear to correlate with overall severity of illness rather than specific surgical procedure. 171 

Extracorporeal Perfusion Factors

The composition of the priming solution, cardioplegia, presence of pulsatile or nonpulsatile perfusion, type of oxygenator and pump, type of extracorporeal circuit, and temperature during CPB are all important factors influencing the inflammatory response. In an isolated circuit, CPB duration correlated with IL-8 concentrations and neutrophil adhesion molecule expression. 52The release of inflammatory mediators appears to be temperature dependent, with warm CPB associated with an increased inflammatory response compared to hypothermic CPB. 172,173However, there is evidence to suggest that hypothermic CPB may simply delay cytokine release and neutrophil activation, and that tepid CPB, in which the core temperature is simply allowed to drift to 32–34°C, may most effectively attenuate the inflammatory response. 173,174Warm blood cardioplegia reduces the inflammatory response as compared to cold crystalloid cardioplegia. 175Heparin-coated CPB circuits reduce complement and proinflammatory cytokine release. 176The type of CPB prime, i.e. , colloid (gelofusine) versus  crystalloid, does not appear to influence cytokine release. 177Membrane oxygenators may result in less activation of the inflammatory system and improve postoperative cardiac, respiratory, and renal function. 178However, a later study demonstrated no sustained advantage over bubble oxygenators in terms of inflammatory activation or postoperative respiratory function. 179In pediatric patients undergoing CPB, use of centrifugal pumps may result in less activation of the inflammatory response 180; however, another study demonstrated no advantage over conventional roller pumps. 181In adult CPB patients, centrifugal pumps may induce a greater inflammatory response than roller pumps. 182Pulsatile CPB flow is associated with less endotoxemia, 23lower cytokine and endothelin-1 concentrations, 23,183and increased NO production. 60,62 

Shear Stress.

During normal circulation within the vasculature, blood is exposed to various physical or mechanical forces. This is termed “shear stress” and may have a physiologic function, such as releasing NO from the endothelium. 60However, excessive shear stress may develop during CPB as a result of large pressure changes across the CPB circuit, causing damage to blood constituents and activating the inflammatory response. Shear stress appears to be especially pronounced along the arterial cannula. 184Shear stress decreases erythrocyte deformability and increases hemolysis. 185Leukocyte adhesiveness is increased, and mechanical disruption, with neutrophil degranulation and release of cytotoxic products, may be seen at high levels of shear stress. 186Excess shear stress also increases platelet activation 187and may contribute to endothelial injury. 188Strategies that minimize shear stress, by decreasing the pressure decrease across the CPB circuit, such as the use of hollow fiber membrane oxygenators, reduce leukocyte activation. 189 


Allogeneic Transfusion.

An estimated 20% of allogeneic blood transfusions in the United States are associated with cardiac surgery. 190The immunomodulatory effects of allogeneic transfusion in cardiac surgical patients are increasingly recognized. Allogeneic blood transfusions appear to exacerbate the proinflammatory response to cardiac surgery. Intraoperative packed erythrocyte transfusions directly increase the concentrations of inflammatory mediators and indirectly stimulate the inflammatory response. 191This may explain, in part, the greater morbidity in patients who receive intraoperative allogeneic packed cells. 191In addition, transfusion-associated graft-versus-host disease is a recognized complication of fresh nonirradiated homologous whole blood. 192 

Allogeneic erythrocytes are usually given to augment systemic oxygen delivery. However, a controlled clinical trial failed to demonstrate a beneficial effect of erythrocyte transfusion on systemic oxygen uptake in critically ill patients with sepsis. In fact, patients receiving old transfused erythrocytes developed evidence of splanchnic ischemia. The investigators postulated that the poorly deformable transfused erythrocytes cause microcirculatory occlusion and tissue ischemia in some organs. 193These concerns have been further highlighted by a recent large multicenter study of critically ill intensive care unit (ICU) patients that demonstrated that a restrictive strategy of erythrocyte transfusion improved mortality in the less severely ill patients and overall was at least as effective as and possibly superior to a liberal transfusion strategy. 194 


Autotransfusion of shed blood from the thoracic cavities during and following CPB is a common clinical practice used to reduce the need for allogeneic blood transfusion. 195,196However, concerns exist regarding the efficacy and safety of autotransfusion. Extensive clotting and fibrinolysis have been demonstrated in blood from the thoracic cavities during CPB. 196Studies to date on the efficacy of autotransfusion in reducing allogeneic blood transfusion have yielded conflicting results. One recent randomized clinical trial demonstrated that autotransfusion reduced allogeneic transfusion requirements but led to increased postoperative bleeding. 197Conversely, in another randomized controlled trial, autotransfusion of blood suctioned from the thoracic cavity during the surgical procedure increased circulating concentrations of thrombin–antithrombin III complex, tissue-type plasminogen activator, fibrin degradation products, and free plasma hemoglobin. Autotransfusion impaired hemostasis, resulting in increased postoperative blood loss and similar if not increased consumption of blood products when compared to patients who were not autotransfused. 196A metaanalysis of randomized trials assessing the effectiveness of cell salvage to minimize perioperative allogeneic blood transfusion in cardiac surgical patients concluded that it was only of marginal benefit. 198Of further concern, the potential exists for autotransfused blood to stimulate the inflammatory response. Shed mediastinal blood contains a high proportion of activated leukocytes with a significantly increased production of TNF-α and IL-6 seen in in vitro  studies. 195However, in one study, while shed mediastinal blood did contain high concentrations of IL-6 and activated leukocytes, autotransfusion in the postoperative period did not cause measurable elevations in cytokines. 195 

Postoperative Factors

Continuous Renal Replacement Therapies.

Continuous renal replacement therapies such as hemofiltration appear to remove both mediators, including TNF-α and IL-1β, and their inhibitors, such as TNFsr1, TNFsr2, and IL-1ra, from the plasma of patients with SIRS. 199This offers the possibility that these therapies may alter the course of SIRS in critically ill patients. However, the use of continuous renal replacement therapy in the absence of conventional indications for dialytic support remains unproven. No significant survival advantage has been demonstrated for critically ill patients with SIRS–MODS when treated with continuous renal replacement therapy as an adjunct to conventional therapy. 200 

Mechanical Ventilation.

Ventilatory strategies involving stretch of unrecruited lung units (i.e. , high tidal volume, low positive end-expiratory pressure), appear to cause—or potentiate— ALI. 201Furthermore, such injury may contribute to the inflammatory response by several mechanisms, such as facilitating translocation of intrapulmonary bacteria across the alveolar capillary barrier, 202accumulation of intrapulmonary cytokines, 203and release of cytokines into the systemic circulation. 204The role of ventilatory strategies in the inflammatory response following CPB is not yet known. However, in patients with acute respiratory distress syndrome, ventilation strategies that minimize overdistention and recruitment– derecruitment of the lung attenuate the inflammatory response. 205 

Clinical Implications of the Inflammatory Response to Cardiac Surgery

Potential Beneficial Effects

A controlled, self-limiting inflammatory response to cardiac surgery has important beneficial effects such as immune system priming, which may aid in preventing perioperative infection and promoting wound healing (fig. 5). CPB priming of neutrophils may be beneficial in preparing the host to mount a robust response to the physiologic stresses of the perioperative period. In this context, experimental pretreatment with inhaled endotoxin induces pulmonary leukocyte recruitment, which protects against subse-quent bacterial lung infections. 206Gut translocation of endotoxin in minute amounts may be a physiologically important phenomenon to boost the reticuloendothelial system, especially Kupffer cells. 207TNF-α and IL-1β have been shown to be necessary for wound healing, 208and TNF-α may even function to down-regulate certain aspects of the inflammatory response. 209Finally, IL-1β pretreatment may reduce the severity of ischemia and reperfusion injury. 210 

Fig. 5. Schematic diagram of the balance between beneficial and adverse effects and the resultant clinical sequelae of the inflammatory response following cardiac surgery.

Fig. 5. Schematic diagram of the balance between beneficial and adverse effects and the resultant clinical sequelae of the inflammatory response following cardiac surgery.

Potential Adverse Effects

An uncontrolled inflammatory response appears to play a significant role in the morbidity or mortality observed in patients undergoing CPB (fig. 5). The inflammatory response contributes to the pathogenesis of acute pulmonary, cardiovascular, neurologic, splanchnic, hematologic, and immune system dysfunction following cardiac surgery. In addition, although less well documented, there is evidence to suggest that the inflammatory response contributes to the pathogenesis of subacute sequelae, such as postoperative fever, 211–215postcardiotomy pericarditis, 211,216and pleural effusions after CPB. 217 


Acute lung injury, defined as the triad of hypoxemia (Pao2/Fio2≥ 300), bilateral pulmonary infiltrates, and normal pulmonary capillary wedge pressure, 218is a serious and poorly understood complication following cardiac surgery. The risk 219,220and severity 221of ALI has been consistently linked to duration of CPB. Other issues related to CPB, such as the type of oxygenator used, may also contribute to the risk of ALI. 178,222Severe ALI following CPB, while relatively uncommon (1–3%), 220,223has been associated with a 50% mortality. 220Lesser degrees of lung injury, such as reduced oxygenation index, increased V̇/Q̇ mismatch, decreased lung compliance, are seen in up to 12% of patients. 96,219Pulmonary injury is detectable even following uncomplicated CPB using sensitive measures of ALI, such as protein accumulation index and bronchoalveolar lavage neutrophil and myeloperoxidase concentrations. 221Early pulmonary dysfunction after cardiac surgery increases morbidity, including renal, neurologic, and infectious complications, duration of mechanical ventilation, ICU and hospital stays, and risk of mortality. 219 

The inflammatory response has deleterious effects on the pulmonary circulation 107,108,224and the lung parenchyma. 107Several lines of evidence implicate the inflammatory response in the pathogenesis of postoperative pulmonary dysfunction. Histologic evidence demonstrates that CPB can cause profound pulmonary endothelial, epithelial, and interstitial damage. 107,225Up to 50% of circulating neutrophils are sequestered in pulmonary capillaries during rewarming, with subsequent degranulation contributing to pulmonary vascular endothelial damage. 108Postoperative elevations of granulocyte elastase, an index of neutrophil lysosomal degranulation, correlate with deteriorations in the oxygenation index, alveolar–arterial gradient, and intrapulmonary shunt. 96,226Increases in pulmonary vascular permeability following CPB correlate with markers of lipid peroxidation and a reduction of plasma antioxidants, both indicators of an oxygen-radical–induced injury process. 224 

Strategies that attenuate the inflammatory response may reduce post-CPB ALI. While serum and alveolar proinflammatory mediator concentrations correlate with post-CPB pulmonary dysfunction, 55,226mechanical mediator removal may decrease lung injury. 56,227Leukocyte depletion during CPB, 228or blockade of neutrophil adhesion, 111,229attenuates postoperative lung dysfunction. Finally, inhibition of complement activation results in significant reduction of post-CPB ALI. 230 


Major perioperative cardiovascular complications (cardiac death, myocardial infarction, heart failure) occur in at least 10% of CABG patients. 231The Multicenter Study of Perioperative Ischemia Research Group, in a multicenter study involving 566 patients after CABG, found that up to 25% fulfilled either electrocardiogram (i.e. , presence of Q waves), CK-MB fraction, or autopsy criteria for myocardial infarction. 232Nearly 10% of patients had a Q-wave infarct, while 20.5% fulfilled CK-MB criteria for myocardial infarction. 232 

The inflammatory response may be involved in the pathogenesis of post-CPB cardiovascular dysfunction. Increased hemodynamic instability during cardiac surgery may result from systemic spillover of proinflammatory cytokines, such as IL-6. 149Furthermore, there appears to be a clear link between CPB-induced inflammatory mediators and postbypass myocardial stunning, ischemia, and dysfunction, and β-adrenergic desensitization. 233,234TNF-α, IL-1β, and IL-6 have been implicated in cardiac myocyte refractoriness to adrenergic stimulation following CPB. 234Myocardial performance in elderly patients after CPB is suppressed by TNF-α, 25while anti-TNF antibodies reverse the myocardial depression seen in sepsis. 235Left ventricular wall motion abnormalities and myocardial ischemic episodes after CPB correlate with IL-6 or IL-8 concentrations. 233 

Alterations in NO homeostasis may play an important role in the pathogenesis of cardiovascular events following cardiac surgery. The human myocardium constitutively produces NO via  cNOS, and this is regulated by the contractile state of the heart, 236possibly by a β-adrenergic signaling pathway. 237This constitutively produced NO has important cardioprotective effects, including regulation of vascular tone (fig. 3), myocardial contractility, 238,239coagulation, 240and pulmonary endothelial function. 84However, up-regulation of iNOS by proinflammatory cytokines following CPB may greatly increase myocardial NO production. 241In this context, NO may have deleterious effects and contribute to postoperative myocardial dysfunction, particularly myocardial stunning. 241IL-1β up-regulates iNOS-mediated NO production 242and has been demonstrated to depress myocardial contractility through a NO-dependent mechanism. 64Mechanisms underlying NO-mediated myocardial dysfunction may include inhibition of mitochondrial activity, 243induction of adrenergic refractoriness, 234increased platelet adhesiveness, 240and peroxynitrite-induced cellular damage. 66 


Neurologic complications increase perioperative morbidity following cardiac surgery, resulting in longer hospitalization, and may increase mortality up to 10-fold. 13Focal cerebral deficits, such as transient ischemic attacks and stroke, occur in 1–3% of patients, while less severe clinical abnormalities, such as seizures, are observed in 5–10%. 244,245Postoperative neurologic dysfunction, including cognitive dysfunction and disability, unrelated to focal injury, is seen in 69% of patients immediately postoperatively and persists for at least 1 month in 36%. 246Patients with the apolipoprotein E-ε 4 allelle 247or previous neurologic injury 248may be predisposed to neurologic complications after CPB. In the largest series to date, the mortality rate was 29% in patients with adverse cerebral complications. 245 

The inflammatory response plays a pivotal role in the pathogenesis of post-CPB neurologic injury. The role of endothelial dysfunction and the endothelial–neutrophil interaction in neurologic injury after CPB is well documented. Loss of cerebrovascular endothelial-mediated vasodilation may contribute to the pathogenesis of postoperative perfusion deficits. 249NO formed by up-regulation of neuronal NOS, e.g. , in response to glutamate, has been implicated as a potent neurotoxin in animal models of post-CPB neurologic injury. 250,251 

Strategies that attenuate the inflammatory response may decrease neurologic injury. Experimental blockade of selectin adhesion molecules reduces cerebral injury in an animal model. 252Aprotinin, a serine protease inhibitor with important hemostatic and antiinflammatory properties, decreases the incidence of stroke after CPB. 253Finally, heparin coating of CPB circuits, which improves its biocompatibility, thereby reducing contact activation of the inflammatory response, may reduce the incidence of neurologic dysfunction in humans. 254 


Perioperative renal dysfunction occurs in 7–13% of patients, with 1–1.5% requiring some form of dialytic therapy. 18,255Renal insufficiency following cardiac surgery increases ICU and hospital stay and greatly increases mortality (27%vs.  0.9%). 18The mortality rate for patients requiring postoperative dialysis ranges from 28–64%. 18,255The incidence of renal dysfunction is directly related to the duration of CPB. 18 

The role of the inflammatory response in the pathogenesis of renal dysfunction continues to be defined. Renal ischemic–reperfusion injury combined with the inflammatory response to CPB may be important causes of renal dysfunction after CPB. Hypoperfusion of the superficial renal cortex has been demonstrated during the rewarming phase of CPB in an animal model. 256The inflammatory response may exacerbate renal hypoperfusion, both indirectly as a result of hemodynamic instability, and directly via  renal arteriolar vasoconstriction and altered intrarenal distribution of perfusion due to alterations in catecholamines and NO concentrations. TNF-α released during CPB induces glomerular fibrin deposition, cellular infiltration, renal cell apoptosis, and vasoconstriction, leading to a reduction in the glomerular filtration rate. 17Furthermore, anti–TNF-α strategies have been proposed to reduce renal insufficiency after CPB. 17 


Hepatic dysfunction following CPB is common, with up to 47% of patients developing at least transient postoperative dysfunction. 257Postoperative hepatic dysfunction is related to the duration of CPB and may greatly increase mortality. 258 

The mechanism of hepatic injury after CPB and the role of the inflammatory response is not well characterized. Nevertheless, there is some evidence that the inflammatory response to CPB may play a role in hepatic injury. Hepatic ischemia–reperfusion injury may result from hepatic venous congestion during weaning from CPB. 19High concentrations of C3a and C4a have been associated with post-CPB liver dysfunction in humans. 257During hypothermic bypass, portal concentrations of endothelin-1, a potent vasoconstrictor, have been associated with decreased hepatic blood flow and post-CPB liver dysfunction in an animal model. 259In patients following CPB, hepatic perfusion may be decreased for up to 24 h. 22Finally, there is increasing evidence that cytokines TNF-α and IL-6 may contribute to the pathogenesis of hepatocellular dysfunction. 260 


Cardiopulmonary bypass–induced hemostatic defects may contribute significantly to perioperative morbidity. Potential mechanisms include direct contact activation of the coagulation and fibrinolytic cascades by the bypass circuit, platelet dysfunction, and capillary leak due to endothelial damage. The inflammatory response may be central to the development of these hemostatic defects. The amount of postoperative blood loss has been correlated with degree of activation of the complement cascade. 261Mechanical removal of cytokines, such as by hemofiltration, has been associated with a reduction in postoperative blood loss following cardiac surgery. 56 

Cardiopulmonary bypass–associated impairment of platelet function may be cyokine mediated. 262Endotoxin and IL-1β stimulate the release of von Willebrand factor from the vascular endothelium, which may promote activation and localization of platelets and enhance thrombogenicity at inflammatory foci. 263Platelet activation during CPB may contribute, through IL-1β release, to endothelial cell activation. 262Preoperative harvest of platelet-rich plasma with reinfusion following CPB may result in significantly less pulmonary dysfunction and shorter ICU stays, in addition to improved hemostatic function. 264In addition, nonsurgical postoperative bleeding is correlated with both leukocyte count and the percentage change in leukocyte count over the course of CPB. 265Finally, CPB with more biocompatible circuits may decrease platelet activation, fibrinolysis, and thrombin generation and increase platelet preservation. 266 


Cardiopulmonary bypass–associated immunosuppression may play an important role in the development of postoperative infectious complications. Immunosuppression may result from a predominance of antiinflammatory cytokine production. 7Cell-mediated immunity is also altered with decreases in CD3+ T-lymphocyte and CD4+ T-helper cell counts, 267increases in CD8+ suppressor–cytotoxic T cells and monocyte counts, 268decreased lymphocyte responsiveness to mitogens, and suppression of the T-helper cell–induced cell-mediated inflammatory response after CPB. 267,269Pretreatment with indomethacin and thymopentin, which stimulates activation and differentiation of the T-lymphocytes, appears to restore certain aspects of this response. 269IL-10 may play a role in postoperative immunosuppression, with IL-10 gene expression correlating with decreased monocyte HLA-DR antigen expression in a study of patients undergoing major abdominal surgery. 270These alterations in the inflammatory response highlight the need to consider both the potential beneficial and adverse aspects of this response and further underline the clinical benefit of a balanced, controlled inflammatory response to CPB.

Therapeutic Strategies to Modulate the Inflammatory Response

The development of strategies to control the inflammatory response following cardiac surgery is currently the focus of considerable research efforts. Diverse techniques, including maintainence of hemodynamic stability, minimization of exposure to CPB circuitry, and pharmacologic and immunomodulatory agents have been examined in clinical studies. Table 5summarizes the findings of recent randomized clinical trials in this field.

