The Systemic Inflammatory Response to Cardiopulmonary Bypass

Cardiac surgery and cardiopulmonary bypass (CPB) activate a systemic inflammatory response characterized clinically by alterations in cardiovascular and pulmonary function. Significant morbidity is rare (approximately 1%-2% of cases), but when severe acute lung injury occurs, mortality is high (50%-70%) [1]. However, most patients undergoing CPB experience some degree of organ dysfunction as a result of activation of the inflammatory response. The purpose of this review is to examine the recent developments in our understanding of the pathophysiological mechanisms responsible for this response, the treatment modalities that have been used to ameliorate it, and the possible implications of these findings for the conduct of anesthesia for cardiac surgery. Pathophysiology Initiation of the Systemic Inflammatory Response The systemic inflammatory response may be initiated during cardiac surgery by a number of processes, including blood contact with the foreign surface of the CPB apparatus [2], development of ischemia and reperfusion injury [3], and presence of endotoxemia [4]. In the course of cardiac surgery using CPB, all three processes (i.e., blood contact activation, ischemia and reperfusion injury, and endotoxemia) are present and contribute concurrently to the humoral and cellular development of the processes leading to the systemic inflammatory response (Figure 1). The extent and duration of the response is influenced by many factors, including the pharmacological agents used to ameliorate the response [3,5-36] (see Table 1, Table 3, and Table 4 and the discussion in the section on therapeutic strategies) (pharmacological), the composition of the priming solution [37-39], the presence of pulsatile perfusion [40,41], the use of mechanical filtration [42-47], the type of oxygenator [6,7,40,42,48-55], the type of extracorporeal circuit [56-64], and the temperature during CPB [6,7,37-44,46-50,52-70] (see Table 2 and Table 5 and the discussion in the section on therapeutic strategies) (mechanical) [4,66-71]. Excellent reviews of the role of complement activation [72] and the effects of ischemia-reperfusion [73,74] have been published previously. We have chosen in this review to focus on the roles of endotoxin release and initiation of cytokine activation, mechanisms that have been relatively recently elucidated.Figure 1: Pathways leading to activation of the systemic inflammatory response syndrome (SIRS) and sites of therapeutic intervention. Therapeutic interventions: 1 = mechanical factors, 2 = glucocorticoids, 3 = pentoxyphylline, 4 = protease inhibitors, 5 = gut therapy. TNF alpha = tumor necrosis factor alpha, IL = interleukin, CPB = cardiopulmonary bypass, DIC = disseminated intravascular coagulation.Table 1: Randomized Trials of Pharmacological Interventions Designed to Reduce the Systemic Inflammatory Response That Occur During Cardiac SurgeryTable 3: Table 1 (Continued)Table 4: Table 1 (Continued)Table 2: Randomized Trials of Mechanical Strategies to Reduce the Systemic Inflammatory Response During Cardiac SurgeryTable 5: Table 2 (Continued)Increased concentrations of endotoxin, a lipopolysaccharide associated with cell membranes of Gramnegative microorganisms (Figure 2), have been measured in plasma during CPB [4,9,13,15,29,30,75,76]. The source and significance of these increases are currently debated. A reduction in splanchnic blood flow has been observed during CPB [77]. It has been hypothesized that this may be associated with the subsequent translocation of endotoxin across the ischemic gut wall, with activation of the systemic inflammatory response [73]. Increased levels of endotoxin have been measured in venous blood from the splanchnic vascular bed during CPB [78], and levels of endotoxin are correlated with the degree of hemodynamic compromise and aortic cross-clamp time (i.e., duration of relative ischemia) during cardiac surgery [75]. Furthermore, sequential elevation of endotoxin followed by increased levels of inflammatory cytokines has been observed [79], and in the elderly, the degree of myocardial dysfunction after CPB correlates with the level of endotoxin measured [80]. Finally, studies of treatments designed to reduce gut endotoxin levels [29,30] or to improve gut perfusion [76] show some efficacy. On the other hand, there have been disturbing inconsistencies in the studies of the role of endotoxin in relation to cardiac surgery and CPB. Investigators have measured endotoxin levels in a variety of fluids other than blood, including the CPB priming fluid and the intravenous solutions used before initiating CPB [81]. In some studies, investigators have been unable to measure increases in endotoxin levels at any time during CPB [82] or to correlate measured levels with organ dysfunction [83]. There have also been problems with the sensitivity and specificity of the endotoxin assay used in some studies [15]. Despite these