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.
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.
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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 proliferation and differentiation and delayed-type hypersensitivity skin response [35]. When administered to humans, IL-2 produces symptoms and features characteristic of the systemic inflammatory response [101]. For IL-2 effects to be observed, an adequate number of both IL-2-producing T-helper cells (Figure 5) and T cells capable of responding to IL-2 (i.e., T cells expressing IL-2 receptors [IL-2R]) are required [35]. Reductions in the number of T-helper cells have been reported after cardiac surgery [35]. Levels of IL-2 have been measured as reduced [102] or unchanged [103]. IL-2R have been found to be reduced [102] or increased [103], and the ability of cells to synthesize IL-2 is consistently impaired after cardiac surgery, resulting in an impaired cell-mediated immune response [33]. The reason that IL-2R increases during cardiac surgery is unknown, but it may represent an attempt to modulate the immune response.
Figure 5: Simplified model of regulation of cell-mediated immune response. Host response is initiated by the antigen presenting cell (APC), a facilitory monocyte (M
phif), which activates resting helper T cells (T
H) by interleukin (IL) 1 synthesis and release. The helper T cell, in return, starts the synthesis and release of IL-2, which acts as an essential mediator for further activation, differentiation, and clonal proliferation of IL-2 receptor
+ (IL-2R
+) effector T cells (T (
C)). Another T lymphocytic-derived cytokine gamma-interferon (gamma-IFN) sustains facilitory monocyte cooperation. These forward regulatory mechanisms are controlled and down-regulated by inhibitory monocytes (M
phifn), which produce prostaglandin E
2 (PGE
2). PGE
2 activates the suppressor T-cell subset (T
S), which blocks IL-2 synthesis and T lymphocytic proliferation by direct cell-cell contact with helper T cells. Additionally, the function of facilitory monocytes is inhibited by PGE
2. From Markewitz et al.
[35] with permission.
Two other cytokines (IL-1 beta and IFN-gamma) are also required for proper cell-mediated immune function. IL-1 beta is required for both initiation of cell-mediated immune response and IL-2 production by T-helper cells [104] and is an important link between activation of the systemic inflammatory response and the cell-mediated immune response. IFN-gamma sustains monocytic participation in the cell-mediated immune response and is required for IL-2R expression on T cells [105]. Alterations in the synthesis or increased destruction of any of these cytokines may have deleterious consequences for the maintenance of the cell-mediated immune response. Prostaglandin E2 (PGE2) increases CD8+ suppressor T-cell activity, which leads to a reduction in IL-2-producing T-helper cell subsets (Figure 5) [35].
IL-6.
The historical development of the cytokine known as IL-6 reflects its multifunctional role [106]. It has been variously described as IFN-beta2, 26 K factor, B-cell stimulatory factor 2, plasmacytoma growth factor, hybridoma growth factor, hepatocyte-stimulating factor, or cytotoxic T-cell differentiation factor. Amino acid sequencing and cloning of these factors has revealed that they are all the same substance, and they have collectively been renamed IL-6. In addition to the effects of IL-6 on the regulation of acute-phase protein production, IL-6 contributes to the terminal differentiation and secretion of immunoglobulins from B cells and to T-cell activation, and it acts as a competence factor to confer responsiveness to hematopoietic growth factors [106]. Along with TNF-alpha and IL-1 beta, it is an endogenous pyrogen [107]. Stimuli for the release of IL-6 include endotoxin, TNF-alpha, and IL-1 [84,99]. IL-6 usually appears in plasma 30 min to 2 h after a stimulus, peaks at 4-6 h, and precedes the increase in acute-phase proteins [108]. This is consistent with the concept that IL-6 release occurs later in the inflammatory cascade, and its appearance is dependent on the up-regulation of IL-6 synthesis by other inflammatory cytokines [84,99]. The role of IL-6 in altering the pharmacokinetics and pharmacodynamics of drugs administered during cardiac surgery using CPB is unknown but may be substantial, given its role as a pyrogen [107], an activator of acute phase protein synthesis [108], and a myocardial depressant [91,92,109]. In contrast to other cytokines, such as TNF-alpha and IL-1 beta, which are variably measured during cardiac surgery, levels of IL-6 are more consistently increased during cardiac surgery [3,15,18,20,26,29,31,34-36,43-47,53,63,66,67].