Table 5. Recent (post-1995) Randomized Controlled Clinical Trials and Meta-analyses of Interventions to Attenuate the Inflammatory Response to Cardiac Surgery, Which Incorporate Assessment of Clinically Relevant Endpoints

CABG = coronary artery bypass grafting; CPB = cardiopulmonary bypass; ICU = intensive care unit; Pao2= arterial oxygen tension; A-ao2gradient = alveolar–arterial gradient for oxygen; LAD = left anterior descending artery; HCC = heparin-coated circuit; CK-MB = creatine kinase myocardial isozyme; COPD = chronic obstructive pulmonary disease; IABP = intraaortic balloon pump; pHi = gastric intramucosal pH; Svo2= mixed venous oxygen saturation; CO = cardiac output; GIT = gastrointestinal tract; AVR = aortic valve replacement; MVR = mitral valve replacement; CI = cardiac index; LVEF = left ventricular ejection fraction; HR = heart rate; MAP = mean arterial pressure; Hb = hemoglobin; PCWP = pulmonary capillary wedge pressure; CNS = central nervous system; MI = myocardial infarction; APACHE = Acute Physiology and Chronic Health Evaluation; NAC = N-acetyl cysteine; SVRI = Systemic Vascular Resistance Index; PIP = peak inspiratory pressure; IL = interleukin.

Table 5. Recent (post-1995) Randomized Controlled Clinical Trials and Meta-analyses of Interventions to Attenuate the Inflammatory Response to Cardiac Surgery, Which Incorporate Assessment of Clinically Relevant Endpoints
Table 5. Recent (post-1995) Randomized Controlled Clinical Trials and Meta-analyses of Interventions to Attenuate the Inflammatory Response to Cardiac Surgery, Which Incorporate Assessment of Clinically Relevant Endpoints

Table 5A. (continued)

Table 5A. (continued)
Table 5A. (continued)

Table 5B. (continued)

Table 5B. (continued)
Table 5B. (continued)

Table 5C. (continued)

Table 5C. (continued)
Table 5C. (continued)

Table 5D. (continued)

Table 5D. (continued)
Table 5D. (continued)

Risk Stratification

Accurate risk stratification would permit selective delivery of potentially useful therapies to those patients who might be expected to derive most benefit. Clinical risk assessment has taken the form of complex multivariate modelling. 271,272An approach that combines assessment of “fixed” baseline risk together with “dynamic” event-related risk related to adverse perioperative events probably holds most promise (fig. 6). In this regard, several key indices of the inflammatory response appear to predict postoperative morbidity following cardiac surgery and may help to further stratify patient risk. In the preoperative phase, elevation of C-reactive protein concentrations predicts a greater likelihood of septic complications and need for catecholamine therapy, longer duration of respiratory support, and increased duration of ICU stay, 273while low preoperative immunoglobulin M antiendotoxin core antibody concentrations independently predict poor postoperative outcome. 27Postoperatively, early elevations in serum soluble TNF receptor-p55 concentrations in high-risk cardiac surgical patients predicts increased mortality. 274Finally, the characterization of particular genotypes, such as apolipoprotein E-ε 4 allele, 247which predicts risk of post-CPB neurologic injury, is a novel approach that holds promise.

Fig. 6. Schematic diagram of potentially useful strategies and therapies that may allow the clinician to control and modulate the inflammatory response to cardiac surgery.

Fig. 6. Schematic diagram of potentially useful strategies and therapies that may allow the clinician to control and modulate the inflammatory response to cardiac surgery.

Novel Cardiac Surgical Techniques

Off-pump Coronary Artery Bypass Grafting.

Concerns regarding complications and cost surrounding the use of CPB has led to renewed interest in off-pump coronary artery bypass grafting (OPCAB) techniques. Extensive observational data suggest a relation between poor outcome and the use of (1) aortic cross-clamping and concomitant global ischemia and reperfusion injury and (2) extracorporeal circulation. Avoidance of aortic cross-clamping and CPB may decrease the inflammatory response and improve postoperative organ function and patient outcome, particularly in high-risk patients.

Off-pump coronary artery bypass grafting does reduce the elaboration of key mediators of the systemic inflammatory response. OPCAB decreases concentrations of cytokines such as TNF-α, 275,276IL-6, 277IL-8, 276–280IL-10, 279,280and TNFsr1 and 2. 277,280OPCAB attenuates the cellular inflammatory response, decreasing neutrophil and monocyte counts, 278neutrophil elastase, 276,278,281and E-selectin 276concentrations. Indices of complement activation, such as C3a 276,281and C5a, 280are decreased. In addition, OPCAB attenuates other indices, including platelet β -thromboglobulin 281and procalcitonin. 282Finally, OPCAB decreases reactive oxygen species–induced injury. 276 

The clinical trials reported to date suggest that OPCAB may attenuate indices of postoperative organ dysfunction but does not eliminate SIRS following cardiac surgery (table 5). 276,278,281,283,284Initial clinical experience with selected patients suggests reduced cardiovascular, 275,279pulmonary, 275neurologic, 285and hemostatic 275dysfunction, with decreased morbidity and shorter ICU and hospital stay. 275One retrospective study comparing elderly patients undergoing OPCAB to matched conventional controls indicated that OPCAB decreased postoperative cardiovascular complications and expedited ICU and hospital discharge. 286However, these trials were small, with enrollment restricted to low-risk patients, often with specific single or double vessel coronary lesions. There are no reported randomized trials of OPCAB in high-risk patients. A retrospective comparison of the first 55 patients who underwent OPCAB at Duke University Medical Center to a larger cohort who underwent conventional CABG failed to demonstrate a reduction in renal risk. 287Therefore, the short-term benefits of OPCAB remain to be convincingly demonstrated.

Minimally Invasive Cardiac Surgery.

Advances in minimally invasive surgery in other areas, such as laparoscopic and thoracoscopic procedures, have prompted interest in approaches that avoid full median sternotomy. 288Minimally invasive cardiac surgery techniques may be utilized in the presence or absence of CPB. The surgical incision may affect the inflammatory response generated, with reduced complement activation following limited anterolateral thoracotomy as opposed to median sternotomy, 289although this is disputed. 280One nonrandomized study of patients undergoing mitral valve surgery via  limited right anterolateral thoracotomy and port access suggested that this group resumed work or normal activity earlier than comparable patients undergoing conventional median sternotomy. 290However, the efficacy of minimally invasive cardiac surgery remains to be clearly demonstrated. At present, operating times are considerably longer with minimal access techniques. 290 

Drew-Anderson Technique.

An intermediate, less invasive approach may be to use the patient's own lungs as an oxygenator via  bilateral extracorporeal circulation. This technique, introduced by Drew and Anderson, allows good surgical access yet avoids the need for an artificial oxygenator. A recent randomized clinical trial, focusing on this method as a means of attenuating the inflammatory response, reported decreased concentrations of IL-6 and IL-8 and an attenuation of postoperative hemostatic and pulmonary dysfunction (table 5). 291 


Since aortic cross-clamping and CPB were universally used for all forms of cardiac surgery, their relative role in the pathogenesis ofpostoperative complications has been unclear. OPCAB will help to delineate the intrinsic effects of bypass on the inflammatory response to cardiac surgery. OPCAB and minimally invasive cardiac surgery have demonstrated encouraging short-term benefits in the small-scale clinical studies of low-risk patients carried out to date, but clinical studies have not been carried out in the high-risk groups most likely to benefit. Finally, concerns regarding the quality of graft anastomoses achieved with OPCAB or minimal access techniques remain to be addressed.

Strategies to Improve Biocompatibility of the Extracorporeal Circuit

Improving the biocompatibility of the CPB circuit in order to reduce contact activation of the immune system, particularly the complement cascade, may be a useful strategy to limit the inflammatory response. Potential approaches include use of more biocompatible materials in the circuit or modifications of the surface of the circuit by coating with compounds that are less immunogenic.

Heparin-coated Circuits.

Heparin-coated CPB circuits (HCCs) enhance biocompatibility, reduce contact activation, and may decrease postoperative cardiovascular, respiratory, hemostatic, and neurologic dysfunction. 254The method by which the circuit is coated and the type of heparin used may have implications for its effects on the coagulation and complement systems. The Duraflo II HCC, which uses ionically bonded unfractionated heparin (Duraflo II surface; Baxter Healthcare Corp., Irvine, CA), reduces kallikrein and complement activation 49but is less effective in attenuating coagulation or fibrinolysis. 292The Carmeda Bioactive Surface system (CBAS; Medtronic Inc., Minneapolis, MN) uses end-attached covalently bonded heparin that has been fragmented by treatment with nitric acid. The Carmeda circuit appears superior to the Duraflo II in reducing complement, 293neutrophil 294activation, and endothelin-1 concentrations. 294 

Clinical studies to date suggest that the beneficial effects of HCCs are confined to high-risk patients (table 5). In low-risk patients, HCCs decrease neutrophil activation, 295decrease myocardial injury, 295and reduce complement activation. 296The largest study to date in low-risk patients revealed no overall clinical benefit, 297although subgroup analysis suggested that women and patients with prolonged aortic cross-clamp times may benefit from HCC. 297Duraflo II HCCs decreased the duration of ventilatory support and ICU stay and reduced the incidence of poor outcome (death or prolonged ICU stay) in a large study of high-risk patients. 49However, a similar but smaller study failed to confirm these benefits. 298The benefits of HCC-based technology may be more apparent in patients with preexisting organ dysfunction. 49Outcome may be enhanced when Duraflo HCCs are combined with the use of silicone-coated oxygenators. 299HCC may attenuate the proinflammatory response more markedly and may have greater myocardial protective effects where perfusion times are prolonged, especially in heart and heart–lung transplantation. 300 

Other Strategies.

Other strategies to improve biocompatibility having therapeutic potential include coating of circuitry with phosphatidylcholine, 301silicone, 302synthetic proteins 303and polymers, 304or surface–modifying additives. 305,306Decreasing oxygenator surface area may also decrease activation of the inflammatory response. 307 

Strategies to Reduce Endotoxemia

Selective Digestive Decontamination.

Selective digestive decontamination (SDD) is a technique to reduce the gut content of enterobacteria. This is achieved by preoperative administration of oral nonabsorbable antibiotics such as polymyxin E, tobramycin, and amphotericin B, and has been demonstrated to reduce plasma concentrations of endotoxin, TNF-α, and IL-6 in patients undergoing CPB. 23A recent metaanalysis of SDD suggests that it reduces rates of postoperative infection, but not mortality, in patients undergoing cardiac surgery. 308Since mortality reduction with SDD in critically ill patients appears to be related to baseline mortality risk, 309trials of SDD in cardiac surgery thus far contain too many low-risk patients, resulting in inadequate study power. SDD may prove worthwhile in high-risk cardiac surgical patients, 308but since its use raises both practical issues (notably the logistics of performing it) and theoretical concerns (changes in bacterial flora, emergence of resistance), its adoption is unlikely pending further studies.

Enteral Nutrition and Immunonutrition.

Hypoalbuminemia and low body mass index independently predict increased morbidity and mortality after cardiac operations. 310In an early study, well-nourished patients undergoing valve surgery had a much shorter hospital stay compared to those with preoperative malnutrition. 311Laboratory evidence in animals suggests that protein-calorie malnutrition decreases left ventricular function 312and that myocardial glycogen concentration correlates with left ventricular function following CPB. 313 

The beneficial role of early institution of enteral nutrition, particularly “immunonutrition,” which contains supplements such as arginine, purine nucleotides, and ω-3 fatty acids, which are considered to enhance immune function, has been established in other groups of postoperative and critically ill patients. In critically ill patients, immunonutrition reduced the duration of ICU and hospital stay, infectious complications, duration of SIRS, and mechanical ventilation compared to patients receiving conventional nutrition. 314In patients for elective gastrointestinal surgery, preoperative and postoperative immunonutrition has beneficial effects on immune function, complication rate, and duration of hospital stay. 315,316The use of glutamine supplementation may improve survival of patients with organ failure who require parenteral nutrition. 317 

There is no information available concerning the effect of nutritional support in patients undergoing cardiac surgery who have a complicated postoperative course.

Strategies to Maintain Hemodynamic Stability and Organ Perfusion

Perioperative hemodynamic instability, especially post-CPB low cardiac output syndrome, is a marker for later adverse outcome and death. Splanchnic perfusion abnormalities, as measured by tonometrically derived intramucosal pH and Pco2, strongly predict postoperative morbidity in cardiac surgical patients. 130Covert hypovolemia may exacerbate splanchnic hypoperfusion during and after CPB, and this may be treatable by increasing intravascular volume. Other therapeutic options include pharmacologic and mechanical circulatory support.

Optimization of intravascular volume status may be beneficial even in apparently stable patients. 318In low-risk cardiac surgical patients, intraoperative intravascular volume expansion with the objective of maximizing stroke volume resulted in improved gastric intramucosal pH values, less hemodynamic interventions, lower complication rates, and shorter ICU and hospital stay. 318Furthermore, low intraoperative filling pressures and high pressor usage may contribute to increased gut permeability and endotoxemia. 319Excessive hemodilution during CPB may play a role in the pathogenesis of post-CPB low cardiac output syndrome. In a multicenter observational study, excessively low hematocrit values during CPB independently predicted in-hospital mortality, need for intraaortic balloon pump usage, and return to bypass following failed separation. 320 

There are no outcome-based data to support the routine use of pharmacologic interventions to maximize splanchnic perfusion in patients undergoing cardiac surgery. However, patients failing to meet preset hemodynamic goals may benefit from such measures. In a recent randomized trial in which early postoperative cardiovascular function was optimized, using preload augmentation and dobutamine to normalize mixed venous oxygen saturation values and lactate concentration, optimized patients had reduced length of hospital stay and reduced organ dysfunction at the time of discharge compared with patients receiving standard care. 321Pharmacologic interventions to maximize splanchnic perfusion may attenuate the inflammatory response. Immune cells contain type IV and type III phosphodiesterase, 322and phosphodiesterase inhibitors appear to directly limit inflammatory activation and organ dysfunction in sepsis models. 322,323Milrinone attenuates the reduction in gastric intramucosal pH, reduces both venous and hepatic endotoxin concentrations, and may decrease postoperative IL-6 concentrations in healthy patients undergoing cardiac surgery, 24although this has been disputed. 324Dopexamine attenuates the postoperative increase in IL-6 concentrations 325and reduces gastrointestinal permeability, 326but does not improve splanchnic perfusion (as measured by intramucosal pH) or decrease plasma endotoxin concentrations, 325following CPB.

The elective use of mechanical circulatory support, such as preoperative intraaortic balloon pump, in selected high-risk patients, especially the elderly 327,328and those with severe left ventricular dysfunction, 329may reduce the incidence of postoperative low cardiac output syndrome, mortality, and ICU stay without significant increases in morbidity or cost.

Filtration Techniques


Hemofiltration is a process that uses ultrafiltration, i.e. , the processes of convection, osmosis under a hydrostatic pressure gradient, to remove fluid and low-molecular-weight substances from plasma. Initially introduced to treat patients with renal failure and to correct accumulation of extravascular water following CPB, hemofiltration appears to exert beneficial antiinflammatory effects, particularly in pediatric patients. 56Hemofiltration may remove proinflammatory mediators, with reductions in postoperative TNF-α, IL-1, IL-6, IL-8, C3a, and myeloperoxidase concentrations. 56,227,330This technique improves hemodynamic stability 227and early postoperative oxygenation, 56,227,331and reduces postoperative blood loss 56,227,331and duration of mechanical ventilation 227,331in pediatric cardiac surgery. Hemofiltration may reduce pulmonary hypertension after congenital heart surgery, possibly by facilitating removal of endothelin-1. 330Modified hemofiltration 332after CPB improves intrinsic left ventricular systolic function and diastolic compliance, increases blood pressure, and decreases inotropic drug use in the early postoperative period in infants. 333 

Hemofiltration appears to be less effective in adults, with no decrease observed in postoperative blood loss, average bank blood transfused, postoperative weight gain, length of stay, or overall patient costs. 334,335Hemofiltration in adults undergoing CPB is less effective in removing proinflammatory cytokines than in pediatric patients, 335,336perhaps explaining its apparent lack of efficacy in this population.

Leukocyte Depletion.

Leukocytes play a central role in the inflammatory response to cardiac surgery. Leukocyte depletion during cardiac surgery, by means of leukocyte-specific filters, decreases circulating leukocyte 228,337,338and platelet concentrations 339and attenuates indices of oxidative stress 340and inflammation. 337There is increasing evidence that leukocyte depletion may attenuate pulmonary and myocardial injury following CPB. Benefit appears most consistent in patients with risk factors such as left ventricular dysfunction, urgent surgery, or long CPB time. Leukodepletion has been shown to improve postoperative respiratory function in CPB patients, 338,339particularly in patients with a low preoperative oxygenation capacity or long CPB time. 339In addition, leukocyte depletion of the residual heart–lung machine blood, which contains high quantities of activated leukocytes, prior to retransfusion, improved lung function in patients undergoing elective CABG. 228Leukodepletion during CPB, combined with leukodepletion of transfused blood, decreased indices of myocardial cell injury in patients undergoing urgent CABG for unstable angina. 340Conversely, in low-risk patients, depletion of activated neutrophils during CPB did not confer clinical benefit. 341Limiting leukocyte depletion to the “reperfusion phase” of CPB (following aortic unclamping) does not appear to confer any clinical benefit in CABG patients. 342 

Leukocyte depletion of blood cardioplegia alone attenuated myocardial cell injury and improved early myocardial function in patients with left ventricular dysfunction undergoing CABG with CPB. 112,343Leukodepletion of terminal blood cardioplegia, (i.e. , blood cardioplegia administered for 10 min immediately prior to aortic unclamping as an adjunct to crystalloid cardioplegia) decreased myocardial injury and improved cardiac function in patients with left ventricular hypertrophy undergoing valve surgery. 344 

The immunomodulatory effects of leukocytes in allogeneic blood has focused attention on the potential benefits of leukodepleting stored blood. 345A large-scale clinical trial conducted in CPB patients demonstrated that leukocyte depletion of transfused blood significantly reduced the overall 60-day mortality. 346The difference in mortality was predominantly due to a dramatic reduction in noncardiac causes of death, particularly multiorgan failure. 346In addition, leukodepletion reduced the postoperative infection rate in patients who received more than 3 units of blood. 346 

Agents That May Suppress the Inflammatory Response

Serine Protease Inhibitors.

Many effector proteins of the cytokine, complement, and hemostatic cascades are serine proteases, i.e. , when activated they catalyze the next step in the cascade by hydrolyzing and activating further proteins, a process termed “cascade amplification.” Control processes that limit inflammation to the sites of injury and reduce systemic inflammation include serine protease inhibitors. Aprotinin is the best known and studied of these inhibitors.


Aprotinin, a complex polypeptide and nonspecific serine protease inhibitor, has clearly been demonstrated to prevent excessive blood loss during cardiac surgery. 347In addition, aprotinin has multiple actions that may suppress the inflammatory response, particularly at higher dosages. Antiinflammatory effects include attenuation of platelet activation, maintenance of platelet function, 348decreased complement activation, 348inhibition of kallikrein production, 348decreased release of TNF-α, 349IL-6, and IL-8, 350inhibition of endogenous cytokine-induced iNOS induction, 351decreased CPB-induced leukocyte activation, 348,352and inhibition of up-regulation of monocyte and granulocyte adhesion molecules. 95,353 

In clinical studies, high-dose aprotinin reduces postbypass myocardial ischemia and myocyte damage 354and length of hospital stay in high-risk patients. 355However, a pump-prime-only dose of aprotinin may increase the risk of postoperative myocardial infarction. 356Levy et al.  found no such increase in the incidence of perioperative myocardial infarction in patients undergoing repeat CABG. 253Concerns over graft patency following aprotinin therapy have been reduced by the IMAGE trial, which found no difference in early (10-day) patency rates for internal mammary artery grafts 357or for saphenous vein grafts after controlling for confounding factors. 358 

Aprotinin may reduce pulmonary and cerebral injury following CPB. Aprotinin decreases experimental CPB-induced and cytokine-induced bronchial inflammation 359and was demonstrated to attenuate lung reperfusion injury following CPB in one small clinical study. 360An early report of use of aprotinin in high-risk cardiac surgery patients indicated an incidence of fatal stroke of 0.5%, compared to rates of 2–3% in contemporary studies that did not use aprotinin. 361,362A multicenter trial of repeat CABG patients found that the incidence of stroke was reduced with high- or low-dose aprotinin. 253Lemmer et al.  failed to show a significant decrease in the incidence of stroke with three different dosage regimens in their large-scale multicenter study. 356However, a pooled analysis of six trials, including the aforementioned trials, found that high-dose aprotinin significantly reduced the incidence of stroke. 363Initial concerns over the potential for adverse effects of aprotinin on renal function appear unfounded. 356 

No single study of aprotinin has clearly demonstrated improved patient outcome to date. 253,356However, a recent metaanalysis reported that aprotinin reduces surgical blood loss, allogeneic blood transfusion, and the need for rethoracotomy, and decreases perioperative mortality almost twofold, with no increase in the risk of myocardial infarction. 347These data provides strong support for the use of aprotinin in patients undergoing cardiac surgery.