difficulties, we believe that current data suggest that the phenomenon of endotoxemia during cardiac surgery is probably a true observation and that it plays a role in the activation of the systemic inflammatory response.Figure 2: Diagram of bacterial lipopolysaccharide [89].Endotoxin is a potent potential initiator of the inflammatory cascade that causes production of cytokines [84] and complement [85] and the activation of neutrophils [86]. Its presence in the systemic circulation has been associated with the development of lactic acidemia, low systemic vascular resistance, and depressed ventricular function [78,87]. The mechanism by which endotoxin stimulates cytokine release has been elucidated. Lipopolysaccharide-binding protein (LBP) is normally present in serum, and blood levels increase several-fold in the acute phase response to infection and endotoxin release [88]. LBP augments the immune response to endotoxin by binding to the lipid A portion of endotoxin to form a LBP-endotoxin complex. The LBP-endotoxin complex is up to 1000-fold more potent than lipopolysaccharide alone in inducing tumor necrosis factor (TNF) release by macrophages [89]. Binding of the LBP-endotoxin complex to the macrophage CD14 receptor [90] causes activation of a protein kinase, and TNF production is initiated (Figure 3).Figure 3: Induction phase of cytokine synthesis. After treatment with antibiotics, lipopolysaccharide (LPS) is released from dying bacteria. LPS binds to LPS-binding protein (LBP) to form the LPS-LBP complex. This complex then binds to the CD14 molecule on the macrophage/monocyte membrane. CD14 is associated with a second protein that has protein kinase activity [89].Maintenance of the Systemic Inflammatory Response Cytokines. Once initiated, the systemic inflammatory response will be maintained by several factors, including cytokine production. Cytokines (TNF, interleukins [IL], interferons [IFN], and colony-stimulating factors) are small proteins generated in tissues under a variety of circumstances. They serve a multiplicity of physiological functions, chiefly acting as intercellular messengers in response to cellular activation. If the stimulus for cytokine production is sustained or of sufficient magnitude, cytokines may become active systemically where they have potential for wide-spread pathophysiological effects on the heart, lungs, liver, coagulation system, and central nervous system [91-94]. Clinical manifestations of systemic cytokine release include fever, reduced level of consciousness, hemodynamic instability, and myocardial depression. These features can all be found in the early postoperative course after CPB. The cytokines often associated with release during and after CPB include TNF alpha, IL-1 beta, IL-2, IL-6, IL-8, and IL-10. TNF-alpha. One of the earliest and most important of the endogenous mediators released in the inflammatory response is TNF-alpha [89]. Intracellular TNF-alpha activity is found in several cell lines, including blood monocytes, peritoneal and alveolar macrophages, Kupffer cells, mast cells, endothelial cells, and lymphocytes. The process by which TNF is produced is well understood, including its transcription (synthesis of mRNA from the DNA template), mRNA processing, translation of mRNA into protein, and posttranslational processing and secretion of the protein (Figure 4) [89]. Binding of endotoxin-LBP complex to the macrophage CD14 receptor increases TNF-alpha gene transcription, resulting in increased levels of mRNA encoding for TNF-alpha. Endotoxin-induced TNF-alpha transcription and translation are independently regulated events and, thus, potentially amenable to independent manipulation by drugs [95].Figure 4: Regulation of tumor necrosis factor (TNF) biosynthesis in macrophages. After the binding of the lipopolysaccharide (LPS)-binding protein complex (LPS-LBP) to the CD14 molecule, the synthesis of TNF is begun by the initiation of translation of preformed TNF mRNA and accelerated transcription of the TNF gene. After translation of mRNA into preprotein monomers, posttranslational modification and trimer formation are required to generate the mature secreted form of TNF. Transcriptional activation is inhibited by agents that increase the intracellular cAMP concentration. Translation of TNF mRNA is inhibited by corticosteroids. After secretion of TNF, toxicity may be inhibited by monoclonal antibodies directed against TNF or by artificial protein inhibitors of TNF. UTR = untranslated region [89].The physiological effects of TNF-alpha include hypotension, fever, increased production of acute phase proteins, and reduced serum albumin levels [96]. Although increases in TNF-alpha levels are variably measured during cardiac surgery [15,18,19,21,29,34,37,43,44,46,47,57,63,66-68,78,82], perhaps related to timing of samples and/or assay sensitivity [15], there are only a few studies that have examined strategies designed to reduce TNF-alpha levels (Table 1, Table 3, and