IL-8.
Properties attributed to IL-8 include regulation of neutrophil-specific chemotaxis [110], stimulation of the respiratory burst [111], regulation of transendothelial migration of neutrophils [112], and neutrophil-dependent plasma leak [113]. This suggests that IL-8 may have an important role in directing polymorphonuclear cells in the development of the systemic inflammatory response during cardiac surgery [20,114-116].
Increases in IL-8 concentrations in plasma have been recorded during cardiac surgery in both children and adults [3,12,17,20,21,26,43-45,47,63,67]. Peaks in circulating IL-8 levels seem to precede or be coincident with the peak in IL-6 levels, and its release is induced by TNF-alpha [117]. The appearance of IL-8 in plasma during cardiac surgery is associated with an increase in elastase, a protease contained in lysosomal granules within the leukocyte, which is released in response to cellular activation and is associated with organ dysfunction [69,114]. IL-8 mRNA expression is up-regulated in heart and skeletal muscle after cardiac surgery [118]. The increase in IL-8 levels is temperature-sensitive (increased with cooling and subsequent rewarming) [119], and this may have a negative impact on the high-risk patient (e.g., patients with bacterial endocarditis or pneumonia).
Cellular Events
Endothelial Activation.
Neutrophils are activated during cardiac surgery, as evidenced by the release of intracellular lysosomal granular contents such as elastase and myeloperoxidase [69,120] and generation of oxygen-derived free radicals [4,71,121]. Such activation may partially explain findings such as increased ventilation-perfusion mismatch [69] and endothelial injury after cardiac surgery [93,120].
Adhesion of neutrophils to the endothelium is an essential prerequisite for these processes to occur [122]. The first stage of adhesion (which is regulated, in part, by cytokines such as IL-1 beta, TNF-alpha, and endotoxin) [123] is characterized by transition to a rolling state so that leukocytes tumble along the wall of the vessel at much slower speeds (Figure 6). This process involves the expression of adhesion molecules called selectins by endothelial cells (e.g., endothelial-leukocyte adhesion molecule 1, intercellular adhesion molecule 1, vascular adhesion molecule) and transient binding to complimentary receptors on neutrophils [122]. Increases of particular selectin levels and increased cellular expression [124] have been variably observed during cardiac surgery [25,26,55,63,70]. This variation may be due to a delay related to a requirement for protein synthesis for selectins such as endothelial-leukocyte adhesion molecule 1 or failure to measure the most appropriate selectin [e.g., GMP-140, which is stored preformed in Wiebel-Palade bodies of endothelial cells [125] and thus is more readily mobilized during cardiac surgery].
Figure 6: Process thought to be involved in the primary and secondary adhesion of neutrophils. From Elliott and Finn
[122] with permission.
The second stage of adhesion is mediated by up-regulation of cell surface neutrophil receptors. IL-8 [and other cytokines, including IL-1 beta [126]] play a pivotal role by increasing the expression of cell surface receptors known as integrins (e.g. CD11a/CD18, CD11b/CD18, CD11c/CD18 [Figure 7] [127]. IL-8 also causes concomitant down-regulation of selectins at this stage [116]. Increased levels of integrins have been measured during cardiac surgery [3,14,19,55,116], and animal studies of CPB in which up-regulation of CD11b/CD18 is prevented by the drug NPC 15669, show reductions in end organ damage [128].
Figure 7: Neutrophil CD11a/CD18 (integrin) adheres to intercellular adhesion molecules 1 and 2 (ICAM1 and ICAM2, respectively) on endothelial cells. CD11b/CD18 also adheres to ICAM1, and possibly also to elements of the extracellular matrix. From Elliott and Finn
[122] with permission.
The final stage (third stage or "secondary adhesion") involves binding to endothelial ligands and migration across the endothelial barrier with the release of neutrophil intracellular enzymes such as elastase and myeloperoxidase [69] (with potential tissue injury). Penetration through the endothelial cell barrier is, in part, regulated by IL-8 induction of integrin expression (Figure 8) [112]. Randomized studies have used changes in the degree of elevation of blood elastase and myeloperoxidase enzymes as markers of neutrophil activation and treatment effect during cardiac surgery [8,10,23,30,31,37,40,41,47,50,51,55,57-60,67,69].