Pentoxifylline is a nonspecific phosphodiesterase inhibitor with diverse antiinflammatory effects, many of which may be mediated by inhibition of phosphodiesterase IV. 364These include attenuation of TNF-α release in sepsis, 365,366decreased endotoxin and cytokine activation of neutrophils, 367reduction of indices of endothelial injury and permeability, 368decreased pulmonary leukocyte sequestration, 369and attenuation of increases in pulmonary vascular resistance. 369Clinical studies to date have been limited. In one study, pentoxifylline decreased the duration of ventilation and hemofiltration and the incidence of MODS when administered postoperatively to selected high-risk cardiac surgical patients 370and may be of therapeutic benefit in human sepsis. 371However, pentoxifylline treatment did not improve postoperative renal 372or pulmonary 373function in other small clinical studies. Most recently, in elderly cardiac surgical patients, pentoxifylline attenuated the increase in neutrophil elastase, C-reactive protein, and proinflammatory cytokines (IL-6, IL-8, and IL-10). These patients also had reduced requirements for vasoactive medication and a shorter time to tracheal extubation. 374In a parallel study, the same investigators reported improved splanchnic perfusion and hepatic–renal function with pentoxifylline. 375 

Free Radical Scavengers and Antioxidants.

Generation of reactive oxygen species (ROS) (hydrogen peroxide and the superoxide and hydroxyl radicals) occurs upon reperfusion following bypass, 376and these may be important contributors to tissue injury. Leukocytes activated during bypass may also release substantial amounts of cytotoxic ROS. 96,97When present in equimolar concentrations, superoxide and NO may combine form peroxynitrite, a more reactive and injurious free radical. 66,67Myocardial antioxidant enzymes, including glutathione reductase, superoxide dismutase, and catalase, are activated in proportion to the degree of myocardial ischemia and reperfusion injury. 377Host antioxidants become depleted after CPB, 378,379presumably as a result of consumption by free radicals. When ROS production exceeds host defense scavenging capacity, cellular injury results. 376,380There is an inverse correlation between preoperative total plasma antioxidant status and lipid peroxidation, the latter of which is directly correlated with indices of myocardial cellular injury. 379Furthermore, post-CPB coronary endothelial dysfunction appears to be partially mediated by ROS. 381Free radical scavengers, such as enzymatic scavengers, antioxidants, and iron chelators, may be potentially useful therapeutic adjuncts to control the deleterious effects of the inflammatory response.

High-dose vitamin C (ascorbic acid) has been demonstrated to effectively scavenge free radicals, decreasing cell membrane lipid peroxidation 376,382and indices of myocardial injury, and improving hemodynamics with a shorter ICU and hospital stay. 382Vitamin E (α-tocopherol) reduces plasma concentrations of hydrogen peroxide, a marker of free radical concentrations, 383and decreases cell membrane lipid peroxidation 376following CPB. Preoperative supplementation with a combination of ascorbic acid, α -tocopherol, and allopurinol reduced cardiovascular dysfunction in both stable and unstable patients undergoing CABG. Unstable CABG patients sustained less myocardial injury and a decreased incidence of perioperative myocardial infarction. 384A more recent trial of combined α-tocopherol and ascorbic acid supplementation in CABG surgery revealed no detectable decrease in myocardial injury. 15 

High-dose N -acetylcysteine before or during bypass appears to act as a free radical scavenger 385and reduces the neutrophil oxidative burst response 385and elastase activity. 386In an early interventional trial in patients with established acute lung injury, N -acetylcysteine was shown to improve oxygenation and lung mechanics, although no impact on progression to acute respiratory distress syndrome was noted. 387 

Allopurinol is an inhibitor of the enzyme xanthine oxidase, a pivotal generator of free radicals during reperfusion injury. Allopurinol may decrease myocardial formation of cytotoxic free radicals, 380,388lower markers of myocardial cellular injury, 389and improve recovery of myocardial function following CPB. 390,391However, other studies have demonstrated no improvement in either myocardial function 392or myocardial cellular injury with allopurinol use, 388,393casting doubt on its therapeutic potential.

Pretreatment of patients with mannitol reduces myocardial formation of cytotoxic free radicals after CPB in humans. 380Other free radical scavengers–antioxidants that appear from animal studies to possess therapeutic potential include methionine, reduced glutathione, dimethylthiourea, mercaptopropionyl glycine, superoxide dismutase, catalase, and desferrioxamine. 381,394–397 


The Corticosteroid Controversy.

The use of corticosteroids in the context of CPB continues to be controversial because of their potential risks. Past negative experience, particularly with the use of corticosteroids in septic shock, 398has served to emphasize the need for caution when considering corticosteroid use, even in noninfective inflammatory conditions, where their potent antiinflammatory actions might be expected to be beneficial. However, there have been significant advances in our understanding of the molecular mechanisms by which corticosteroids might blunt the inflammatory response to cardiac surgery.

Corticosteroid pretreatment may blunt the inflammatory response in humans by several distinct mechanisms. Administration of glucocorticoids prior to CPB may attenuate endotoxin release 399and complement activation. 400,401Methylprednisolone lowers post-CPB concentrations of the proinflammatory cytokines TNF-α, 349IL-6, and IL-8, 402and increases concentrations of the antiinflammatory cytokines IL-10 and IL-1ra, 402but not IL-4. 403Corticosteroids also attenuate post-CPB leukocyte activation, 20neutrophil adhesion molecule up-regulation, 349and pulmonary neutrophil sequestration. 401 

Prebypass administration of methylprednisolone in aprotinin-treated patients improves early postoperative indices of pulmonary, cardiovascular, hemostatic, and renal function. 404Glucocorticoid pretreatment may improve cardiac performance 405and reduce evidence of bronchial inflammation following CPB. 406Low-dose methylprednisolone in the pump prime solution appears to attenuate myocardial cell damage. 407Dexamethasone 213,214and methylprednisolone 212,215decrease the incidence of postoperative fever. In animal studies, corticosteroid pretreatment improved several indices of lung injury, including pulmonary compliance, alveolar– arterial gradient, pulmonary vascular resistance, and extracellular fluid accumulation. 408However, the ability of corticosteroid pretreatment to attenuate post-CPB pulmonary inflammation, 409endotoxemia, 400and complement activation is disputed. 20,410 

The clinical implications of corticosteroid use are not yet fully elucidated, and clear benefit is not yet demonstrated. The dosage, formulation, and timing of administration of corticosteroids may be critical, and differences in dosage regimens may explain conflicting results. Preoperative combined with prebypass administration may be superior to prebypass administration alone. 408It is premature to advocate the use of corticosteroids in the absence of proven outcome benefit, determination of optimal dosage regimens, and characterization of harmful effects, e.g. , immunosuppression, which may result from their use.

Cyclooxygenase Inhibitors.

Aspirin, the prototype nonsteroidal antiinflammatory drug (NSAID), is widely used in cardiac surgical patients for the purposes of pain relief and antiplatelet activity. However, the potential for NSAID's inhibitors to attenuate the inflammatory response to cardiac surgery has not been widely evaluated in clinical trials. Traditional NSAIDs, such as indomethacin, inhibit both the constitutive cyclooxygenase 1 (COX-1) as well as COX-2, the inducible isoform activated by inflammatory stimuli. Nonspecific COX inhibition attenuates the increase in pulmonary vascular resistance and ALI 411and reverses pulmonary microvascular dysfunction 412in CPB models. One older clinical study of indomethacin demonstrated that it decreased the duration of postoperative fever, chest pain, malaise, and myalgias following CPB. 211However, inhibition of COX-1 appears to increase free radical–generated isoprostane formation, which aggravates postischemic myocardial dysfunction. 413,414 

Specific COX-2 inhibitors exhibit considerable potential to attenuate the inflammatory response following cardiac surgery. COX-2 has been implicated in the pathogenesis of adverse events after cardiac surgery. 415,416COX-2 is up-regulated following CPB, 415in multiple tissues, including the brain, 416while COX-2 products, particularly thromboxanes 417and vasoconstrictor prostaglandins, are increased. 412COX-2 up-regulation following experimental CPB may contribute to postoperative coronary vasospasm 415and increased pulmonary vascular resistance. 418In addition, myocardial COX-2 is up-regulated during cardiac allograft rejection 419and myocardial infarction 420and contributes to endotoxin-induced myocardial depression. 421Inhibition of COX-2 attenuates the myocardial inflammatory response during cardiac allograft rejection, 419reduces endothelial dysfunction following myocardial ischemia and reperfusion, 422and improves cardiac function in experimental myocardial infarction. 420In addition, COX-2 inhibition decreases endotoxin-induced myocardial depression 421and lung ischemia and reperfusion injury. 423However, the clinical efficacy of specific COX-2 inhibitors in attenuating the inflammatory response to cardiac surgery remains to be determined.

Complement-directed Therapies.

Therapies that utilize endogenous soluble complement inhibitors may be a suitable approach to reduce contact activation and thereby control the inflammatory response. A recent two-stage randomized clinical trial of a monoclonal antibody specific for human C5 demonstrated its efficacy and safety in patients undergoing CPB. 50The generation of activated complement mediators and leukocyte adhesion molecule formation was inhibited in a dose-dependent manner. Furthermore, C5 inhibition resulted in a dose-dependent reduction in myocardial injury, postoperative cognitive deficits, and coagulation dysfunction. These data suggest that C5 inhibition may represent a promising therapeutic modality for preventing complement-mediated inflammation and tissue injury in patients undergoing CPB. 50Compstatin, a recently discovered peptide inhibitor of complement, may have the potential to prevent complement activation during and after cardiac surgery. In preliminary primate studies, compstatin completely inhibited in vivo  heparin–protamine-induced complement activation without adverse effects. 31 

Other promising strategies include the C1 inhibitor, recombinant soluble inhibitor-1, monoclonal antibodies to C3 and C5a, and strategies that attenuate complement receptor 3–mediated adhesion of inflammatory cells to the vascular endothelium. Utilization of membrane-bound complement regulators may also be feasible by means of transfection techniques. 424 

Antimediator Therapies.

Direct antimediator therapies that focus upon the endotoxin molecule itself and the proinflammatory cytokine cascade following CPB offer new approaches. However, the complex pathway observed in patients with SIRS does not appear to readily respond to antimediator therapy. Multicenter clinical trials blocking endotoxin and proinflammatory mediators such as IL-1 or TNF-α conducted in SIRS patients have shown no benefit in reducing mortality secondary to sepsis. Reasons for the relative failure of immunomodulatory therapies to date may include the timing of intervention, the heterogeneous nature of the inflammatory response, and the reciprocating and redundant nature of the proinflammatory cascades. High circulating concentrations of antiinflammatory mediators, such as the cytokine antagonists IL-1ra, TNFsr1, and TNFsr2, may also limit the efficacy of therapies that aim to augment natural defenses against endotoxin or the proinflammatory cytokines. 425 

The experience with antimediator therapy in sepsis suggests a need for caution in considering the application of these therapies to control the inflammatory response to CPB. Nevertheless, antimediator therapies may be worthy of investigation for two reasons. These therapies may enhance our understanding of the inflammatory process following CPB. Their administration prior to bypass, in order to modulate the inflammatory pathways at their earliest stages, might constitute a more successful approach than that used in other clinical scenarios, such as in sepsis, where the inflammatory response may be already well developed before antimediator therapy is possible.

Therapies to Attenuate Endothelial Injury.

Current evidence suggests that therapeutic efforts in patients with SIRS should include modulation of endothelial cell function. Better definition of the molecular mechanisms of endothelial cell activation may facilitate development of therapies that allow selective inhibition of vascular endothelial activation. Adhesion molecule blockade may prevent neutrophil adherence during the first 24 h after CPB, thereby preventing the neutrophils from mediating widespread organ damage. In this regard, blockade of endothelial and neutrophil selectin adhesion molecules results in marked attenuation of cerebral injury in an animal model of CPB and deep hypothermic circulatory arrest. 252Inhibition of neutrophil adhesion markedly reduced pulmonary injury in a porcine model of CPB. 229However, there may be limits to this approach because adhesion molecule blockade increases susceptibility to infection. 426Finally, methods to prevent nuclear localization of the transcriptional activator NF-κB in order to prevent endothelial cell activation are also being studied in animal models. 98 

Future Research Directions

The development of organ dysfunction following CPB remains an indicator of poor outcome despite advances in resuscitation, drug, and adjunctive therapies.Organ support therapies, e.g. , mechanical ventilation, can sustain life but may impair both local and remote organ function, e.g. , ventilator-associated lung injury. 201A better understanding of the inflammatory response to cardiac surgery may be the key to development of successful strategies to minimize patient morbidity. With some exceptions, such as recent data on HCCs and inhibition of complement activity, the link between the inflammatory response and adverse clinical sequelae, while persuasive, is currently associative rather than causative. A primary research priority must be to establish direct causal links between (and mechanistic insights into) the inflammatory response to surgery or CPB and clinical outcome. Therapeutic interventions cannot be justified in the absence of clear cause-and-effect relations.

There remains a need to document clear clinical benefits from interventions designed to modify the inflammatory response. Modulation of the human inflammatory response has always been difficult, primarily as a result of our incomplete understanding of this response, and may lead to unexpected sequelae. The complexity of the inflammatory response is a significant obstacle to identification of the mechanism(s) by which alteration of a particular aspect of the response may affect clinical outcome. Indiscriminate inhibition– prevention of the inflammatory response to CPB may have detrimental effects, such as loss of appropriate wound healing and defenses against infection. Certain proinflammatory cytokines, such as IL-1β210and even endotoxin, 206appear to have poorly understood protective effects. In this regard, IL-1β pretreatment protects against subsequent myocardial ischemia and reperfusion injury. 210The emphasis of future strategies must therefore be on the control of, rather than the simple inhibition of, the inflammatory response to CPB.

Further research is required to determine why certain patients appear to be at increased risk of clinically important bypass-induced injury. Monitoring tools such as gastric tonometry and other indicators of systemic organ hyoperfusion in CPB patients have provided physiologic insights, but their role in therapy remains to be clarified. Preoperative or early perioperative identification of patients most likely to develop adverse clinical sequelae from SIRS would allow focusing of investigative, preventive, and therapeutic maneuvers, and should be a research priority.

The heterogeneity of the patient population undergoing CPB is well illustrated by the finding of a near 20-fold difference in mortality (1.8%vs.  34.3%) for first time elective versus  high-risk reoperative coronary artery bypass procedures. 5Many studies of therapeutic interventions have been carried out in relatively low-risk patients, in whom the risk of adverse postoperative events might be expected to be minimal. It is possible that beneficial effects of these therapeutic strategies may be diluted by studies that include low-risk patients. Therefore, future investigations of interventions to control the inflammatory response to CPB may be best focused on patients at high risk of postoperative organ dysfunction. Future studies should utilize direct clinical indicators of organ injury as outcome measures rather than simply measurement of mediator concentrations as surrogates of injury. Many of the previously conducted clinical trials do not contain adequate patient numbers to detect meaningful differences in outcome. There is a clear need for large-scale clinical trials of more promising strategies such as selective gut decontamination, maintenance of splanchnic perfusion, drug therapies including corticosteroid pretreatment, aprotinin, acadesine, and adjunctive measures, such as hemofiltration, and use of biocompatible materials in the extracorporeal circuit. These trials, restricted to patients at significant risk of perioperative morbidity, may have to be completed using multiple centers. Finally, more investigation is needed to determine the efficacy and safety of off-pump cardiac surgery, and new methods for myocardial protection in this context need to be developed.


Cardiac surgery evokes a generalized inflammatory response in all patients, with serious clinical consequences in a minority, despite advances in pharmacology, perfusion technology, cardiovascular monitoring, and anesthetic and surgical technique. This is most clearly evident with regard to postoperative pulmonary and cardiovascular dysfunction. The etiology of these events is probably a composite of unstable peribypass hemodynamics, global myocardial ischemia, suboptimal organ perfusion during CPB, and immune events related to exposure to extracorporeal circulation per se . A balanced, controlled inflammatory response is potentially beneficial, aiding host defenses against infection and facilitating wound healing, but loss of control of the inflammatory response may herald the onset of SIRS and single or multiple organ dysfunction.

The complex interaction of key proinflammatory and antiinflammatory components of the inflammatory response, the significance of alterations in the magnitude or time course of release, and their relation to the clinical sequelae seen following CPB remain to be fully elucidated. Further work to establish direct causal links between the inflammatory response to CPB and organ dysfunction may lead to mechanistic insights and in turn stimulate the development of successful preventive and therapeutic strategies. The increasing use of minimally invasive surgical techniques such as OPCAB will contribute to these insights, particularly the relative roles of CPB and peribypass events. The link between interventions and clinical benefit is gradually being established for several strategies, including improved circuit biocompatibility, maintenance of splanchnic perfusion, hemofiltration (in the pediatric population), aprotinin, and corticosteroid therapy. The need to better characterize and focus therapeutic interventions on the patient at risk of MODS following CPB is imperative.

The goal of modulation of the perioperative inflammatory response is to attenuate its deleterious effects while preserving the ability of the patient to mount an appropriate defense to the physiologic trespasses of the perioperative period. Although knowledge is growing about the role of altered immune function, the role of immunomodulatory therapies will remain investigational (especially in view of the failures of these therapies in recent sepsis trials) until the initiating events in postoperative SIRS become clearer.

The authors thank Wil Gamble, Medical Illustrator, Montreal, Quebec, Canada, for his expert art work in relation to figure 4.