Table 4 and Table 2 and Table 5). IL-1. IL-1 (previously known as lymphocyte-activating factor, endogenous or leukocyte pyrogen, leukocyte endogenous mediator, osteoclast-activating factor, B cell-stimulatory factor, catabolin, hemopoietin 1, or proteolysis-inducing factor) shares many of the biological properties of TNF-alpha, including the production of fever, somnolence, and hypotension; expression of the inducible form of nitric oxide synthase; induction of prostaglandin synthesis; inhibition of lipoprotein lipase; procoagulant activity; and increased synthesis of acute phase proteins [97]. TNF-alpha can stimulate IL-1 synthesis [98], and IL-1 is capable of stimulating the production of other proinflammatory cytokines, e.g., IL-6 [99]. IL-1 has two isoforms: IL-1 alpha and IL-1 beta. IL-1 alpha has not been detected in the circulation of patients with any disease state and is not further considered in this review. Because more than 80% of detectable IL-1 beta is located intracellularly, its appearance in the circulation is likely a reflection of tissue destruction [100]. IL-1 beta has been variably reported as increased during CPB [15,17,21,29,31,34-36,66,67]. Of the cytokines that have been frequently measured during cardiac surgery, IL-1 beta has the weakest association and, therefore, the least apparent potential for therapeutic manipulation (Table 1, Table 3, and Table 4 and Table 2 and Table 5). Possible reasons for this include poor assay sensitivity, inadequate timing of sampling in relation to changing plasma concentrations, or no true difference. The most likely explanation, however, concerns differences in the degree of tissue destruction that occurs at the time of surgery in any particular study. IL-2. It has been recognized for many years that cardiac surgery is associated with alterations in the function of the immune system, affecting mainly cell-mediated immunity [35]. IL-2 is a cytokine involved in the cell-mediated immune response (Figure 5). It is responsible for a number of immune functions, including T-cell and and response [35]. to IL-2 and features of the systemic inflammatory response IL-2 effects to be number of (Figure and capable of to IL-2 (i.e., IL-2 are required [35]. in the number of have been reported after cardiac surgery [35]. of IL-2 have been measured as reduced or have been found to be reduced or increased and the of to IL-2 is after cardiac surgery, resulting in cell-mediated immune response The that increases during cardiac surgery is but it may to the immune response.Figure 5: of of cell-mediated immune response. response is initiated by the cell a which by 1 synthesis and The in the synthesis and release of IL-2, which as for further activation, and of IL-2 cytokine These mechanisms are and by which prostaglandin the T-cell which IL-2 synthesis and by contact with the function of is inhibited by with other cytokines beta and are also required for cell-mediated immune function. IL-1 beta is required for initiation of cell-mediated immune response and IL-2 production by and is important activation of the systemic inflammatory response and the cell-mediated immune response. in the cell-mediated immune response and is required for expression on in the synthesis or increased destruction of any of these cytokines may have for the of the cell-mediated immune response. increases T-cell which to a reduction in cell (Figure [35]. The development of the cytokine known as IL-6 its role It has been as factor, factor factor, factor, factor, or T-cell and of these has that they are all the and they have been In to the effects of IL-6 on the of protein IL-6 to the and secretion of from B and to T-cell activation, and it as a factor to to with TNF-alpha and IL-1 beta, it is endogenous for the release of IL-6 include endotoxin, TNF-alpha, and IL-1 IL-6 in plasma to 2 after a at and the increase in proteins This is with the that IL-6 release occurs in the inflammatory and its appearance is on the of IL-6 synthesis by other inflammatory cytokines The role of IL-6 in the and of drugs during cardiac surgery using CPB is but may be its role as a of acute phase protein synthesis and a myocardial In to other cytokines, as TNF-alpha and IL-1 beta, which are variably measured during cardiac surgery, levels of IL-6 are more increased during cardiac surgery to include of of the of of neutrophils and plasma This that may have important role in in the development of the systemic inflammatory response during cardiac surgery in concentrations in plasma have been during cardiac surgery in and in levels to or be with the in IL-6 and its release is by TNF-alpha The appearance of in plasma during cardiac surgery is associated with increase in a protease in the which is released in response to cellular activation and is associated with organ dysfunction mRNA expression is in and after cardiac surgery The increase in levels is with and subsequent and this may have a on the patients with bacterial or are