Figure 8: Possible role of CD11b/CD18-mediated endothelial adhesion in the intracellular signaling of degranulation and release of superoxide radicals. From Elliott and Finn
[122] with permission.
Nitric Oxide Production.
Under the influence of endotoxin and cytokines, including TNF-alpha and IL-1 beta, an inducible form of the enzyme nitric oxide synthase is expressed by vascular endothelium and smooth muscle cells, which leads to increased production and release of nitric oxide [129]. Resultant effects include vascular smooth muscle relaxation (leading to hypotension) [130], myocardial depression [92], and lung injury [18]-events observed after cardiac surgery. Nitric oxide inhibits neutrophil adhesion to endothelial cells by down-regulating integrin expression by neutrophils [131], inhibits platelet aggregation [132], and may have a role in ischemia-reperfusion injury [133]. The generation of nitric oxide during cardiac surgery has been demonstrated [18], and levels of the inducible form of nitric oxide synthase were found to be increased in human lungs after CPB [134].
Termination of the Systemic Inflammatory Response
The systemic inflammatory response is self-limiting in most patients. Once the initiating stimulus is removed (e.g., after termination of CPB), processes initiated either during the procedure or in the early period thereafter serve to terminate the systemic inflammatory response. Several endogenous factors that serve to limit the response have been identified, including TNF-alpha receptors, IL-1 receptor antagonist (IL-1RA), and IL-10.
TNF-alpha Receptors.
Like other transmembrane protein receptors, TNF-alpha receptors have a hydrophilic extracellular portion that contains the ligand binding site [135]. The hydrophilic portion of the TNF-alpha receptor may be shed from the cell surface and circulate as a soluble receptor capable of binding circulating TNF-alpha. The amino acid sequence for the TNF-alpha receptor has been characterized, the gene has been cloned, and the compound is now available for investigation. Two TNF-alpha receptor subtypes are recognized: type I and type II. Healthy subjects have circulating levels of both subtypes of TNF-alpha receptors, and a brisk increase in TNF-alpha type I receptor can be found after the injection of endotoxin [136]. Endogenous soluble TNF-alpha receptors are increased during CPB [63,68,103,137].
IL-1RA.
A specific antagonist to IL-1 beta (IL-1RA) is produced naturally in response to an appropriate inflammatory stimulus and has been noted to be increased after the onset of CPB [137].
IL-10.
IL-10 exerts a number of antiinflammatory effects, including inhibition of the synthesis of the inflammatory cytokines (e.g., TNF-alpha, IL-1 beta, IL-6, IL-8) [138]. The production of IL-10 seems to be predominantly stimulated by TNF-alpha. IL-10 does not inhibit the production of receptors for TNF-alpha or IL-1 beta [139]. Increased levels of IL-10 have been detected during cardiac surgery after increases in the proinflammatory cytokines, such as TNF-alpha, and may represent an endogenous response to limit the inflammatory response in this setting [21,137,140]. Of interest, pretreatment with IL-10 (and morphine) reduced the degree of neutrophil activation of cells exposed to human plasma collected during CPB [141].
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 Approaches
Corticosteroids.
There are several mechanisms by which steroids might exert a beneficial effect on the inflammatory response. Steroids reduce the release of TNF-alpha and IL-1 beta from stimulated alveolar macrophages [142], inhibit TNF-alpha mRNA translation [143], reduce the endothelial expression of selectins via a glucocorticoid receptor-mediated mechanism [144], and reduce the neutrophil expression of integrins, perhaps by preventing cytokine-mediated up-regulation [14]. Steroids also reduce nitric oxide production, possibly by interfering with endotoxin- or cytokine-mediated increases in inducible nitric oxide synthase at the level of mRNA transcription [18].
Most randomized studies reported in Table 1, Table 3, and Table 4[5-22] show steroid use to be associated with the amelioration of some aspect of the inflammatory response, including improved hemodynamics, reduced complement activation, reduced levels of proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6, and IL-8), increased levels of IL-10, and reduced integrin receptor up-regulation. There are discrepancies among the results reported, which may be explained, at least in part, by the small numbers of patients in most studies, the variable end points, and the differing types and doses of corticosteroids used in the studies. These studies have mostly considered epiphenomena, and few reports have examined effects on outcome, including morbidity and mortality. The generally favorable results suggest that a large-scale clinical trial might be warranted, but the possibility of an enhanced risk of infection would require close monitoring. It must be appreciated that in another similar clinical scenario (sepsis), with few exceptions, no large-scale trial of steroids in the treatment of the inflammatory response has demonstrated a benefit on outcome [145].