Davies MG, Hagen PO: Systemic inflammatory response syndrome. Br J Surg 1997; 84: 920–35
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101: 1644–55
Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP: The natural history of the systemic inflammatory response syndrome (SIRS): A prospective study. JAMA 1995; 273: 117–23
Quartin AA, Schein RM, Kett DH, Peduzzi PN: Magnitude and duration of the effect of sepsis on survival. JAMA 1997; 277: 1058–63
Grover FL: The Society of Thoracic Surgeons National Database: Current status and future directions. Ann Thorac Surg 1999; 68: 367–73
Kollef MH, Wragge T, Pasque C: Determinants of mortality and multiorgan dysfunction in cardiac surgery patients requiring prolonged mechanical ventilation. Chest 1995; 107: 1395–401
McBride WT, McBride SJ: The balance of pro- and anti-inflammatory cytokines in cardiac surgery. Curr Opin Anaesth 1998; 11: 15–22
Saadia R, Schein M: Multiple organ failure: How valid is the “two hit” model? J Accid Emerg Med 1999; 16: 163–6
Bone RC: Towards a theory regarding the pathogenesis of the systemic inflammatory response system: What we do and do not know about cytokine regulation. Crit Care Med 1996; 24: 163–72
Picone AL, Lutz CJ, Finck C, Carney D, Gatto LA, Paskanik A, Searles B, Snyder K, Nieman G: Multiple sequential insults cause post-pump syndrome. Ann Thorac Surg 1999; 67: 978–85
Bone RC: Sir Isaac Newton, sepsis, SIRS and CARS. Crit Care Med 1996; 24: 1125–8
Wan S, Marchant A, DeSmet JM, Antoine M, Zhang H, Vachiery JL, Goldman M, Vincent JL, LeClerc JL: Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996; 111: 469–77
Roach GW, Kanchuder M, Mangano CM, Newman M, Nussmeier N, Wolman R, Aggarwal A, Marschall K, Graham SH, Ley C: Adverse cerebral outcomes after coronary bypass surgery: Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335: 1857–63
Mangano DT: Effects of acadesine on myocardial infarction, stroke, and death following surgery: A meta-analysis of the 5 international randomized trials. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group. JAMA 1997; 277: 325–32
Westhuyzen J, Cochrane AD, Tesar PJ, Mau T, Cross DB, Frenneaux MP, Khafagi FA, Fleming SJ: Effect of preoperative supplementation with alpha-tocopherol and ascorbic acid on myocardial injury in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 1997; 113: 942–8
Christenson JT, Aeberhard JM, Badel P, Pepcak F, Maurice J, Simonet F, Velebit V, Schmuziger M: Adult respiratory distress syndrome after cardiac surgery. Cardiovasc Surg 1996; 4: 15–21
Meldrum DR, Donnahoo KK: Role of TNF in mediating renal insufficiency folowing cardiac surgery: Evidence of a postbypass cardiorenal syndrome. J Surg Res 1999; 85: 185–99
Mangano CM, Diamontstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT: Renal dysfunction after myocardial revascularization: Risk factors, adverse outcomes, and hospital utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med 1998; 128: 194–203
Yamashita C, Wakiyama H, Okada M, Nakao K: Hepatic microcirculation during transient hepatic venous occlusion: Intravital microscopic observation using hepatic venous clamp model in the mouse. Kobe J Med Sci 1998; 44: 199–203
Jansen NJ, van Oeveren W, van Vliet M, Stoutenbeek CP, Eysman L, Wildevuur CR: The role of different types of corticosteroids on the inflammatory mediators in cardiopulmonary bypass. Eur J Cardiothorac Surg 1991; 5: 211–7
Davies SW, Duffy JP, Wickens DG, Underwood SM, Hill A, Alladine MF, Feneck RO, Dormandy TL, Walesby RK: Time-course of free radical activity during coronary artery operations with cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 105: 979–87
Takahashi T, Kunimoto F, Ichikawa H, Ishikawa S, Sato Y, Hasegawa Y, Morishita Y: Gastric intramucosal pH and hepatic venous oximetry after cardiopulmonary bypass in valve replacement patients. Cardiovasc Surg 1996; 4: 308–10
Martinez-Pellus AE, Merino P, Bru M, Canovas J, Seller G, Sapina J, Fuentes T, Moro J: Endogenous endotoxemia of intestinal origin during cardiopulmonary bypass. Intens Care Med 1997; 23: 1251–7
Mollhoff T, Loick HM, Van Aken H, Schmidt C, Rolf N, Tjan TD, Asfour B, Berendes E: Milrinone modulates endotoxemia, systemic inflammation, and subsequent acute phase response after cardiopulmonary bypass (CPB). A nesthesiology 1999; 90: 72–80
te Velthuis H, Jansen PG, Oudemans-van Straaten HM, Sturk A, Eijsman L, Wildevuur CR: Myocardial performance in elderly patients after cardiopulmonary bypass is suppressed by tumour necrosis factor. J Cardiothorac Cardiovasc Surg 1995; 110: 1663–9
Berendes E, Molhoff T, Aken HV, Erren M, Deng MC, Loick HM: Increased plasma concentrations of serum amyloid A: An indicator of the acute phase response after cardiopulmonary bypass. Crit Care Med 1997; 25: 1527–33
Bennett-Guerrero E, Ayuso L, Hamilton-Davies C, White WD, Barclay GR, Smith PK, King SA, Muhlbaier LH, Newman MF, Mythen MG: Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery. JAMA 1997; 277: 646–50
Andersen LW, Landow L, Baek L, Jansen E, Baker S: Association between gastric intramucosal pH and splanchnic endotoxin, antibody to endotoxin, and tumour necrosis factor-α concentrations in patients undergoing cardiopulmonary bypass. Crit Care Med 1993; 21: 210–7
Andersen LW, Baek L, Degn H, Lehd J, Krasnik M, Rasmussen JP: Presence of circulating endotoxins during cardiac operations. J Thorac Cardiovasc Surg 1987; 93: 115–9
Riddington DW, Venkatesh B, Boivin CM, Bonser RS, Elliott TS, Marshall T, Mountford PJ, Bion JF: Intestinal permeability, gastric intramucosal pH and systemic endotoxemia in patients undergoing cardiopulmonary bypass. JAMA 1996; 275: 1007–12
Soulika AM, Khan MM, Hattori T, Bowen FW, Richardson BA, Hack CE, Sahu A, Edmunds LH, Lambris JD: Inhibition of heparin/protamine complex-induced complement activation by Compstatin in baboons. Clin Immunol 2000; 96: 212–21
Cavarocchi NC, England MD, Schaff HV, Russo P, Orszulak TA, Schnell WAJ, O'Brien JF: Oxygen free radical generation during cardiopulmonary bypass: Correlation with complement activation. Circulation 1986; 74: III130—3
Seghaye MC, Duchateau J, Grabitz RG, Faymonville ML, Messmer BJ, Buro-Rathsmann K, von Bernuth G: Complement activation during cardiopulmonary bypass in infants and children: Relation to postoperative multiple system organ failure. J Thorac Cardiovasc Surg 1993; 106: 978–87
Gong J, Larsson R, Ekdahl KN, Mollnes TE, Nilsson U, Nilsson B: Tubing loops as a model for cardiopulmonary bypass circuits: Both the biomaterial and the blood-gas phase induce complement activation in an in vitro model. J Clin Immunol 1996; 16: 222–9
Bruins P, te Velthuis H, Eerenberg-Belmer AJ, Yazdanbakhsh AP, de Beaumont EM, Eijsman L, Trouwborst A, Hack CE: Heparin-protamine complexes and C-reactive protein induce activation of the classical complement pathway: Studies in patients undergoing cardiac surgery and in vitro. Thromb Haemost 2000; 84: 237–43
Bruins P, te Velthuis H, Yazdanbakhsh AP, Jansen PG, van Hardvelt FW, de Beaumont EM, Wildevuur CR, Eijsman L, Hack CE: Activation of the complement system during and after cardiopulmonary bypass surgery: Postsurgery activation involves C-reactive protein and is associated with postoperative arrythmia. Circulation 1997; 96: 3542–8
Chai PJ, Nassar R, Oakeley AE, Craig DM, Quick GJ, Jaggers J, Sanders SP, Ungerleider RM, Anderson PA: Soluble complement receptor-1 protects heart, lung, and cardiac myofilament function from cardiopulmonary bypass damage. Circulation 2000; 101: 541–6
Rinder CS, Rinder HM, Johnson K, Smith M, Lee DL, Tracey J, Polack G, Higgins P, Yeh CG, Smith BR: Role of C3 cleavage in monocyte activation during extracorporeal circulation. Circulation 1999; 100: 553–8
Park KW, Tofukuji M, Metais C, Communale ME, Dai HB, Simons M, Stahl GL, Agah A, Sellke FW: Attenuation of endothelium-dependent dilation of pig pulmonary arterioles after cardiopulmonary bypass is prevented by monoclonal antibody to C5a. Anesth. Analg 1999; 89: 42–8
Tofukuji M, Stahl GL, Agah A, Metais C, Simons M, Sellke FW: Anti-C5a monoclonal antibody reduces cardiopulmonary bypass and cardioplegia-induced coronary endothelial dysfunction. J Thorac Cardiovasc Surg 1998; 116: 1060–8
Tofukuji M, Stahl GL, Metais C, Tomita M, Agah A, Bianchi C, Fink MP, Sellke FW: Mesenteric dysfunction after cardiopulmonary bypass: Role of complement C5a. Ann Thorac Surg 2000; 69: 799–807
Gupta-Bansal R, Parent JB, Brunden KR: Inhibition of complement alternative pathway function with anti-properdin monoclonal antibodies. Mol Immunol 2000; 37: 191–201
Larsson R, Elgue G, Larsson A, Ekdahl KN, Nilsson UR, Nilsson B: Inhibition of complement activation by soluble recombinant CR1 under conditions resembling those in a cardiopulmonary bypass circuit: Reduced upregulation of CD11b and complete abrogation of binding of PMNs to the biomaterial surface. Immunopharmacology 1997; 38: 119–27
Nilsson B, Larsson R, Hong J, Elgue G, Ekdahl KN, Sahu A, Lambris JD: Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation. Blood 1998; 92: 1661–7
Rinder CS, Rinder HM, Smith BR, Fitch JC, Tracey JB, Polack G, Mathis LA, Seqiunto SP, Rollins SA: Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation. J Clin Invest 1995; 96: 1564–72
Rinder CS, Rinder HM, Smith MJ, Tracey JB, Fitch J, Li L, Rollins SA, Smith BR: Selective blockade of membrane attack complex formation during simulated extracorporeal circulation inhibits platelet but not leukocyte activation. Thorac Cardiovasc Surg 1999; 118: 460–6
Shastri KA, Logue GL, Rehman S, Raza S: Complement activation by heparin-protamine complexes during cardiopulmonary bypass: Effect of C4A null allelle. J Cardiothorac Cardiovasc Surg 1997; 114: 482–8
Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD: Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983; 86: 845–57
Ranucci M, Mazzucco A, Pessotto R, Grillone G, Casati V, Porreca L, Maugeri R, Meli M, Magagna P, Cirri S, Giomarelli P, Lorusso R, de Jong A: Heparin-coated circuits for high-risk patients: A multicenter, prospective, randomized trial. Ann Thorac Surg 1999; 67: 994–1000
Fitch JC, Rollins S, Matis L, Alford B, Aranki S, Collard CD, Dewar M, Elefteriades J, Hines R, Kopf G, Kraker P, Li L, O'Hara R, Rinder C, Rinder H, Shaw R, Smith B, Stahl G, Shernan SK: Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Circulation 1999; 100: 2499–506
Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, Umberger R, Leeper K: Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Chest 1995; 107: 1062–73
McBride WT, Armstrong MA, Crockard AD, McMurray TJ, Rea JM: Cytokine balance and immunosuppressive changes at cardiac surgery: Contrasting response between patients and isolated CPB circuits. B J Anaesth 1995; 75: 724–33
Kawamura T, Wakausawa R, Okada K, Inada S: Elevation of cytokines during open heart surgery with cardiopulmonary bypass: Participation of interleukin 8 and 6 in reperfusion injury. Can J Anaesth 1993; 40: 1016–21
Sablotzki A, Mann V, Simm A, Czeslick E: Changes in the cytokine network through escalating SIRS after heart surgery. Anasthesiol Intensivmed Notfallmed Schmerzther 2001; 36: 552–9
Hauser GJ, Ben-Ari J, Colvin MP, Dalton HJ, Hertzog JH, Bearb M, Hopkins RA, Walker SM: Interleukin-6 levels in serum and lung lavage fluid of children undergoing open heart surgery correlate with postoperative morbidity. Intens Care Med 1998; 24: 481–6
Journois D, Israel-Biet D, Pouard P, Rolland B, Silvester W, Vouhe P, Safran D: High volume, zero balanced hemofiltration to reduce delayed inflamatory response to cardiopulmonary bypass in children. A nesthesiology 1996; 85: 965–76
Sandison A, Evans TW: NObel laurels, but where is the therapeutic advance? Anaesthesia 1999; 54: 411–2
Herskowitz A, Mangano DT: Inflammatory cascade: A final common pathway for perioperative injury. A nesthesiology 1996; 85: 957–60
Hammon JWJ, Vinten-Johansen J: Augmentation of microvascular nitric oxide improves myocardial performance following global ischemia. J Card Surg 1995; 10: 423–7
Macha M, Yamazaki K, Gordon LM, Watach MJ, Konishi H, Billiar TR, Borovetz HS, Kormos RL, Griffith BP, Hattler BG: The vasoregulatory role of endothelium derived nitric oxide during pulsatile cardiopulmonary bypass. ASAIO J 1996; 42: M800–4
Vedrinne C, Tronc F, Martinot S, Robin J, Allevard AM, Vincent M, Lehot JJ, Franck M, Champsaur G: Better preservation of endothelial function and decreased activation of the fetal renin-angiotensin pathway with the use of pulsatile flow during experimental fetal bypass. J Thorac Cardiovasc Surg 2000; 120: 770–7
Busse R, Fleming I: Pulsatile stretch and shear stress: Physical stimuli determining the production of endothelium-derived relaxing factors. J Vasc Res 1998; 35: 73–84
Hutcheson IR, Griffith TM: Release of endothelium-derived relaxing factor is modulated both by frequency and amplitude of pulsatile flow. Am J Physiol 1991; 261: H257–62
Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL: Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257: 387–9
Mayers I, Salas E, Hurst T, Johnson D, Radomski MW: Increased nitric oxide synthase activity is increased after canine cardiopulmonary bypass is suppressed by s-nitrosoglutathione. J Thorac Cardiovasc Surg 1999; 117: 1009–16
Beckman JS, Koppenol WH: Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and ugly. Am J Physiol 1996; 271: C1424–37
Salzman AL: Endotoxic notrosopenia. Intens Care Med 1998; 24: 1239–41
Knowles RG, Merret M, Salter M, Moncada S: Differential induction of brain, lung and liver nitric oxide synthase by endotoxin in the rat. Biochem J 1990; 270: 833–6
Bhagat K, Hingorani AD, Palacios M, Charles IG, Vallance P: Cytokine-induced venodilatation in humans in vivo: eNOS masquerading as iNOS. Cardiovasc Res 1999; 41: 754–64
Beghetti M, Silkoff PE, Caramori M, Holtby HM, Slutsky AS, Adatia I: Decreased exhaled nitric oxide may be a marker of cardiopulmonary bypass-induced injury. Ann Thorac Surg 1998; 66: 532–4
Brett S, Quinlan GJ, Mitchell J, Pepper JR, Evans TW: Production of nitric oxide during surgery using cardiopulmonary bypass. Crit Care Med 1998; 26: 272–8
Burman JF, Chung HI, Lane DA, Philippou H, Adami A, Lincoln JC: Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass. Lancet 1994; 344: 1192–3
Boyle EMJ, Pohlman TH, Johnson MC, Verrier ED: Endothelial cell injury in cardiovascular surgery: The systemic inflammatory response. Ann Thorac Surg 1997; 63: 277–84
Ereth MH: A contemporary view of coagulation, The Relationship between Coagulation, Inflammation, and the Endothelium: A Pyramid Towards Outcome. Edited by Speiss B, Monograph. Society of Cardiovascular Anesthesiologists. Baltimore, Lippincott Williams and Wilkins, 2000, pp 129–46
Esmon CT, Fukudome K, Mather T, Bode W, Regan LM, Stearns-Kurosawa DJ, Kurosawa S: Inflammation, sepsis, and coagulation. Haematologica 1999; 84: 254–9
Cicala C, Cirino G: Linkage between inflammation and coagulation: An update on the molecular basis of the crosstalk. Life Sci 1998; 62: 1817–24
Tyrrell DJ, Horne AP, Holme KR, Preuss JM, Page CP: Heparin in inflammation: Potential therapeutic applications beyond anticoagulation. Adv Pharmacol 1999; 46: 151–208
Carr JA, Silverman N: The heparin-protamine interaction: A review. J Cardiovasc Surg (Torino) 1999; 40: 659–66
Chandler WL, Fitch JC, Wall MH, Verrier ED, Cochran RP, Soltow LO, Spiess D: Individual variations in the fibrinolytic response during and after cardiopulmonary bypass. Thromb Haemost 1995; 74: 1293–7
McGilvray ID, Rotstein OD: Role of the coagulation system in the local and systemic inflammatory response. World J Surg 1998; 22: 179–86
Sheppard KA, Rose DW, Haque ZK, Kurokawa R, McInerney E, Westin S, Thanos D, Rosenfeld MG, Glass CK, Collins T: Transcriptional activation by NF-kappaB requires multiple coactivators. Mol Cell Biol 1999; 19: 6367–78
Elliott MJ, Finn AHR: Interaction between neutrophils and the endothelium. Ann Thorac Surg 1993; 56: 1503–8
Hill GE, Whitten CW: The role of the vascular endothelium in inflammatory syndromes, atherogenesis, and the propagation of disease. J Cardiothorac Vasc Anesth 1997; 11: 316–21
Schulze-Neick I, Penny DJ, Rigby ML, Morgan C, Kelleher A, Collins P, Li J, Bush A, Shinebourne EA, Redington AN: L-arginine and substance P reverse the pulmonary endothelial dysfunction caused by congenital heart surgery. Circulation 1999; 100: 749–55
Kinlay S, Ganz P: Relation between endothelial dysfunction and the acute coronary syndrome: Implications for therapy. Am J Cardiol 2000; 86: 10J–3J
Vallance P, Collier J, Bhagat K: Infection, inflammation, and infarction: Does acute endothelial dysfunction provide a link? Lancet 1997; 349: 1391–2
Bhagat K, Vallance P: Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo. Circulation 1997; 96: 3042–7
Bhagat K, Moss R, Collier J, Vallance P: Endothelial “stunning” following a brief exposure to endotoxin: A mechanism to link infection and infarction? Cardiovasc Res 1996; 32: 822–9
Hingorani AD, Cross J, Kharbanda RK, Mullen MJ, Bhagat K, Taylor M, Donald AE, Palacios M, Griffin GE, Deanfield JE, MacAllister RJ, Vallance P: Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation 2000; 102: 994–9
Schachinger V, Britten MB, Zeiher AM: Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary artery disease. Circulation 2000; 101: 1899–1906
Gimbrone MA, Topper JN, Nagel T, Anderson KR, Garcia-Cardena G: Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci 2000; 902: 230–9
Landmesser U, Hornig B, Drexler H: Endothelial dysfunction in hypercholesterolemia: Mechanisms, pathophysiological importance, and therapeutic interventions. Semin Thromb Hemost 2000; 26: 529–37