during cardiac surgery, as by the release of intracellular as and and of activation may findings as increased and endothelial injury after cardiac surgery of neutrophils to the is for these processes to The of is in by cytokines as IL-1 beta, TNF-alpha, and is characterized by to a state that the of the at (Figure This process the expression of by endothelial molecule 1, intercellular molecule 1, vascular and binding to on neutrophils of particular levels and increased cellular expression have been variably observed during cardiac surgery This may be to a related to a for protein synthesis for as molecule 1 or to measure the most which is preformed in of endothelial and is more during cardiac to be involved in the and of and with second of is by of cell surface other cytokines, including IL-1 beta a role by the expression of cell surface known as also causes of at this Increased levels of have been measured during cardiac surgery and studies of CPB in which of is by the show in organ to intercellular 1 and 2 and on endothelial also to and also to of the and with or binding to endothelial and across the endothelial with the release of intracellular as and potential tissue the endothelial cell in regulated by induction of expression (Figure Randomized studies have used in the degree of elevation of blood and as of activation and treatment during cardiac surgery Possible role of endothelial in the intracellular of and release of and with the of endotoxin and cytokines, including TNF-alpha and IL-1 beta, inducible form of the nitric oxide is by vascular and cells, which to increased production and release of nitric oxide effects include vascular to myocardial and lung injury observed after cardiac surgery. oxide to endothelial by expression by neutrophils and may have a role in ischemia-reperfusion injury The of nitric oxide during cardiac surgery has been and levels of the inducible form of nitric oxide found to be increased in after CPB of the Systemic Inflammatory Response The systemic inflammatory response is in most Once the initiating stimulus is after of processes initiated during the or in the early serve to the systemic inflammatory response. endogenous that serve to the response have been including TNF-alpha IL-1 receptor and IL-10. TNF-alpha other protein TNF-alpha have a portion that the binding The portion of the TNF-alpha receptor may be from the cell surface and as a receptor capable of binding TNF-alpha. The for the TNF-alpha receptor has been the gene has been and the is for TNF-alpha receptor are type and type have levels of of TNF-alpha and a increase in TNF-alpha type receptor can be found after the of endotoxin TNF-alpha are increased during CPB A to IL-1 beta is produced in response to inflammatory stimulus and has been to be increased after the of CPB IL-10. a number of including inhibition of the synthesis of the inflammatory cytokines TNF-alpha, IL-1 beta, IL-6, The production of to be by TNF-alpha. not the production of for TNF-alpha or IL-1 beta Increased levels of have been detected during cardiac surgery after increases in the proinflammatory cytokines, as TNF-alpha, and may endogenous response to the inflammatory response in this Of with reduced the degree of activation of to plasma during CPB Therapeutic Strategies Randomized studies have examined a variety of strategies to ameliorate the systemic inflammatory response during cardiac surgery (Table 1, Table 3, and Table 4 and Table 2 and Table 5). Pharmacological There are several mechanisms by which a on the inflammatory response. reduce the release of TNF-alpha and IL-1 beta from alveolar macrophages TNF-alpha mRNA translation reduce the endothelial expression of a mechanism and reduce the expression of perhaps by also reduce nitric oxide by with or increases in inducible nitric oxide at the level of mRNA transcription studies reported in Table 1, Table 3, and Table show use to be associated with the of some of the inflammatory response, including reduced complement activation, reduced levels of proinflammatory cytokines IL-1 beta, IL-6, and increased levels of and reduced receptor There are the which may be at least in by the small of patients in most studies, the and the and of used in the These studies have considered and few have examined effects on including morbidity and The suggest that a be but the of of infection It be that in with few no of in the treatment of the inflammatory response has a on inhibitors, including and have been to reduce levels of proinflammatory cytokines released during cardiac surgery and to reduce the of (Table 1, Table 3, and Table 4) They have in been to reduce a on endothelial activation. The mechanism by which these agents activity is and inhibition of complement activation, with subsequent in cytokine release and inhibition of protease activation. The on cytokine activation may be of and the of neutrophils in fluid in patients with with a which a reduction in lung after The use of drugs to