Protease Inhibitors.
Protease inhibitors, including aprotinin, ulinastatin, and nafamstat, have been shown to reduce levels of proinflammatory cytokines released during cardiac surgery and to reduce the up-regulation of integrins (Table 1, Table 3, and Table 4) [3,19,23-26,28]. They have not, in general, been shown to reduce selectin levels, thus indicating a limited effect on endothelial activation. The mechanism by which these agents exert their antiinflammatory activity is varied and includes inhibition of complement activation, with subsequent reductions in cytokine release and inhibition of serine protease activation. The effect on cytokine activation may be dose-dependent [23,28,146]. Concentrations of IL-8 were reduced, and the chemotactic ability of neutrophils in bronchoalveolar lavage fluid was blunted in patients treated with aprotinin, compared with a control group, which suggests a reduction in neutrophil lung accumulation after aprotinin therapy [27].
Gut Therapy.
The use of drugs to preserve gut flora (selective gut decontamination) or to promote intestinal mechanical function (laxatives) (Table 1, Table 3, and Table 4) [29,30] is predicated on the hypothesis that such therapy may prevent or reduce the release of gut-derived endotoxin during cardiac surgery. Endotoxin levels have been variably shown to be increased during cardiac surgery [4,9,13,15,29,30,75,76], and they are perhaps a reflection of reduced gut blood flow during CPB [29,30,76,78]. A practical limitation of these therapies is that they are likely to be more successful if given over several days, rather than a single day before surgery.
Drugs That Increase Intracellular cAMP.
Drugs that increase intracellular levels of cAMP decrease levels of TNF-alpha mRNA through mechanisms yet to be identified [31,95,143]. However, a state of hyperresponsiveness may occur after abrupt discontinuation of these drugs, potentially sensitizing the organism to effects of otherwise insignificant amounts of endotoxin [143]. Butler et al. [31] could not demonstrate a clinical benefit from the attempted inhibition of TNF-alpha mRNA production in terms of improved oxygenation or reduced release of neutrophil elastase (a marker of white blood cell activation) or IL-6 after the administration of pentoxifylline to patients undergoing cardiac surgery (Table 1, Table 3, and Table 4).
Immunomodulation.
Studies directed at investigating manipulation of the immune response have demonstrated preservation of cell-mediated immunity with a nonsteroidal antiinflammatory drug (indomethacin) or an immunomodulatory drug (thymopentin) but not with glucocorticoids (Table 1, Table 3, and Table 4) [22,32-36]. The combination of thymopentin with indomethacin was shown to be better than either drug alone. Indomethacin was used because of its ability to inhibit the production of PGE2, which acts to increase the activity of suppressor T cells and to reduce IL-2 production (Figure 5). Thymopentin can restore immune balance, induce T-cell activation, and accelerate T-cell recruitment in a manner analogous to thymopoietin released from the thymus [33]. Glucocorticoids enhanced the previously described impairment of cell-mediated immunity [22]. There have been no outcome studies that demonstrate an effect on the incidence of septic-related complications.
Mechanical Approaches
Mechanical therapies (Table 2 and Table 5) modify the degree of activation of blood components after contact with the foreign surfaces of the CPB circuit [2,6,7,40,49-52,54-62,147]. Interpretation of these studies must be tempered by their age and by the realization that many of the interventions examined (e.g., oxygenators) are constantly being improved and that the reported results may not reflect these changes.
Filters.
The use of hemoconcentration filters has been demonstrated to remove proinflammatory cytokines (Table 2 and Table 5) [42-45] and to improve outcome [65]. However, the use of leukocyte-specific filters [46] and the modification of the ultrafiltration technique so that it can be used after CPB [47] have had only limited efficacy.
Oxygenators.
In general, review of studies examining the use of membrane versus bubble oxygenators to ameliorate the systemic inflammatory response suggests that there is no striking improvement in outcome with the use of membrane oxygenators (Table 2 and Table 5) [6,7,40,42,48-55].