Foreman KE, Vaporciyan AA, Bonish BK, Jones ML, Johnson KJ, Glovsky MM, Eddy SM, Ward PA: C5a-induced expression of P-selectin in endothelial cells. J Clin Invest 1994; 94: 1147–55
Pinsky DJ, Naka Y, Liao H, Oz MC, Wagner DD, Mayadas TN, Johnson RC, Hynes RO, Heath M, Lawson CA, Stern DM: Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies: A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest 1996; 97: 493–500
Gilliland HE, Armstrong MA, Uprichard S, Clarke G, McMurray TJ: The effect of aprotinin on interleukin-8 concentration and leukocyte adhesion molecule expression in an isolated cardiopulmonary bypass system. Anaesthesia 1999; 54: 427–33
Tonz M, Mihaljevic T, von Segesser LK, Fehr J, Schmid ER, Turina MI: Acute lung injury during cardiopulmonary bypass: Are the neutrophils responsible? Chest 1995; 108: 1551–6
Kharazmi A, Andersen LW, Baek L, Valerius NH, Laub M, Rasmussen JP: Endotoxemia and enhanced generation of oxygen radicals by neutrophils from patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989; 98: 381–5
Boyle EMJ, Morgan EN, Kovacich JC, Canty TGJ, Verrier ED: Microvascular responses to cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1999; 13: 30–5
Stefano GB, Bilfiger TV: Human neutrophil and macrophage chemokinesis induced by cardiopulmonary bypass: Loss of DAME and IL-1 chemotaxis. J Neuroimmunol 1993; 47: 189–97
Bilfinger TV, Stefano G: Evidence of immunocyte stimulatory molecule(s) in plasma of patients undergoing cardiopulmonary bypass. J Cardiovasc Surg (Torino) 1993; 34: 129–33
Kawahito K, Kawakami M, Fujiwara T, Adachi H, Ino T: Interleukin-8 and monocyte chemotactic activating factor responses to cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995; 110: 99–102
Tsuchida M, Watanabe H, Watanabe T, Hirahara H, Haga M, Ohzeki H, Hayashi J, Miyamura H, Hirono T, Abo T, Eguchi S: Effect of cardiopulmonary bypass on cytokine release and adhesion molecule expression in alveolar macrophages: Preliminary report in six cases. Am J Respir Crit Care Med 1997; 156: 932–8
Kawahito K, Kobayashi E, Ohmori M, Harada K, Kitoh Y, Fujimura A, Fuse K: Enhanced responsiveness of circulatory neutrophils after cardiopulmonary bypass: Increased aggregability and superoxide producing capacity. Artif Organs 2000; 24: 37–42
Partrick DA, Moore EE, Fullerton DA, Barnett CCJ, Meldrum DR, Silliman CC: Cardiopulmonary bypass renders patients at risk for multiple organ failure via early neutrophil priming and late neutrophil disability. J Surg Res 1999; 86: 42–9
Shimono T, Yada I, Kusagawa M, Sato T, Kondo C, Tanaka K, Yuasa H, Kusagawa M: Reticuloendothelial function following cardiopulmonary bypass: Laboratory and electron microscopy findings. J Surg Res 1994; 56: 446–51
Shimono T, Yada I, Kusagawa M, Nose Y: Oversaturation status of reticuloendothelial system following cardiopulmonary bypass. Artif Organs 1994; 18: 596–602
Ratliff NB, Young WGJ, Hackel DB, Mikat E, Wilson JW: Pulmonary injury secondary to extracorporeal circulation: An ultrastructural study. J Thorac Cardiovasc Surg 1973; 65: 425–32
Royston D, Fleming JS, Desai JB, Westaby S, Taylor KM: Increased production of peroxidation products associated with cardiac operations: Evidence for free radical generation. J Thorac Cardiovasc Surg 1986; 91: 759–66
Wilson I, Gillinov AM, Curtis WE, DiNatale J, Burch RM, Gardner TJ, Cameron DE: Inhibition of neutrophil adherence improves postischemic ventricular performance of the neonatal heart. Circulation 1993; 88: II372–9
Mayers I, Hurst T, Johnston D, Cujec B, Ang LC, Thomson D, Fox JA, Blank GS, Saxena A, Richardson JS: Anti-CD18 antibodies improve cardiac function following cardiopulmonary bypass in dogs. J Crit Care 1996; 11: 189–97
Friedman M, Wang SY, Selike FW, Cohn WE, Weintraub RM, Johnson RG: Neutrophil adhesion blockade with NPC 15669 decreases pulmonary injury after total cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996; 111: 460–8
Roth M, Kraus B, Scheffold T, Reuthebuch O, Klovekorn WP, Bauer EP: The effect of leukocyte-depleted blood cardioplegia in patients with severe left ventricular dysfunction: A randomized, double-blind study. J Thorac Cardiovasc Surg 2000; 120: 642–50
Tashiro H, Shimokawa H, Yanamoto K, Momohara M, Tada H, Takeshita A: Altered plasma levels of cytokines in patients with ischemic heart disease. Coron Art Dis 1997; 8: 143–7
Deng MC, Dasch B, Erren M, Mollhoff T, Scheld HH: Impact of left ventricular dysfunction on cytokines, hemodynamics, and outcome in bypass grafting. Ann Thorac Surg 1996; 62: 184–90
Matata BM, Galinanes M: Cardiopulmonary bypass exacerbates oxidative stress but does not increase proinflammatory cytokine release in patients with diabetes compared with patients without diabetes: Regulatory effects of exogenous nitric oxide. J Thorac Cardiovasc Surg 2000; 120: 1–11
Reinhold D, Ansorge S, Schleicher ED: Elevated glucose levels stimulate transforming growth factor-beta 1 (TGF-beta 1), suppress interleukin IL-2, IL-6 and IL-10 production and DNA synthesis in peripheral blood mononuclear cells. Horm Metab Res 1996; 28: 267–70
Roth-Isigkeit A, Schwarzenberger J, v. Borstel T, Gehring H, Ocklitz E, Wagner K, Schmucker P, Seyfarth M: Perioperative cytokine release during coronary artery bypass grafting in patients of different ages. Clin Exp Immunol 1998; 114: 26–32
Reich DL, Bodian CA, Krol M, Kuroda M, Osinski T, Thys DM: Intraoperative hemodynamic predictors of mortality, stroke, and myocardial infarction after coronary artery bypass surgery. Anesth Analg 1999; 89: 814–22
Rady MY, Ryan T, Starr NJ: Perioperative determinants of morbidity and mortality in elderly patients undergoing cardiac surgery. Crit Care Med 1998; 26: 225–35
Bams JL, Mariani MA, Groeneveld AB: Predicting outcome after cardiac surgery: Comparison of global haemodynamic and tonometric variables. Br J Anaesth 1999; 82: 33–7
Nugent WC: Innovative uses of a cardiothoracic database. Ann Thorac Surg 1999; 68: 359–61
Xiao F, Eppihimer MJ, Young JA, Nguyen K, Carden DL: Lung neutrophil retention and injury after intestinal ischemia/reperfusion. Microcirculation 1997; 4: 359–67
Turnage RH, Wright JK, Iglesias J, LaNoue JL, Nguyen H, Kim L, Myers S: Intestinal reperfusion-induced pulmonary edema is related to increased pulmonary inducible nitric oxide synthase activity. Surgery 1998; 124: 457–62
Koike K, Moore FA, Moore EE, Read RA, Carl VS, Banerjee A: Gut ischemia mediates lung injury by a xanthine oxidase-dependent neutrophil mechanism. J Surg Res 1993; 54: 469–73
Caty MG, Guice KS, Oldham KT, Remick DG, Kunkel SI: Evidence for tumor necrosis factor-induced pulmonary microvascular injury after intestinal ischemia-reperfusion injury. Ann Surg 1990; 212: 694–700
Sorkine P, Setton A, Halpern P, Miller A, Rudick V, Marmor S, Klausner JM, Goldman G: Soluble tumor necrosis factor receptors reduce bowel ischemia-induced lung permeability and neutrophil sequestration. Crit Care Med 1995; 23: 1377–81
Gutierrez G, Palizas F, Doglio G, Wainsztein N, Gallesio A, Pacin J, Dubin A, Schiavi E, Jorge M, Pusajo J, Klein F, San Roman E, Dorfman B, Shottlender J, Giniger R: Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients. Lancet 1992; 339: 195–9
Uusaro A, Ruokonen E, Takala J: Splanchnic oxygen transport after cardiac surgery: Evidence for inadequate tissue perfusion after stabilization of hemodynamics. Intens Care Med 1996; 22: 26–33
Fiddian-Green RG, Baker S: Predictive value of the stomach wall pH for complications after cardiac operations: Comparison with other monitoring. Crit Care Med 1987; 15: 153–6
Bennett-Guerrero E, Panah MH, Bodian CA, Methikalam BJ, Alfarone JR, DePerio M, Mythen MG: Automated detection of gastric luminal partial pressure of carbon dioxide during cardiovascular surgery using the Tonocap. A nesthesiology 2000; 92: 38–45
Loick HM, Schmidt C, Van Aken H, Junker R, Erren M, Berendes E, Rolf N, Meissner A, Schmid C, Scheld HH, Mollhoff T: High thoracic epidural anesthesia, but not clonidine, attenuates the perioperative stress response via sympatholysis and reduces the release of troponin T in patients undergoing coronary artery bypass grafting. Anesth Analg 1999; 88: 701–9
Brix-Christensen V, Tonnesen E, Sorensen IJ, Bilfinger TV, Sanchez RG, Stefano GB: Effects of anaesthesia based on high versus low doses of opioids on the cytokine and acute-phase protein responses in patients undergoing cardiac surgery. Acta Anaes Scand 1998; 42: 63–70
Muller H, Hugel W, Reifschneider HJ, Horpacsy G, Hannekum A, Dalichau H: Lysosomal enzyme activity influenced by various types of respiration during extracorporeal circulation. Thorac Cardiovasc Surg 1989; 37: 65–71
Magnusson L, Zemgulis V, Tenling A, Wernlund J, Tyden H, Thelin S, Hedenstierna G: Use of a vital capacity maneuver to prevent atelectasis after cardiopulmonary bypass: An experimental study. A nesthesiology 1998; 88: 134–42
Berry CB, Butler PJ, Myles PS: Lung management during cardiopulmonary bypass: Is continuous positive airways pressure beneficial? Br J Anaesth 1993; 71: 864–8
Christiansen CL, Ahlburg P, Jakobsen CJ, Andresen EB, Paulsen PK: The influence of propofol and midazolam/halothane anesthesia on hepatic SvO2and gastric mucosal pH during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1998; 12: 418–21
Gilliland HE, Armstrong MA, Carabine U, McMurray TJ: The choice of anesthetic maintenance technique influences the antiinflammatory cytokine response to abdominal surgery. Anesth Analg 1997; 85: 1394–8
Galley HF, Dubbels AM, Webster NR: The effect of midazolam and propofol on interleukin-8 from human polymorphonuclear leukocytes. Anesth Analg 1998; 86: 1289–93
Mathy-Hartert M, Deby-Dupont G, Hans P, Deby C, Lamy M: Protective activity of propofol, diprivan and intralipid against active oxygen species. Mediators Inflamm 1998; 7: 327–33
Szekely A, Heindl B, Zahler S, Conzen PF, Becker BF: Nonuniform behavior of intravenous anesthetics on postischemic adhesion of neutrophils in the guinea pig heart. Anesth Analg 2000; 90: 1293–300
Heller A, Heller S, Blecken S, Urbaschek R, Koch T: Effects of intravenous anesthetics on bacterial elimination in human blood in vitro. Acta Anaesthesiol Scand 1998; 42: 518–26
Frohlich D, Rothe G, Schwall B, Schmitz G, Hobbhahn J, Taeger K: Thiopentone and propofol, but not methohexitone nor midazolam, inhibit neutrophil oxidative responses to the bacterial peptide FMLP. Eur J Anaesthesiol 1996; 13: 582–8
O'Donnell NG, McSharry CP, Wilkinson PC, Asbury AJ: Comparison of the inhibitory effect of propofol, thiopentone and midazolam on neutrophil polarization in vitro in the presence or absence of human serum albumin. Br J Anaesth 1992; 69: 70–4
Skoutelis A, Lianou P, Papageorgiou E, Kokkinis K, Alexopoulos K, Bassaris H: Effects of propofol and thiopentone on polymorphonuclear leukocyte functions in vitro. Acta Anaesthesiol Scand 1994; 38: 858–62
Hulse D, Kusel JR, O'Donnell NG, Wilkinson PC: Effects of anaesthetics on membrane mobility and locomotor responses of human neutrophils. FEMS Immunol Med Microbiol 1994; 8: 241–8
Jensen AG, Dahlgren C, Eintrei C: Propofol decreases random and chemotactic stimulated locomotion of human neutrophils in vitro. Br J Anaesth 1993; 70: 99–100
Murphy PG, Ogilvy AJ, Whiteley SM: The effect of propofol on the neutrophil respiratory burst. Eur J Anaesthesiol 1996; 13: 471–3
Heine J, Leuwer M, Scheinichen D, Arseniev L, Jaeger K, Piepenbrock S: Flow cytometry evaluation of the in vitro influence of four i.v. anaesthetics on respiratory burst of neutrophils. Br J Anaesth 1996; 77: 387–92
Roytblat L, Talmor D, Rachinsky M, Greemberg L, Pekar A, Appelbaum A, Gurman GM, Shapira Y, Duvdenani A: Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg 1998; 87: 266–71
Lysle DT, Hoffman KE, Dykstra LA: Evidence for the involvement of the caudal region of the periaqueductal gray in a subset of morphine-induced alterations of immune status. J Pharmacol Exp Therap 1996; 277: 1533–40
Makman MH, Bilfinger TV, Stefano GB: Human granulocytes contain an opiate alkaloid-selective receptor mediating inhibition of cytokine-induced activation and chemotaxis. J Immunol 1995; 154: 1323–30
Brix-Christensen V, Tonnesen E, Sanchez RG, Bilfinger TV, Stefano GB: Endogenous morphine levels increase following cardiac surgery as part of the antiinflammatory response? Int J Cardiol 1997; 62: 191–7
Bussiere JL, Adler MW, Rogers TJ, Eisenstein TK: Cytokine reversal of morphine-induced suppression of the antibody response. J Pharmacol Exp Ther 1993; 264: 591–7
Bilfinger TV, Fimiani C, Stefano GB: Morphine's immunoregulatory actions are not shared by fentanyl. Int J Cardiol 1998; 64: S61–6
McBride WT, Armstrong MA, McMurray TJ: An investigation of the effects of heparin, low molecular weight heparin, protamine, and fentanyl on the balance of pro- and anti-inflammatory cytokines in in-vitro monocyte cultures. Anaesthesia 1996; 51: 634–40
Mitsuhata H, Shimizu R, Yokoyama MM: Suppressive effects of volatile anesthetics on cytokine release in human peripheral blood mononuclear cells. Int J Immunopharmacol 1995; 17: 529–34
Kotani N, Hashimoto H, Sessler DI, Kikuchi A, Suzuki A, Takahashi S, Muraoka M, Matsuki A: Intraoperative modulation of alveolar macrophage function during isoflurane and propofol anesthesia. A nesthesiology 1998; 89: 1125–32
Louvier N, Lancon JP: Do halogenated anesthetics protect from ischemic and reperfusion myocardial injuries? Ann Fr Anesth Reanim 1994; 13: 690–8
Tanguay M, Blaise G, Dumont L, Beique G, Hollmann C: Beneficial effects of volatile anesthetics on decrease in coronary flow and myocardial contractility induced by oxygen-derived free radicals in isolated rabbit hearts. J Cardiovasc Pharmacol 1991; 18: 863–70
Nakamura T, Kashimoto S, Oguchi T, Kumazawa T: Hydroxyl radical formation during inhalation anesthesia in the reperfused working rat heart. Can J Anaesth 1999; 46: 470–5
Kowalski C, Zahler S, Becker BF, Flaucher A, Conzen PF, Gerlach E, Peter K: Halothane, isoflurane, and sevoflurane reduce postischemic adhesion of neutrophils in the coronary system. A nesthesiology 1997; 86: 188–95
Heindl B, Conzen PF, Becker BF: The volatile anesthetic sevoflurane mitigates cardiodepressive effects of platelets in reperfused hearts. Basic Res Cardiol 1999; 94: 102–11
Heindl B, Becker BF, Zahler S, Conzen PF: Volatile anaesthetics reduce adhesion of blood platelets under low-flow conditions in the coronary system of isolated guinea pig hearts. Acta Anaesthesiol Scand 1998; 42: 995–1003
Heindl B, Reichle FM, Zahler S, Conzen PF, Becker BF: Sevoflurane and isoflurane protect the reperfused guinea pig heart by reducing postischemic adhesion of polymorphonuclear neutrophils. A nesthesiology 1999; 91: 521–30
Holsapple MP, Malave A, Lowy MT, Yim GK: Central and peripheral anti-inflammatory actions by clonidine and a structurally related imidazoline analog. J Pharmacol Exp Ther 1984; 229: 399–403
Lindgren BR, Brundin A, Andersson RG: Inhibitory effects of clonidine on the allergen-induced wheal-and-flare reactions in patients with extrinsic asthma. J Allergy Clin Immunol 1987; 79: 941–6
Lindgren BR, Grundstrom N, Andersson RG: Effects of an alpha-2 adrenoceptor agonist on angiotensin converting enzyme inhibitor-induced hypotension and potentiated allergen-evoked inflammatory skin responses. J Pharmacol Exp Ther 1988; 245: 932–5
Kulkarni SK, Mehta AK, Kunchandy J: Anti-inflammatory actions of clonidine, guanfacine and B-HT 920 against various inflammagen-induced acute paw oedema in rats. Arch Int Pharmacodyn Ther 1986; 279: 324–34
Spengler RN, Allen RM, Remick DG, Strieter RM, Kunkel SL: Stimulation of alpha-adrenergic receptor augments the production of macrophage-derived tumor necrosis factor. J Immunol 1990; 145: 1430–4
Welters I, Menges T, Ballesteros M, Sablotzki A, Gorlach G, Hempelmann G: Acute phase and opsonin response in cardiac surgery patients: Influence of underlying cardiac disease. Perfusion 1998; 13: 447–54
Fingerle-Rowson G, Auers J, Kreuzer E, Fraunberger P, Blumenstein M, Ziegler-Heitbrock LH: Expansion of CD14+CD16+ monocytes in critically ill cardiac surgery patients. Inflammation 1998; 22: 367–79
Chello M, Mastroroberto P, Romano R, Ascione R, Pantaleo D, De Amicis V: Complement and neutrophil activation during cardiopulmonary bypass: A randomized comparison of hypothermic and normothermic circulation. Eur J Cardiothorac Surg 1997; 11: 162–8
Menasche P, Haydar S, Peynet J, Du Buit C, Merval R, Bloch G, Piwnica A, Tedgui A: A potential mechanism of vasodilation after warm heart surgery: The temperature dependent release of cytokines. J Thorac Cardiovasc Surg 1994; 107: 293–9
Ohata T, Sawa Y, Kadoba K, Masai T, Ichikawa H, Matsuda H: Effect of cardiopulmonary bypass under tepid temperature on inflammatory reactions. Ann Thorac Surg 1997; 64: 124–8
Wan S, Yim AP, Arifi AA, Lee TW, DeSmet JM, LeClerc JL, Vincent JL: Can cardioplegia management influence cytokine responses during clinical cardiopulmonary bypass. Ann Thorac Cardiovasc Surg 1999; 5: 81–5
Steinberg BM, Gossi EA, Schwartz DS, McLoughlin DE, Aquinaga M, Bizekis C, Greenwald J, Flisser A, Spencer FC, Galloway AC, Colvin SB: Heparin bonding of bypass circuits reduces cytokine release during cardiopulmonary bypass. Ann Thorac Surg 1995; 60: 525–9
Jansen PG, te Velthuis H, Wildevuur WR, Huybregts MA, Bulder ER, van der Spoel HI, Sturk A, Eijsman L, Wildevuur CR: Cardiopulmonary bypass with modified fluid gelatin and heparin coated circuits. Br J Anaesth 1996; 76: 13–9
Nilsson L, Tyden H, Johansson O, Nilsson U, Ronquist G, Venge P, Aberg P, Nystrom SO: Bubble and membrane oxygenators: Comparison of postoperative organ dysfunction with special reference to inflammatory activity. Scand J Thorac Cardiovasc Surg 1990; 24: 59–64