gut gut or to mechanical function (Table 1, Table 3, and Table 4) [29,30] is on the that may or reduce the release of endotoxin during cardiac surgery. levels have been variably to be increased during cardiac surgery and they are perhaps a reflection of reduced gut blood flow during CPB A of these is that they are likely to be more several than a before surgery. That Intracellular that increase intracellular levels of cAMP levels of TNF-alpha mRNA mechanisms to be However, a state of may after of these potentially the to effects of of endotoxin not a from the inhibition of TNF-alpha mRNA production in of or reduced release of of blood cell or IL-6 after the of to patients undergoing cardiac surgery (Table 1, Table 3, and Table directed at manipulation of the immune response have of cell-mediated immunity with a or but not with (Table 1, Table 3, and Table 4) The of with to be than used of its to the production of which to increase the activity of and to reduce IL-2 production (Figure 5). can immune T-cell activation, and T-cell in a to released from the the of cell-mediated immunity There have been no studies that on the of Mechanical Mechanical (Table 2 and Table the degree of activation of blood after contact with the foreign of the CPB circuit of these studies be by and by the that many of the examined are and that the reported may not these The use of has been to proinflammatory cytokines (Table 2 and Table and to improve However, the use of and the modification of the that it can be used after CPB have only efficacy. In review of studies the use of to ameliorate the systemic inflammatory response that there is no in with the use of (Table 2 and Table extracorporeal with show in proinflammatory cytokines, and which activation of (Table 2 and Table However, studies are and have not been perfusion to the gut associated with pulsatile perfusion to in systemic levels of endotoxin with However, two small have of pulsatile perfusion in the inflammatory response (Table 2 and Table the relative role of CPB in the systemic inflammatory response have produced (Table 2 and Table in proinflammatory cytokines are variably differences in elevation of levels the of increased have been measured during CPB CPB. These studies are by low have with to when bypass is however, the for to systemic blood in the of is with increased activation of the systemic inflammatory response during CPB. but of as The be considered as potential in a of patients (i.e., undergoing which our understanding of the systemic inflammatory response as it occurs during cardiac surgery. They be for of the systemic inflammatory response for at this to TNF-alpha or TNF-alpha of antibodies to TNF-alpha or of TNF-alpha reduce the level of TNF-alpha and its subsequent proinflammatory However, in any to this before the release of TNF-alpha to be cardiac surgery, this to the early of the before the of CPB If after TNF-alpha capable of levels of TNF-alpha, other initiated and mediators released by TNF-alpha will to It be that in no to has reduced mortality with these agents has been characterized and for therapeutic Its potential role as to ameliorate the systemic inflammatory response is to the as that used for TNF-alpha However, IL-1 is to more than thus, the for designed to reduce IL-1 levels be as of the use of for the of have not any for the on organ function to cytokines and release during CPB, it is to that some of the in and observed during cardiac surgery may be to alterations in and This has and the may be and blood flow during CPB [77]. of this is to flow associated with may also release of endotoxin during CPB is associated with in blood flow perfusion result in of pharmacological for drugs on blood flow for Cytokines also function and may is to alterations in when function is in Binding TNF-alpha and IL-6, are responsible for increased production of acute phase proteins during the acute inflammatory response and reduced synthesis of other proteins This may protein binding for drugs with potential in in the to after CPB. in The myocardial and in vascular to cytokines may of with potential in The response to by TNF-alpha IL-1 beta and IL-6 is associated clinically with a reduced level of The potential or of a response has not been but important potential with the immune system to leukocyte and and in cellular may the leukocyte immune function during cardiac surgery of as may reduce cytokine release and the use of using of during cardiac surgery to a has been and variably in the The of and/or the timing of may the degree and of the subsequent inflammatory response and its there are no data to or this understanding of the systemic inflammatory response to CPB has in the two further to the roles of the cytokines and the potential for therapeutic that effects a In it has become apparent that the effects of the systemic inflammatory response on and have important potential implications for the of patients undergoing CPB. The for in the of this and for the