Martin W, Carter R, Tweddel A, Belch J, el-Fiky M, McQuiston AM, McLaren M, Wheatley DJ: Respiratory function and white cell activation following cardiopulmonary bypass: Comparison of membrane and bubble oxygenators. Eur J Cardiothorac Surg 1996; 10: 774–83
Morgan IS, Codispoti M, Sanger K, Mankad PS: Superiority of centrifugal pump over roller pump in paediatric cardiac surgery: Prospective randomised trial. Eur J Cardiothorac Surg 1998; 13: 526–32
Ashraf SS, Tian Y, Cowan D, Shaikh R, Parsole M, Martin P, Watterson KG: Proinflammatory cytokine release during pediatric cardiopulmonary bypass: Influence of centrifugal and roller pumps. J Cardiothorac Vasc Anesth 1997; 11: 718–22
Ashraf S, Butler J, Tian Y, Cowan D, Lintin S, Saunders NR, Watterson KG, Martin PG: Inflammatory mediators in adults undergoing cardiopulmonary bypass: Comparison of centrifugal and roller pumps. Ann Thorac Surg 1998; 65: 480–4
Orime Y, Shiono M, Hata H, Yagi S, Tsukamoto S, Okumura H, Nakata K, Hata M, Sezai A, Sezai Y: Cytokine and endothelial damage in pulsatile and non-pulsatile cardiopulmonary bypass. Artif Organs 1999; 23: 508–12
De Somer D, Foubert L, Vanackere M, Dujardin D, Delanghe J, Van Nooten G: Impact of oxygenator design on hemolysis, shear stress, and white blood cell and platelet counts. J Cardiothorac Vasc Anesth 1996; 10: 884–9
Kameneva MV, Undar A, Antaki JF, Watach MJ, Calhoon JH, Borovetz HS: Decrease in red blood cell deformability caused by hypothermia, hemodilution, and mechanical stress: Factors related to cardiopulmonary bypass. ASAIO J 1999; 45: 307–10
Dewitz TS, Hung TC, Martin RR, McIntire LV: Mechanical trauma in leukocytes. J Lab Clin Med 1977; 90: 728–36
Butler J, Rocker GM, O'Brien JR, Etherington M, Pillai R, Westaby S: Platelet responses to cardiopulmonary bypass: Assessment by a shear stress activation technique. J Cardiovasc Surg (Torino) 1992; 33: 33–7
Boyle EM, Lille ST, Allaire E, Clowes AW, Verrier ED: Endothelial cell injury in cardiovascular surgery: Atherosclerosis. Ann Thorac Surg 1997; 63: 885–94
Gu YJ, Boonstra PW, Graaff R, Rijnsburger AA, Mungroop H, van Oeveren W: Pressure drop, shear stress, and activation of leukocytes during cardiopulmonary bypass: A comparison between hollow fiber and flat sheet membrane oxygenators. Artif Organs 2000; 24: 43–8
Stover EP, Siegel LC, Parks R, Levin J, Body SC, Maddi R, D'Ambra MN, Mangano DT, Spiess BD: Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines: A 24-institution study. Institutions of the Multicenter Study of Perioperative Ischemia Research Group. A nesthesiology 1998; 88: 327–33
Fransen E, Maessen J, Dentener M, Senden N, Buurman W: Impact of blood transfusions on inflammatory mediator release in patients undergoing cardiac surgery. Chest 1999; 116: 1233–9
Yasuura K, Okamoto H, Matsuura A: Transfusion-associated graft-versus-host disease with transfusion practice in cardiac surgery. J Cardiovasc Surg (Torino) 2000; 41: 377–80
Marik PE, Sibbald WJ: Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993; 269: 3024–9
Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E: A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340: 409–17
Schmidt H, Bendtzen K, Mortensen PE: The inflammatory cytokine response after autotransfusion of shed mediastinal blood. Acta Anaesth Scand 1998; 42: 558–64
de Haan J, Boonstra PW, Monnink SH, Ebels T, van Oeveren W: Retransfusion of suctioned blood during cardiopulmonary bypass impairs hemostasis. Ann Thorac Surg 1995; 59: 901–7
Martin J, Robitaille D, Perrault LP, Pellerin M, Page P, Searle N, Cartier R, Hebert Y, Pelletier LC, Thaler HT, Carrier M: Reinfusion of mediastinal blood after heart surgery. J Thorac Cardiovasc Surg 2000; 120: 499–504
Huet C, Salmi LR, Fergusson D, Koopman-van Gemert AW, Rubens F, Laupacis A: A meta-analysis of the effectiveness of cell salvage to minimize perioperative allogeneic blood transfusion in cardiac and orthopedic surgery. International Study of Perioperative Transfusion (ISPOT) Investigators. Anesth Analg 1999; 89: 861–9
van Bommel EF, Hesse CJ, Jutte NH, Zietse R, Bruining HA, Weimar W: Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome. Ren Fail 1997; 19: 443–54
van Bommel EF: Should continuous renal replacement therapy be used for ‘non-renal’ indications in critically ill patients with shock? Resuscitation 1997; 33: 257–70
Slutsky AS: Mechanical ventilation. American College of Chest Physicians’ Consensus Conference. Chest 1993; 104: 1833–59
Nahum A, Hoyt J, Schmitz L, Moody J, Shapiro R, Marini JJ: Effect of mechanical ventilation strategy on dissemination of intratracheally instilled Esterichia coli in dogs. Crit Care Med 1997; 25: 1733–43
Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS: Injurious ventilatory strategies increase cytokines and c-fos mRNA expression in an isolated rat lung model. J Clin Invest 1997; 99: 944–52
von Bethmann AN, Brasch F, Nusing R, Vogt K, Volk HD, Muller KM, Wendel A, Uhlig S: Hyperventilation induces release of cytokines from perfused mouse lung. Am J Resp Crit Care Med 1998; 157: 263–72
Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A, Bruno F, Slutsky AS: Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: A randomized controlled trial. JAMA 1999; 282: 54–61
Jean D, Rezaiguia-Delclaux S, Delacourt C, Leclercq R, LAfuma C, Brun-Buisson C, Harf A, Delclaux C: Protective effect of endotoxin instillation on subsequent bacteria-induced acute lung injury in rats. Am J Respir Crit Care Med 1998; 158: 1702–8
Van Leeuwen PA, Boermeester MA, Houdijk AP, Ferwerda CC, Cuesta MA, Meyer S, Wesdorp RI: Clinical significance of translocation. Gut 1994; 35: S28–34
Hubner G, Brauchle M, Smola H, Madlener M, Fassler R, Werner S: Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid treated mice. Cytokine 1996; 8: 548–56
Ogle CK, Guo X, Chance WT, Ogle JD: Induction of endotoxin tolerance in rat bone marrow cells by in vivo infusion of tumour necrosis factor. Crit Care Med 1997; 25: 827–33
Brown JM, White CW, Terada LS, Ma G, Shanley PF, Mulvin DW, Banerjee A, Whitman GJ, Harken AH, Repine IE: Interleukin 1 pretreatment decreases ischemia/reperfusion injury. Proc Natl Acad Sci U S A 1990; 87: 5026–30
Livelli FD, Johnson RA, McEnany MT, Sherman E, Newell J, Block PC, DeSanctis RW: Unexplained in-hospital fever following cardiac surgery: Natural history, relationship to postpericardiotomy syndrome, and a prospective study of therapy with indomethacin versus placebo. Circulation 1978; 57: 968–75
Butler J, Pathi VL, Paton RD, Logan RW, MacArthur KJ, Jamieson MP, Pollock JC: Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms. Ann Thorac Surg 1996; 62: 538–42
Yared JP, Starr NJ, Hoffmann-Hogg L, Bashour CA, Insler SR, O'Connor M, Piedmonte M, Cosgrove DM: Dexamethasone decreases the incidence of shivering after cardiac surgery: A randomized, double-blind, placebo-controlled study. Anesth Analg 1998; 87: 795–9
Miranda DR, Stoutenbeek C, Karliczek G, Rating W: Effects of dexamethason on the early postoperative course after coronary artery bypass surgery. Thorac Cardiovasc Surg 1982; 30: 21–7
Toft P, Christiansen K, Tonnesen E, Nielsen CH, Lillevang S: Effect of methylprednisolone on the oxidative burst activity, adhesion molecules and clinical outcome following open heart surgery. Scand Cardiovasc J 1997; 31: 283–8
Nkere UU, Whawell SA, Thompson EM, Thompson JN, Taylor KM: Changes in pericardial morphology and fibrinolytic activity during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 106: 339–45
Peng MJ, Vargas FS, Cukier A, Terra-Filho M, Teixeira LR, Light RW: Postoperative pleural changes after coronary revascularization: Comparison between saphenous vein and internal mammary artery grafting. Chest 1992; 101: 327–30
Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R: The American-European consensus conference on ARDS: Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Resp Crit Care Med 1994; 149: 818–24
Rady MY, Ryan T, Starr NJ: Early onset of acute pulmonary dysfunction after cardiovascular surgery: Risk factors and clinical outcome. Crit Care Med 1997; 25: 1831–9
Messent M, Sullivan K, Keogh BF, Morgan CJ, Evans TW: Adult respiratory distress syndrome following cardiopulmonary bypass: Incidence and prediction. Anaesthesia 1992; 47: 267–8
Sinclair DG, Haslam PL, Quinlan GJ, Pepper JR, Evans TW: The effect of cardiopulmonary bypass on intestinal and pulmonary endothelial permeability. Chest 1995; 108: 718–24
Reeve WG, Ingram SM, Smith DC: Respiratory function after cardiopulmonary bypass: A comparison of bubble and membrane oxygenators. J Cardiothorac Vasc Anesth 1994; 8: 502–8
Kaul TK, Fields BL, Riggins LS, Wyatt DA, Jones CR, Nagle D: Adult respiratory distress syndrome following cardiopulmonary bypass: Incidence, prophylaxis and management. J Cardiovasc Surg (Torino) 1998; 39: 777–81
Messent M, Sinclair DG, Quinlan GJ, Mumby SE, Gutteridge JM, Evans TW: Pulmonary vascular permeability after cardiopulmonary bypass and its relationship to oxidative stress. Crit Care Med 1997; 25: 425–9
Cavarocchi NC, Pluth JR, Schaff HV, Orszulak TA, Homburger HA, Solis E, Kaye MP, Clancy MS, Kolff J, Deeb GM: Complement activation during cardiopulmonary bypass: Comparison of bubble and membrane oxygenators. J Thorac Cardiovasc Surg 1986; 91: 252–8
Ito H, Hamano K, Gohra H, Katoh T, Fujimura Y, Tsuboi H, Esato K: Relationship between respiratory failure and cytokine response after cardiopulmonary bypass. Surg Today 1997; 27: 220–5
Journois D, Pouard P, Greeley WJ, Mauriat P, Vouhe P, Safran D: Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery: Effects on hemostasis, cytokines, and complement components. A nesthesiology 1994; 81: 1181–9
Gu YJ, deVries AJ, Boonstra PW, van Oeveren W: Leukocyte depletion results in improved lung function and reduced inflammatory response after cardiac surgery. J Thorac Cardiovasc Surg 1996; 112: 494–500
Gillinov AM, Redmond JM, Zehr KJ, Wilson IC, Curtis WE, Bator JM, Burch RM, Reitz BA, Baumgartner WA, Herskowitz A, Cameron DE: Inhibition of neutrophil adhesion during cardiopulmonary bypass. Ann Thorac Surg 1994; 57: 126–33
Gillinov A, DeValeria PA, Winklestein JA, Ilson I, Curtis WE, Shaw D, Yeh CG, Rudolph AR, Baumgartner WA, Herskowitz A, Cameron DE: Complement inhibition with soluble complement receptor type 1 in cardiopulmonary bypass. Ann Thorac Surg 1993; 55: 619–24
Mangano DT: Cardiovascular morbidity and CABG surgery—A perspective: Epidemiology, costs, and potential therapeutic solutions. J Card Surg 1995; 10: 366–8
Jain U, Laflamme CJ, Aggarwal A, Ramsay JG, Comunale ME, Ghoshal S, Ngo L, Ziola K, Hollenberg M, Mangano DT: Electrocardiographic and hemodynamic changes and their association with myocardial infarction during coronary artery bypass surgery: A multicenter study. Multicenter Study of Perioperative Ischemia (McSPI) Research Group. A nesthesiology 1997; 86: 576–91
Hennein HA, Ebba H, Rodriguez JL, Merrick SH, Keith FM, Bronstein MH, Leung JM, Mangano DT, Greenfield LJ, Rankin JS: Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Cardiothoras Cardiovasc Surg 1994; 108: 626–35
Oddis CV, Finkel MS: Cytokines and nitric oxide synthase inhibitor as mediators of adrenergic refractoriness in cardiac myocytes. Eur J Pharmacol 1997; 320: 167–74
Vincent JL, Bakker J, Marecaux G, Schandene L, Kahn RJ, Dupont E: Administration of anti-TNF antibody improves left ventricular function in septic shock patients. Chest 1992; 101: 810–5
Hattler BG, Oddis CV, Zeevi A, Luss H, Shah N, Geller DA, Billiar TR, Simmons RL, Finkel MS: Regulation of constitutive nitric oxide synthase activity by the human heart. Am J Cardiol 1995; 76: 957–9
Kanai AJ, Mesaros S, Finkel MS, Oddis CV, Birder LA, Malinski T: Beta-adrenergic regulation of constitutive nitric oxide synthase in cardiac myocytes. Am J Physiol 1997; 273: C1371–7
Finkel MS, Oddis CV, Mayer OH, Hattler BG, Simmons RL: Nitric oxide synthase inhibitor alters papillary muscle force-frequency relationship. J Pharmacol Exp Ther 1995; 272: 945–52
Haque R, Kan H, Finkel MS: Effects of cytokines and nitric oxide on myocardial E-C coupling. Basic Res Cardiol 1998; 93: 86–94
Radomski MW, Vallance P, Whitley G, Foxwell N, Moncada S: Platelet adhesion to human vascular endothelium is modulated by constitutive and cytokine induced nitric oxide. Cardiovasc Res 1993; 27: 1380–2
Hattler BG, Gorcsan JR, Shah N, Oddis CV, Billiar TR, Simmons RL, Finkel MS: A potential role for nitric oxide in myocardial stunning. J Card Surg 1994; 9: 425–9
Oddis CV, Simmons RL, Hattler BG, Finkel MS: Protein kinase A activation is required for IL-1-induced nitric oxide production by cardiac myocytes. Am J Physiol 1996; 271: C429–34
Oddis CV, Finkel MS: Cytokine-stimulated nitric oxide production inhibits mitochondrial activity in cardiac myocytes. Biochem Biophys Res Commun 1995; 213: 1002–9
Ahlgren E, Aren C: Cerebral complications after coronary bypass and heart valve surgery: Risk factors and onset of symptoms. J Cardiothorac Vasc Anesth 1998; 12: 270–3
Carrascal Y, Guerrero AL, Maroto LC, Cortina JM, Rodriguez JE, Renes E, Rufilanchas JJ: Neurological complications after cardiopulmonary bypass: An update. Eur Neurol 1999; 41: 128–34
Engelman RM, Pleet AB, Rousou JA, Flack JER, Deaton DW, Peckow PS, Gregory CA: Influence of cardiopulmonary bypass perfusion temperature on neurologic and hematologic function after coronary artery bypass grafting. Ann Thorac Surg 1999; 67: 1547–55
Tardiff BE, Newman MF, Saunders AM, Strittmatter WJ, Blumenthal JA, White WD, Croughwell ND, Davis RDJ, Roses AD, Reves JG: Preliminary report of a genetic basis for cognitive decline after cardiac operations. The Neurologic Outcome Research Group of the Duke Heart Center. Ann Thorac Surg 1997; 64: 715–20
Redmond JM, Greene PS, Goldsborough MA, Cameron DE, Stuart RS, Sussman MS, Watkins LJ, Laschinger JC, McKhann GM, Johnston MV, Baumgartner WA: Neurologic injury in cardiac surgical patients with a history of stroke. Ann Thorac Surg 1996; 61: 42–7
Wagerle LC, Russo P, Dahdah NS, Kapadia N, Davis DA: Endothelial dysfunction in cerebral microcirculation during hypothermic cardiopulmonary bypass in newborn lambs. J Thorac Cardiovasc Surg 1998; 115: 1047–54
Baumgartner WA, Walinsky PL, Salazar JD, Tseng EE, Brock MV, Doty JR, Redmond JM, Blue ME, Goldsborough MA, Troncoso MA, Johnston MV: Assessing the impact of cerebral injury after cardiac surgery: Will determining the mechanism reduce this injury? Ann Thorac Surg 1999; 67: 1871–3
Tseng EE, Brock MV, Kwon CC, Annanata M, Lange MS, Troncoso JC, Johnston MV, Baumgartner WA: Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest. Ann Thorac Surg 1999; 67: 371–6
Shin'oka T, Nagashima M, Nollert G, Shum-Tim D, Laussen PC, Lidov HG, du Plessis A, Jonas RA: A novel sialyl Lewis X analog attenuates cerebral injury after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 1999; 117: 1204–11
Levy JH, Pifarre R, Schaff HV, Horrow JC, Albus R, Spiess B, Rosengart TK, Murray J, Clark RE, Smith P: A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995; 92: 2236–44
Jansen PG, Baufreton C, Le Besnerais P, Loisance DY, Wildevuur CR: Heparin-coated circuits and aprotinin prime for coronary artery bypass grafting. Ann Thorac Surg 1996; 61: 1363–6
Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J: Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 1998; 104: 343–8
Pathi VL, Morrison J, MacPhaden A, Martin W, McQuiston AM, Wheatley DJ: Alterations in renal microcirculation during cardiopulmonary bypass. Ann Thorac Surg 1998; 65: 993–8
Nomoto S, Shimahara Y, Kumada K, Okamoto Y, Ban T: Influence of hepatic mitochondrial redox state on complement biosynthesis and activation during and after cardiopulmonary operations. Eur J Cardiothorac Surg 1996; 10: 272–8
Collins JD, Bassendine MF, Ferner R, Blesovsky A, Murray A, Pearson DT, James OF: Incidence and prognostic importance of jaundice after cardiopulmonary bypass surgery. Lancet 1983; 1: 1119–23
Wakiyama H, Yamashita C, Okada M, Maeda H: Increased portal endothelin-1 level is associated with liver function post cardiopulmonary bypass in rabbits: Influence of hypothermia on the damage. Kobe J Med Sci 1997; 43: 245–57
Wang P, Ba ZF, Chaudry IH: Mechanism of hepatocellular dysfunction during early sepsis: Key role of increased gene expression and release of proinflammatory cytokines tumour necrosis factor and interleukin-6. Arch Surg 1997; 132: 364–70
Khuri SF, Wolfe JA, Josa M, Axford TC, Szymanski I, Assousa S, Ragno G, Patel M, Silverman A, Park M, Valeri CR: Hematologic changes during and after cardiopulmonary bypass and their relationship to the bleeding time and nonsurgical blood loss. J Thorac Cardiovasc Surg 1992; 104: 94–107
Ferroni P, Speziale G, Ruvolo G, Giovannelli A, Pulcinelli FM, Lenti L, Pignatelli P, Criniti A, Tonelli E, Marino B, Gazzaniga PP: Platelet activation and cytokine production during hypothermic cardiopulmonary bypass: A possible correlation? Thromb Haemost 1998; 80: 58–64
Schorer AE, Moldow CF, Rick ME: Interleukin 1 or endotoxin increases the release of von Willebrand factor from human endothelial cells. Br J Hematol 1987; 67: 193–7
Christenson JT, Reuse J, Badel P, Simonet F, Schmuziger M: Plateletpheresis before redo CABG diminishes excessive blood transfusion. Ann Thorac Surg 1996; 62: 1373–8
Despotis GJ, Levine V, Goodnough LT: Relationship between leukocyte count and patient risk for excessive blood loss after cardiac surgery. Crit Care Med 1997; 25: 1338–46
Rubens FD, Labow RS, Lavallee GR, Watson MI, Robblee JA, Voorhees ME, Nathan HJ: Hematologic evaluation of cardiopulmonary bypass circuits prepared with a novel block copolymer. Ann Thorac Surg 1999; 67: 689–96
Markewitz A, Faist E, Niesel T, Lang S, Weinhold C, Reichart B: Changes in lymphocyte subsets and mitogen responsiveness following open-heart surgery and possible therapeutic approaches. Thorac Cardiovasc Surg 1992; 40: 14–8
Markewitz A, Faist E, Lang S, Endres S, Fuchs D, Reichart B: Successful restoration of cell-mediated immune responses after cardiopulmonary bypass by immunomodulation. J Thorac Cardiovasc Surg 1993; 105: 15–24
Markewitz A, Faist E, Lang S, Hultner L, Weinhold C, Reichart B: An imbalance in T-helper cell subsets alters immune response after cardiac surgery. Eur J Cardiothorac Surg 1996; 10: 61–7
Klava A, Windsor AC, Farmery SM, Woodhouse LF, Reynolds JV, Ramsden CW, Boylston AW, Guillou PJ: Interleukin-10: A role in the development of postoperative immunosuppression. Arch Surg 1997; 132: 425–9
Parsonnet V, Dean D, Bernstein AD: A method of uniform stratification of risk for evaluating the results of surgery in acquired adult heart disease. Circulation 1989; 79: I3–12
Dupuis J-Y, Wang F, Nathan H, Lam M, Grimes S, Bourke M: The cardiac anesthesia risk evaluation score: A clinically useful predictor of mortality and morbidity after cardiac surgery. A nesthesiology 2001; 94: 194–204
Boeken U, Feindt P, Zimmermann N, Kalweit G, Petzold T, Gams E: Increased preoperative C-reactive protein (CRP)-values without signs of an infection and complicated course after cardiopulmonary bypass (CPB)-operations. Eur J Cardio Thorac Surg 1998; 13: 541–5
Pilz G, Fraunberger P, Appel R, Kreuzer E, Werdan K, Walli A, Seidel D: Early prediction of outcome in score-identified, postcardiac surgical patients at high risk for sepsis, using soluble tumor necrosis factor receptor-p55 concentrations. Crit Care Med 1996; 24: 596–600
Brasil LA, Gomes WJ, Salomao R, Buffolo E: Inflammatory response after myocardial revascularization with or without cardiopulmonary bypass. Ann Thorac Surg 1998; 66: 56–9
Matata BM, Sosnowski AW, Galinanes M: Off-pump bypass graft operation significantly reduces oxidative stress and inflammation. Ann Thorac Surg 2000; 69: 785–91
Struber M, Cremer JT, Gohrbandt B, Hagl C, Jankowski M, Volker B, Ruckoldt H, Martin M, Haverich A: Human cytokine responses to coronary artery bypass grafting with and without cardiopulmonary bypass. Ann Thorac Surg 1999; 68: 1330–5
Ascione R, Lloyd CT, Underwood MJ, Gomes WJ, Angelini GD: On-pump versus off-pump coronary revascularization: Evaluation of renal function. Ann Thorac Surg 1999; 68: 493–8
Wan S, Izzat MB, Lee TW, Wan IY, Tang NL, Yim AP: Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg 1999; 68: 52–6
Diegeler A, Doll N, Rauch T, Haberer D, Walther T, Falk V, Gummert J, Autschbach R, Mohr FW: Humoral immune response during coronary artery bypass grafting: A comparison of limited approach, “Off-Pump” technique, and conventional cardiopulmonary bypass. Circulation 2000; 102: III95–100
Gu YJ, Mariani MA, van Oeveren W, Grandjean JG, Boonstra PW: Reduction of the inflammatory response in patients undergoing minimally invasive coronary artery bypass grafting. Ann Thorac Surg 1998; 65: 420–4
Kilger E, Pichler B, Goetz AE, Rank N, Welte M, Morstedt K, Vetter HO, Godje O, Schmitz C, Lamm P, Engelschalk E, Muehlbeyer D, Frey L: Procalcitonin as a marker of systemic inflammation after conventional or minimally invasive coronary artery bypass grafting. Thorac Cardiovasc Surg 1998; 46: 130–3
Ascione R, Lloyd CT, Underwood MJ, Lotto AA, Pitsis AA, Angelini GD: Inflammatory response after coronary revascularization with or without cardiopulmonary bypass. Ann Thorac Surg 2000; 69: 1198–204
Cox CM, Ascione R, Cohen AM, Davies IM, Ryder IG, Angelini GD: Effect of cardiopulmonary bypass on pulmonary gas exchange: A prospective randomized study. Ann Thorac Surg 2000; 69: 140–5
Murkin JM, Boyd WD, Ganapathy S, Adams SJ, Peterson RC: Beating heart surgery: Why expect less central nervous system morbidity? Ann Thorac Surg 1999; 68: 1498–501
Boyd WD, Desai ND, Del Rizzo DF, Novick RJ, McKenzie FN, Menkis AH: Off-pump surgery decreases postoperative complications and resource utilization in the elderly. Ann Thorac Surg 1999; 68: 1490–3
Gamoso MG, Phillips-Bute B, Landolfo KP, Newman MF, Stafford-Smith M: Off-pump versus on-pump coronary artery bypass surgery and postoperative renal dysfunction. Anesth Analg 2000; 91: 1080–4
Duhaylongsod FG: Minimally invasive cardiac surgery defined. Arch Surg 2000; 135: 296–301
Gu YJ, Mariani MA, Boonstra PW, Grandjean JG, van Oeveren W: Complement activation in coronary artery bypass grafting patients without cardiopulmonary bypass: The role of tissue injury by surgical incision. Chest 1999; 116: 892–8
Glower DD, Landolfo KP, Clements F, Debruijn NP, Stafford-Smith M, Smith PK, Duhaylongsod F: Mitral valve operation via port access versus median sternotomy. Eur J Cardiothorac Surg 1998; 14: S143–7
Richter JA, Meisner H, Tassani P, Barankay A, Dietrich W, Braun SL: Drew-Anderson technique attenuates systemic inflammatory response syndrome and improves respiratory function after coronary artery bypass grafting. Ann Thorac Surg 2000; 69: 77–83
te Velthuis H, Baufreton C, Jansen PG, Thijs CM, Hack CE, Sturk A, Wildevuur CR, Loisance DY: Heparin coating of extracorporeal circuits inhibits contact activation during cardiac operations. J Thorac Cardiovasc Surg 1997; 114: 117–22
Baufreton C, Moczar M, Intrator L, Jansen PG, te Velthuis H, Le Besnerais P, Farcet JP, Wildevuur CR, Loisance DY: Inflammatory response to cardiopulmonary bypass using two different types of heparin-coated extracorporeal circuits. Perfusion 1998; 13: 419–27
Lundblad R, Moen O, Fosse E: Endothelin-1 and neutrophil activation during heparin-coated cardiopulmonary bypass. Ann Thorac Surg 1997; 63: 1361–7
Belboul A, Lofgren C, Storm C, Jungbeck M: Heparin-coated circuits reduce occult myocardial damage during CPB: A randomized, single blind clinical trial. Eur J Cardiothorac Surg 2000; 17: 580–6
Fosse E, Thelin S, Svennevig JL, Jansen P, Mollnes TE, Hack E, Venge P, Moen O, Brockmeier V, Dregelid E, Halden E, Hagman L, Videm V, Pedersen T, Mohr B: Duraflo II coating of cardiopulmonary bypass circuits reduces complement activation, but does not affect the release of granulocyte enzymes: A European multicentre study. Eur J Cardiothorac Surg 1997; 11: 320–7
Wildevuur CR, Jansen PG, Bezemer PD, Kuik DJ, Eijsman L, Bruins P, De Jong AP, Van Hardevelt FW, Biervliet JD, Hasenkam JM, Kure HH, Knudsen L, Bellaiche L, Ahlburg P, Loisance DY, Baufreton C, Le Besnerais P, Bajan G, Matta A, Van Dyck M, Renotte MT, Ponlot-Lois A, Baele P, McGovern EA, McCarthy J, McCarthy A, O'Donnell A, Fosse E, Moen O, Dregelid E, Brockmeier E, Anderson C, Pomar JL, Ranucci M, Conti D, Cirri S, Conti E, Ditta A, Von Segesser LK, Tkebuchava T, Weiss BM, Turina MI, Svennevig JL, Mohr B, Videm V, Karlsen H, Pedersen TH, Thelin S, Halden E, Hagman L, Thorno E, Ahlvin E: Clinical evaluation of Duraflo II heparin treated extracorporeal circulation circuits (2nd version). The European Working Group on heparin coated extracorporeal circulation circuits. Eur J Cardiothorac Surg 1997; 11: 616–23
Videm V, Mollnes TE, Fosse E, Mohr B, Bergh K, Hagve TA, Aasen AO, Svennevig JL: Heparin-coated cardiopulmonary bypass equipment: I. Biocompatibility markers and development of complications in a high risk population. J Thorac Cardiovasc Surg 1999; 117: 794–802
Shimamoto A, Kanemitsu S, Fujinaga K, Takao M, Onoda K, Shimono T, Tanaka K, Shimpo H, Yada I: Biocompatibility of silicone-coated oxygenator in cardiopulmonary bypass. Ann Thorac Surg 2000; 69: 115–20
Wan S, LeClerc JL, Antoine M, DeSmet JM, Yim AP, Vincent JL: Heparin-coated circuits reduce myocardial injury in heart or heart-lung transplantation: A prospective, randomized study. Ann Thorac Surg 1999; 68: 1230–5
De Somer F, Francois K, van Oeveren W, Poelaert J, De Wolf D, Ebels T, Van Nooten G: Phosphorylcholine coating of extracorporeal circuits provides natural protection against blood activation by the material surface. Eur J Cardiothorac Surg 2000; 18: 602–6
Watanabe H, Hayashi J, Ohzeki H, Moro H, Sugawara M, Eguchi S: Biocompatibility of a silicone-coated polypropylene hollow fiber oxygenator in an in vitro model. Ann Thorac Surg 1999; 67: 1315–9
Wimmer-Greinecker G, Matheis G, Martens S, Oremek G, Abdel-Rahman U, Moritz A: Synthetic protein treated versus heparin coated cardiopulmonary bypass surfaces: Similar clinical results and minor biochemical differences. Eur J Cardiothorac Surg 1999; 16: 211–7
Baksaas ST, Videm V, Pedersen T, Karlsen H, Mollnes TE, Brosstad F, Svennevig JL: Comparison of three oxygenator-coated and one total-circuit-coated extracorporeal devices. Perfusion 1999; 14: 119–27
Rubens FD, Ruel M, Lavallee G, Watson M, Robblee J, Wozny D, Nathan H: Circuits with surface modifying additive alter the haemodynamic response to cardiopulmonary bypass. Eur J Cardiothorac Surg 1999; 15: 353–8
Gu YJ, Boonstra PW, Rijnsburger AA, Haan J, van Oeveren W: Cardiopulmonary bypass circuit treated with surface-modifying additives: A clinical evaluation of blood compatibility. Ann Thorac Surg 1998; 65: 1342–7
de Vroege R, Rutten PM, Kalkman C, Out TA, Jansen PG, Eijsman L, de Mol BJ, Wildevuur CR: Biocompatibility of three different membrane oxygenators: Effect on complement, neutrophil and monocyte activation. Perfusion 1997; 12: 369–75
Nathens AB, Marshall JC: Selective decontamination of the digestive tract in surgical patients: A systematic review of the evidence. Arch Surg 1999; 134: 170–6
Sun X, Wagner DP, Knaus WA: Does selective decontamination of the digestive tract reduce mortality for severely ill patients? Crit Care Med 1996; 24: 753–5
Engelman DT, Adams DH, Byrne JG, Aranki SF, Collins JJ, Couper GS, Allred EN, Cohn LH, Rizzo RJ: Impact of body mass index and albumin on morbidity and mortality after cardiac surgery. J Thorac Cardiovasc Surg 1999; 118: 866–73
Walesby RK, Goode AW, Bentall HH: Nutritional status of patients undergoing valve replacement by open heart surgery. Lancet 1978; 1: 76–7
Abel RM, Grimes JB, Alonso D, Alonso M, Gay WAJ: Adverse hemodynamic and ultrastructural changes in dog hearts subjected to protein-calorie malnutrition. Am Heart J 1979; 97: 733–44
Wittnich C, Chiu RC, McArdle AH: Protection of ischemic myocardium: The roles of nutrition and myocardial glycogen. Can J Surg 1982; 25: 534–7
Atkinson S, Sieffert E, Bihari D: A prospective, randomized, double-blind, controlled clinical trial of enteral immunonutrition in the critically ill. Guy's Hospital Intensive Care Group. Crit Care Med 1998; 26: 1164–72
Gianotti L, Braga M, Vignali A, Balzano G, Zerbi A, Bisagni P, Di Carlo V: Effect of route of delivery and formulation of postoperative nutritional support in patients undergoing major operations for malignant neoplasms. Arch Surg 1997; 132: 1222–9
Braga M, Gianotti L, Radaelli G, Vignali A, Mari G, Gentilini O, Di Carlo V: Perioperative immunonutrition in patients undergoing cancer surgery: Results of a randomized double-blind phase 3 trial. Arch Surg 1999; 134: 428–33
Griffiths RD: Outcome of critically ill patients after supplementation with glutamine. Nutrition 1997; 13: 752–4
Mythen MG, Webb AR: Perioperative plasma volume expansion reduces the incidence of gut mucosal hypoperfusion during cardiac surgery. Arch Surg 1995; 130: 423–9
Oudemans-van Straaten HM, Jansen PG, Hoek FJ, van Deventer SJ, Sturk A, Stoutenbeek CP, Tytgat GN, Wildevuur CR, Eysman L: Intestinal permeability, circulating endotoxin, and postoperative systemic responses in cardiac surgery patients. J Cardiothorac Vasc Anesth 1996; 10: 187–4
DeFoe GR, Ross CS, Olmstead EM, Surgenor SD, Fillinger MP, Groom RC, Forest RJ, Pieroni JW, Warren CS, Bogosian ME, Krumholz CF, Clark C, Clough RA, Weldner PW, Lahey SJ, Leavitt BJ, Marrin CA, Charlesworth DC, Marshall P, O'Connor GT: Lowest hematocrit on bypass and adverse outcomes associated with coronary artery bypass grafting. Northern New England Cardiovascular Disease Study Group. Ann Thorac Surg 2001; 71: 769–76
Pölönen P, Ruokonen E, Hippeläinen M, Pöyhönen M, Takala J: A prospective, randomized study of goal-oriented hemodynamic therapy in cardiac surgical patients. Anesth Analg 2000; 90: 1052–9
Hasko G, Szabo C, Nemeth ZH, Salzman AL, Vizi ES: Suppression of IL-12 production by phosphodiesterase inhibition in murine endotoxemia is IL-10 independent. Eur J Immunol 1998; 28: 468–72
Takeuchi K, del Nido PJ, Ibrahim AE, Cao-Danh H, Friehs I, Glynn P, Poutias D, Cowan DB, McGowan FXJ: Vesnarinone and amrinone reduce the systemic inflammatory response syndrome. J Thorac Cardiovasc Surg 1999; 117: 375–82
McNicol L, Andersen LW, Liu G, Doolan L, Baek L: Markers of splanchnic perfusion and intestinal translocation of endotoxins during cardiopulmonary bypass: Effects of dopamine and milrinone. J Cardiothorac Vasc Anesth 1999; 13: 292–8
Berendes E, Molhoff T, Van Aken H, Schmidt C, Erren M, Deng MC, Weyland M, Loick HM: Effects of dopexamine on creatinine clearance, systemic inflammation, and splanchnic oxygenation in patients undergoing coronary artery bypas grafting. Anesth Analg 1997; 84: 950–7
Sinclair DG, Houldsworth PE, Keogh B, Pepper J, Evans TW: Gastrointestinal permeability following cardiopulmonary bypass: A randomised study comparing the effects of dopamine and dopexamine. Intens Care Med 1997; 23: 510–6
Christenson JT, Simonet F, Badel P, Schmuziger M: Optimal timing of preoperative intraaortic balloon pump support in high-risk coronary patients. Ann Thorac Surg 1999; 68: 934–9
Gutfinger DE, Ott RA, Eugene J, Gazzaniga AB: Concepts in the application of pneumatic ventricular assist devices for ischemic myocardial injury. ASAIO J 1995; 41: 162–8
Dietl CA, Berkheimer MD, Woods EL, Gilbert CL, Pharr WF, Benoit CH: Efficacy and cost-effectiveness of preoperative IABP in patients with ejection fraction of 0. 25 or less. Ann Thorac Surg 1996; 62: 401–8
Bando K, Vijay P, Turrentine MW, Sharp TG, Means LJ, Ensing GJ, Lalone BJ, Sekine Y, Szekely L, Brown JW: Dilutional and modified ultrafiltration reduces pulmonary hypertension after operations for congenital heart disease: A prospective randomized study. J Thorac Cardiovasc Surg 1998; 115: 517–25
Bando K, Turrentine MW, Vijay P, Sharp TG, Sekine Y, Lalone BJ, Szekely L, Brown JW: Effect of modified ultrafiltration in high-risk patients undergoing operations for congenital heart disease. Ann Thorac Surg 1998; 66: 821–7
Naik SK, Knight A, Elliott MJ: A successful modification of ultrafiltration for cardiopulmonary bypass in children. Perfusion 1991; 6: 41–50
Davies MJ, Nguyen K, Gaynor JW, Elliott MJ: Modified ultrafiltration improves left ventricular systolic function in infants after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1998; 115: 361–9
Babka RM, Petress J, Briggs R, Helsal R, Mack J: Conventional haemofiltration during routine coronary bypass surgery. Perfusion 1997; 12: 187–92
Boga M, Islamoglu F, Badak I, Cikirikcioglu M, Bakalim T, Yagdi T, Buket S, Hamulu A: The effects of modified hemofiltration on inflammatory mediators and cardiac performance in coronary artery bypass grafting. Perfusion 2000; 15: 143–50
Watanabe T, Sakai Y, Mayumi T, Shimomura T, Song MH, Tajima K, Suenaga Y, Kawaradani Y, Saito Y, Yamada T: Effect of ultrafiltration during cardiopulmonary bypass for pediatric cardiac surgery. Artif Organs 1998; 22: 1052–5
Gu YJ, de Vries AJ, Vos P, Boonstra PW, van Oeveren W: Leukocyte depletion during cardiac operation: A new approach through the venous bypass circuit. Ann Thorac Surg 1999; 67: 604–9
Johnson D, Thomson D, Mycyk T, Burbridge B, Mayers I: Depletion of neutrophils by filter during aortocoronary bypass surgery transiently improves postoperative cardiorespiratory status. Chest 1995; 107: 1253–9
Morioka K, Muraoka R, Chiba Y, Ihaya A, Kimura T, Noguti H, Uesaka T: Leukocyte and platelet depletion with a blood cell separator: Effects on lung injury after cardiac surgery with cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996; 111: 45–54
Di Salvo C, Louca LL, Pattichis K, Hooper J, Walesby RK: Does activated neutrophil depletion on bypass by leukocyte filtration reduce myocardial damage? A preliminary report. J Cardiovasc Surg (Torino) 1996; 37: 93–100
Hurst T, Johnson D, Cujec B, Thomson D, Mycyk T, Burbridge B, Mayers I: Depletion of activated neutrophils by a filter during cardiac valve surgery. Can J Anaesth 1997; 44: 131–9
Baksaas ST, Flom-Halvorsen HI, Ovrum E, Videm V, Mollnes TE, Brosstad F, Svennevig JL: Leucocyte filtration during cardiopulmonary reperfusion in coronary artery bypass surgery. Perfusion 1999; 14: 107–17
De Vecchi E, Paroni R, Pala MG, Di Credico G, Agape V, Gobbi C, Bonini PA, Paolini G, Grossi A: Role of leucocytes in free radical production during myocardial revascularisation. Heart 1997; 77: 449–55
Sawa Y, Taniguchi K, Kadoba K, Nishimura M, Ichikawa H, Amemiya A, Kuratani T, Matsuda H: Leukocyte depletion attenuates reperfusion injury in patients with left ventricular hypertrophy. Circulation 1996; 93: 1640–6
Vignon D: Leukodepletion of labile blood products. Ann Pharm Fr 1999; 57: 61–7
van de Watering LM, Hermans J, Houbiers JG, van den Broek PJ, Bouter H, Boer F, Harvey MS, Huysmans HA, Brand A: Beneficial effects of leukocyte depletion of transfused blood on postoperative complications in patients undergoing cardiac surgery: A randomized clinical trial. Circulation 1998; 97: 562–8
Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR: Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999; 354: 1940–7
Wachtfogel YT, Kucich U, Hack CE, Gluszko P, Niewiarowski S, Colman RW, Edmunds LHJ: Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993; 106: 1–9
Hill GE, Alonso A, Spurzem JR, Stammers AH, Robbins RA: Aprotinin and methylprednisolone equally blunt cardiopulmonary bypass induced inflammation in humans. J Thorac Cardiovasc Surg 1995; 110: 1658–62
Harig F, Feyrer R, Mahmoud FO, Blum U, von der Emde J: Reducing the post pump syndrome by using heparin-coated circuits, steroids, or aprotinin. Thorac Cardiovasc Surg 1999; 47: 111–8
Hill GE, Robbins RA: Aprotinin but not tranexamic acid inhibits cytokine-induced inducible nitric oxide synthase expression. Anesth Analg 1997; 84: 1198–202
Soeparwata R, Hartman AR, Frerichmann U, Stefano GB, Scheld HH, Bilfinger TV: Aprotinin diminishes inflammatory processes. Int J Cardiol 1996; 26: S55–63
Alonso A, Whitten CW, Hill GE: Pump prime only aprotinin inhibits cardiopulmonary bypass-induced neutrophil CD11b up-regulation. Ann Thorac Surg 1999; 67: 392–5
Wendel HP, Heller W, Michel J, Mayer G, Ochsenfahrt C, Graeter U, Schulze J, Hoffmeister HM, Hoffmeister HE: Lower cardiac troponin T levels in patients undergoing cardiopulmonary bypass and receiving high-dose aprotinin therapy indicate reduction of perioperative myocardial damage. J Thorac Cardiovasc Surg 1995; 109: 1164–72
Gott JP, Cooper WA, Schmidt FEJ, Brown WMr, Wright CE, Merlino JD, Fortenberry JD, Clark WS, Guyton RA: Modifying risk for extracorporeal circulation: trial of four antiinflammatory strategies. Ann Thorac Surg 1998; 66: 747–53
Lemmer JHJ, Dilling EW, Morton JR, Rich JB, Robicsek F, Bricker DL, Hantler CB, Copeland JGR, Ochsner JL, Daily PO, Whitten CW, Noon GP, Maddi R: Aprotinin for primary coronary artery bypass grafting: A multicenter trial of three dose regimens. Ann Thorac Surg 1996; 62: 1659–67
Rich JB: The efficacy and safety of aprotinin use in cardiac surgery. Ann Thorac Surg 1998; 66: S6–11
Alderman EL, Levy JH, Rich JB, Nili M, Vidne B, Schaff H, Uretzky G, Pettersson G, Thiis JJ, Hantler CB, Chaitman B, Nadel A: Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998; 116: 716–30
Bruda NL, Hurlbert BJ, Hill GE: Aprotinin reduces nitric oxide production in vitro and in vivo in a dose dependent manner. Clin Sci (Colch) 1998; 94: 505–9
Rahman A, Ustunda B, Burma O, Ozercan IH, Cekirdekci A, Bayar MK: Does aprotinin reduce lung reperfusion damage after cardiopulmonary bypass? Eur J Cardiothorac Surg 2000; 18: 583–8
Bidstrup BP, Harrison J, Royston D, Taylor KM, Treasure T: Aprotinin therapy in cardiac operations: A report on use in 41 cardiac centers in the United Kingdom. Ann Thorac Surg 1993; 55: 971–6
Royston D: Aprotinin versus lysine analogues: The debate continues. Ann Thorac Surg 1998; 65: S9–19
Smith PK, Muhlbaier LH: Aprotinin: Safe and effective only with the full-dose regimen. Ann Thorac Surg 1996; 62: 1575–7
Badger AM, DL O, Esser KM: Beneficial effects of the phosphodiesterase inhibitors BRL 61063, pentoxifylline, and rolipram in a murine model of endotoxin shock. Circ Shock 1994; 44: 188–95
Doherty GM, Jensen JC, Alexander HR, Buresh CM, Norton JA: Pentoxifylline suppression of tumour necrosis factor gene transcription. Surgery 1991; 110: 192–8
Schade UF: Pentoxifilline increases survival in murine endotoxin shock and decreases formation of tumour necrosis factor. Circ Shock 1990; 31: 171–81
Sullivan GW, Carper HT, Novick WJJ, Mandell GL: Inhibition of the inflammatory action of interleukin-1 and tumour necrosis factor (alpha) on neutrophil function by pentoxifylline. Infect Immun 1988; 56: 1722–9
Tsang GM, Allen S, Pagano D, Wong C, Graham TR, Bonser RS: Pentoxifylline preloading reduces endothelial injury and permeability in cardiopulmonary bypass. ASAIO J 1996; 42: M429–34
Turkoz R, Yorukoglu K, Akcay A, Yilik L, Baltalarli A, Karahan N, Adanir T, Sagban M: The effect of pentoxifylline on the lung during cardiopulmonary bypass. Eur J Cardiothorac Surg 1996; 10: 339–46
Hoffmann H, Markewitz A, Kreuzer E, Reichert K, Jochum M, Faist E: Pentoxifylline decreases the incidence of multiple organ failure in patients after major cardio-thoracic surgery. Shock 1998; 9: 235–40
Lauterbach R, Pawlik D, Kowalczyk D, Ksycinski W, Helwich E, Zembala M: Effect of the immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: A placebo-controlled, double-blind trial. Crit Care Med 1999; 27: 807–14
Kleinschmidt S, Bauer M, Grundmann U, Schneider A, Wagner B, Graeter T:[Effect of gamma-hydroxybutyric acid and pentoxyfylline on kidney function parameters in coronary surgery interventions]. Anaesthesiol Reanim 1997; 22: 102–7
Butler J, Baigrie RJ, Parker D, Chong JL, Shale DJ, Pillai R, Westaby S, Rocker GM: Systemic inflammatory responses to cardiopulmonary bypass: A pilot study of the effects of pentoxifylline. Respir Med 1993; 87: 285–8
Boldt J, Brosch C, Lehmann A, Haisch G, Lang J, Isgro F: Prophylactic use of pentoxifylline on inflammation in elderly cardiac surgery patients. Ann Thorac Surg 2001; 71: 1524–9
Boldt J, Brosch C, Piper SN, Suttner S, Lehmann A, Werling C: Influence of prophylactic use of pentoxifylline on postoperative organ function in elderly cardiac surgery patients. Crit Care Med 2001; 29: 952–8
Barta E, Pechan I, Cornak V, Luknarova O, Rendekova V, Verchovodko P: Protective effect of alpha-tocopherol and L-ascorbic acid against the ischemic-reperfusion injury in patients during open-heart surgery. Bratisl Lek Listy 1991; 92: 174–83
Mezzetti A, Lapenna D, Pierdomenico SD, Di Giammarco G, Bosco G, Di Ilio C, Santarelli P, Calafiore AM, Cuccurullo F: Myocardial antioxidant defenses during cardiopulmonary bypass. J Card Surg 1993; 8: 167–71
Ballmer PE, Reinhart WH, Jordan P, Buhler E, Moser UK, Gey KF: Depletion of plasma vitamin C but not of vitamin E in response to cardiac operations. J Thorac Cardiovasc Surg 1994; 108: 311–20
McColl AJ, Keeble T, Hadjinikolaou L, Cohen A, Aitkenhead H, Glenville B, Richmond W: Plasma antioxidants: Evidence for a protective role against reactive oxygen species following cardiac surgery. Ann Clin Biochem 1998; 35: 616–23
England MD, Cavarocchi NC, O'Brien JF, Solis E, Pluth JR, Orszulak TA, Kaye MP, Schaff HV: Influence of antioxidants (mannitol and allopurinol) on oxygen free radical generation during and after cardiopulmonary bypass. Circulation 1986; 74: III134–7
Sellke FW, Shafique T, Ely DL, Weintraub RM: Coronary endothelial injury after cardiopulmonary bypass and ischemic cardioplegia is mediated by oxygen-derived free radicals. Circulation 1993; 88: II395–400
Dingchao H, Zhiduan Q, Liye H, Xiaodong F: The protective effects of high-dose ascorbic acid on myocardium against reperfusion injury during and after cardiopulmonary bypass. Thorac Cardiovasc Surg 1994; 42: 276–8
Cavarocchi NC, England MD, O'Brien JF, Solis E, Russo P, Schaff HV, Orszulak TA, Pluth JR, Kaye MP: Superoxide generation during cardiopulmonary bypass: Is there a role for vitamin E? J Surg Res 1986; 40: 519–27
Sisto T, Paajanen H, Metsa-Ketela T, Harmoinen A, Nordback I, Tarkka M: Pretreatment with antioxidants and allopurinol diminishes cardiac onset events in coronary artery bypass grafting. Ann Thorac Surg 1995; 59: 1519–23
Andersen LW, Thiis J, Kharazmi A, Rygg I: The role of N-acetylcystein administration on the oxidative response of neutrophils during cardiopulmonary bypass. Perfusion 1995; 10: 21–6
De Backer WA, Amsel B, Jorens PG, Bossaert L, Hiemstra PS, van Noort P, van Overveld FJ: N-acetylcysteine pretreatment of cardiac surgery patients influences plasma neutrophil elastase and neutrophil influx in bronchoalveolar lavage fluid. Intens Care Med 1996; 22: 900–8
Suter PM, Domenighetti G, Schaller MD, Laverriere MC, Ritz R, Perret C: N-acetylcysteine enhances recovery from acute lung injury in man: A randomized, double-blind, placebo-controlled clinical study. Chest 1994; 105: 190–4
Zoran P, Juraj F, Ivana D, Reik H, Dusan N, Mihailo V: Effects of allopurinol on oxygen stress status during open heart surgery. Int J Cardiol 1994; 44: 123–9
Tabayashi K, Suzuki Y, Nagamine S, Ito Y, Sekino Y, Mohri H: A clinical trial of allopurinol (Zyloric) for myocardial protection. J Thorac Cardiovasc Surg 1991; 101: 713–8
Castelli P, Condemi AM, Brambillasca C, Fundaro P, Botta M, Lemma M, Vanelli P, Santoli C, Gatti S, Riva E: Improvement of cardiac function by allopurinol in patients undergoing cardiac surgery. J Cardiovasc Pharmacol 1995; 25: 119–25
Bochenek A, Religa Z, Spyt TJ, Mistarz K, Bochenek A, Zembala M, Gryzbek H: Protective influence of pretreatment with allopurinol on myocardial function in patients undergoing coronary artery surgery. Eur J Cardiothorac Surg 1990; 4: 538–42
Coetzee A, Roussouw G, Macgregor L: Failure of allopurinol to improve left ventricular stroke work after cardiopulmonary bypass surgery. J Cardiothorac Vasc Anesth 1996; 10: 627–33
Taggart DP, Young V, Hooper J, Kemp M, Walesby R, Magee P, Wright JE: Lack of cardioprotective efficacy of allopurinol in coronary artery surgery. Br Heart J 1994; 71: 177–81
Chambers DJ, Astras G, Takahashi A, Manning AS, Braimbridge MV, Hearse DJ: Free radicals and cardioplegia: Organic anti-oxidants as additives to the St Thomas’ Hospital cardioplegic solution. Cardiovasc Res 1989; 23: 351–8
Morita K, Ihnken K, Buckberg GD, Ignarro LJ: Oxidative insult associated with hyperoxic cardiopulmonary bypass in the infantile heart and lung. Jpn Circ J 1996; 60: 355–63
Dworkin GH, Abd-Elfattah AS, Yeh TJ, Wechsler AS: Efficacy of recombinant-derived human superoxide dismutase on porcine left ventricular contractility after normothermic global myocardial ischemia and hypothermic cardioplegic arrest. Circulation 1990; 82: IV359–66
Prasad K, Chan WP, Bharadwaj B: Superoxide dismutase and catalase in protection of cardiopulmonary bypass-induced cardiac dysfunction and cellular injury. Can J Cardiol 1996; 12: 1083–91
Sprung CL, Caralais PV, Marcial EH, Pierce M, Gelbard MA, Long WM, Duncan RC, Tendler MD, Karpf M: The effects of high dose corticosteroids in patients with septic shock. N Engl J Med 1984; 311: 1137–43
Wan S, LeClerc JL, Huynh CH, Schmartz D, DeSmet JM, Yim AP, Vincent JL: Does steroid pretreatment increase endotoxin release during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 1999; 117: 1004–8
Andersen LW, Baek L, Thompsen BS, Rasmussen JP: The effect of methylprednisolone on endotoxemia and complement activation during cardiac surgery. J Cardiothorac Anesth 1989; 3: 544–9
Dernek S, Tunerir B, Sevin B, Aslan R, Uyguc O, Kural T: The effects of methylprednisolone on complement, immunoglobulins and pulmonary neutrophil sequestration during cardiopulmonary bypass. Cardiovasc Surg 1999; 7: 414–8
Kawamura T, Inada K, Nara N, Wakusawa R, Endo S: Influence of methylprednisolone on cytokine balance during cardiac surgery. Crit Care Med 1999; 27: 545–8
Wan S, LeClerc JL, Schmartz D, Barvais L, Huynh CH, Deviere J, DeSmet JM, Vincent JL: Hepatic release of interleukin-10 during cardiopulmonmary bypass in steroid treated patients. Am Heart J 1997; 133: 335–9
Tassani P, Richter JA, Barankay A, Braun SL, Haehnel C, Spaeth P, Schad H, Meisner H: Does high-dose methylprednisolone in aprotinin-treated patients attenuate the systemic inflammatory response during coronary artery bypass grafting procedures? J Cardiothorac Vasc Anesth 1999; 13: 165–72
Kawamura T, Inada K, Okada H, Okada K, Wakusawa R: Methylprednisolone inhibits increase of interleukin 8 and 6 during open heart surgery. Can J Anaesth 1995; 42: 399–403
Hill GE, Snider S, Galbraith TA, Forst S, Robbins RA: Glucocorticoid reduction of bronchial epithelial inflammation during cardiopulmonary bypass. Am J Resp Crit Care Med 1995; 152: 1791–5
Yilmaz M, Ener S, Akalin H, Sagdic K, Serdar OA, Cengiz M: Effect of low-dose methyl prednisolone on serum cytokine levels following extracorporeal circulation. Perfusion 1999; 14: 201–6
Lodge AJ, Chai PJ, Daggett CW, Ungerleider RM, Jaggers J: Methylprednisolone reduces the inflammatory response to cardiopulmonary bypass in neonatal piglets: Timing of dose is important. J Thorac Cardiovasc Surg 1999; 117: 515–22
Jorens PG, De Jongh R, De Backer W, Van Damme J, Van Overveld F, Bossaert L, Walter P, Herman AG, Rampart M: Interleukin-8 production in patients undergoing cardiopulmonary bypass: The influence of pretreatment with methylprednisolone. Am Rev Respir Dis 1993; 148: 890–5
van Overveld FJ, De Jongh R, Jorens PG, Walter P, Bossaert L, De Backer WA: Pretreatment with methylprednisolone in coronary artery bypass grafting influences the levels of histamine and tryptase in serum but not in bronchoalveolar lavage fluid. Clin Sci (Colch) 1994; 86: 49–53
Cave AC, Manche A, Derias NW, Hearse DJ: Thromboxane A2 mediates pulmonary hypertension after cardiopulmonary bypass in the rabbit. J Thorac Cardiovasc Surg 1993; 106: 959–67
Shafique T, Johnson RG, Dai HB, Weintraub RM, Sellke FW: Altered pulmonary microvascular reactivity after total cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 106: 479–86
Heindl B, Becker BF: Aspirin, but not the more selective cyclooxygenase (COX)-2 inhibitors meloxicam and SC 58125, aggravates postischaemic cardiac dysfunction, independent of COX function. Naunyn Schmiedebergs Arch Pharmacol 2001; 363: 233–40
Mobert J, Becker BF: Cyclooxygenase inhibition aggravates ischemia-reperfusion injury in the perfused guinea pig heart: Involvement of isoprostanes. J Am Coll Cardiol 1998; 31: 1687–94
Metais C, Li J, Simons M, Sellke FW: Serotonin-induced coronary contraction increases after blood cardioplegia-reperfusion: Role of COX-2 expression. Circulation 1999; 100: II328–34
Hindman BJ, Moore SA, Cutkomp J, Smith T, Ross-Barta SE, Dexter F, Brian JE Jr: Brain expression of inducible cyclooxygenase 2 messenger RNA in rats undergoing cardiopulmonary bypass. A nesthesiology 2001; 95: 1380–8
Erez E, Erman A, Snir E, Raanani E, Abramov D, Sulkes J, Boner G, Vidne BA: Thromboxane production in human lung during cardiopulmonary bypass: Beneficial effect of aspirin? Ann Thorac Surg 1998; 65: 101–6
Sato K, Li J, Metais C, Bianchi C, Sellke F: Increased pulmonary vascular contraction to serotonin after cardiopulmonary bypass: Role of cyclooxygenase. J Surg Res 2000; 90: 138–43
Yang X, Ma N, Szabolcs MJ, Zhong J, Athan E, Sciacca RR, Michler RE, Anderson GD, Wiese JF, Leahy KM, Gregory S, Cannon PJ: Upregulation of COX-2 during cardiac allograft rejection. Circulation 2000; 101: 430–8
Saito T, Rodger IW, Hu F, Shennib H, Giaid A: Inhibition of cyclooxygenase-2 improves cardiac function in myocardial infarction. Biochem Biophys Res Commun 2000; 273: 772–5
Grandel U, Fink L, Blum A, Heep M, Buerke M, Kraemer HJ, Mayer K, Bohle RM, Seeger W, Grimminger F, Sibelius U: Endotoxin-induced myocardial tumor necrosis factor-alpha synthesis depresses contractility of isolated rat hearts: Evidence for a role of sphingosine and cyclooxygenase-2-derived thromboxane production. Circulation 2000; 102: 2758–64
Bouchard JF, Lamontagne D: Mechanisms of protection afforded by cyclooxygenase inhibitors to endothelial function against ischemic injury in rat isolated hearts. J Cardiovasc Pharmacol 1999; 34: 755–63
Sunose Y, Takeyoshi I, Tsutsumi H, Kawata K, Tokumine M, Iwazaki S, Tomizawa N, Ohwada S, Matsumoto K, Morishita Y: Effects of FK3311 on pulmonary ischemia-reperfusion injury in a canine model. J Surg Res 2001; 95: 167–73
Kirschfink M: Controlling the complement system in inflammation. Immunopharmacology 1997; 38: 51–62
Goldie AS, Fearon KC, Ross JA, Barclay GR, Jackson RE, Grant IS, Ramsay G, Blyth AS, Howie JC: Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome. The Sepsis Intervention Group. JAMA 1995; 274: 172–7
Sharar SR, Winn RK, Murry CE, Harlan JM, Rice CL: A CD18 monoclonal antibody increases the incidence and severity of subcutaneous abscess formation after high-dose Staphylococcus aureus injection in rabbits. Surgery 1991; 110: 213–9
Hall RI, StaffordSmith M, Rocker G: The systemic inflammatory response to cardiopulmonary bypass: Pathophysiological, therapeutic and pharmacological considerations. Anesth Analg 1997; 85: 766–82
Sablotzki A, Welters I, Lehmann N, Menges T, Gorlach G, Dehne M, Hempelmann G: Plasma levels of immunoinhibitory cytokines interleukin-10 and transforming growth factor-beta in patients undergoing coronary artery bypass grafting. Eur J Cardiothorac Surg 1997; 11: 763–8
Aziz T, Saad RA, Burgess M, Yonan N, Hasleton P, Hutchinson IV: Transforming growth factor beta and myocardial dysfunction following heart transplantation. Eur J Cardio Thorac Surg 2001; 20: 177–86
Lefer AM, Tsao P, Aoki N, Palladino MA: Mediation of cardioprotection by transforming growth factor-b. Science 1990; 249: 61–4
Stefano GB, Scharrer B, Smith EM, Hughes TKJ, Magazine HI, Bilfinger TV, Hartman AR, Fricchione GL, Liu Y, Makman MH: Opioid and opiate immunoregulatory processes (review). Crit Rev Immunol 1996; 16: 109–44
Grossi EA, Kallenbach K, Chau S, Derivaux CC, Aguinaga MG, Steinberg BM, Kim D, Iyer S, Tayyarah M, Artman M, Galloway AC, Colvin SB: Impact of heparin bonding on pediatric cardiopulmonary bypass: A prospective randomized study. Ann Thorac Surg 2000; 70: 191–6
Loick HM, Mollhoff T, Berendes E, Hammel D, Van Aken H: Influence of enoximone on systemic and splanchnic oxygen utilization and endotoxin release following cardiopulmonary bypass. Intens Care Med 1997; 23: 267–75
Parviainen I, Ruokonen E, Takala J: Dobutamine-induced dissociation between changes in splanchnic blood flow and gastric intramucosal pH after cardiac surgery. Br J Anaesth 1995; 74: 277–82