Extracorporeal Circuits.
Studies comparing heparinbonded extracorporeal circuits with conventional circuits show reductions in proinflammatory cytokines, selectins, complement, and elastase levels, which indicates less activation of polymorphonuclear cells (Table 2 and Table 5) [56-64]. However, large-scale outcome studies are lacking, and cost-benefit results have not been reported.
Pulsatile Perfusion.
Improved perfusion [particularly to the gut [73]] associated with pulsatile perfusion might lead to reductions in systemic levels of endotoxin with improved outcome. However, two small randomized trials have demonstrated conflicting results of pulsatile perfusion in ameliorating the inflammatory response (Table 2 and Table 5) [40,41].
Temperature.
Studies examining the relative role of hypothermic versus normothermic CPB in activating the systemic inflammatory response have produced conflicting results (Table 2 and Table 5) [66-70]. Elevations in proinflammatory cytokines are variably reported. No differences in elevation of selectin levels (with the exception of increased p-selectin [platelet-associated] levels) have been measured during hypothermic CPB versus normothermic CPB. These studies are limited by low patient numbers. Large-scale clinical trials [148,149] have shown inconsistent results with respect to neurological outcome when normothermic bypass is used; however, the greater requirement for vasopressors to maintain systemic blood pressure in the study of Christakis et al. [149] is consistent with an increased activation of the systemic inflammatory response during normothermic CPB.
Therapies Not Yet Explored but of Potential Value as Investigative Tools
The approaches described below might best be considered as potential interventions in a homogeneous group of patients (i.e., those undergoing CPB), which might extend our understanding of the systemic inflammatory response as it occurs during cardiac surgery. They cannot be recommended for modulation of the CPB-induced systemic inflammatory response for clinical purposes at this time.
Anticytokine Therapy
Antibodies to TNF-alpha or Soluble TNF-alpha Receptors.
Exogenous administration of antibodies to TNF-alpha or exogenous administration of soluble TNF-alpha receptors might reduce the overall level of free TNF-alpha and its subsequent proinflammatory activity. However, in any study to assess this effect, administration should occur before the release of TNF-alpha to be maximally effective. For cardiac surgery, this would apply to the early phases of the procedure before the onset of CPB [15,18,19,21,29,34,37,43,44,46,47,57,63,66-68,78,82,150]. If administered after TNF-alpha release, although capable of reducing circulating levels of TNF-alpha, other pathways initiated and mediators released by TNF-alpha will continue to express their activity. It should be noted that in another clinical scenario (sepsis), no clinical trial to date has shown reduced mortality with these agents [151].
IL-1RA.
IL-1RA has been characterized and developed for therapeutic application [152]. Its potential role as an agent to ameliorate the systemic inflammatory response is subject to the same reasoning as that used for TNF-alpha antagonists. However, IL-1 measurement is subject to even more variability than TNF-alpha; thus, the basis for interventions designed to reduce IL-1 levels must be regarded as very speculative. Studies of the use of IL-1RA for the therapy of sepsis have not demonstrated any additional value beyond standard therapy [153].
Implications for Anesthesia
Given the widespread effect on organ function attributed to cytokines and their release during CPB, it is reasonable to propose that some of the changes in drug metabolism and effect observed during cardiac surgery [154] may be due to cytokine-mediated alterations in pharmacokinetics and pharmacodynamics. This area has received little study, and the following considerations may be relevant.
Liver Blood Flow and Reticuloendothelial Function
Liver blood flow changes during CPB [77]. Part of this change is due to abnormal flow associated with nonpulsatile perfusion, although cytokine-mediated changes may also contribute. For example, release of endotoxin during CPB is associated with reductions in mesenteric blood flow [78]. Reduced hepatic perfusion could result in prolongation of pharmacological effect for drugs dependent on liver blood flow for metabolism (e.g., alfentanil) [155]. Cytokines also inhibit reticuloendothelial function [94] and thus may impair drug metabolism. Alfentanil is subject to alterations in metabolism when reticuloendothelial function is disturbed [156].
Alterations in Protein Binding
Cytokines, particularly TNF-alpha and IL-6, are responsible for increased production of acute phase proteins (e.g., alpha1-acid glycoprotein) during the acute inflammatory response [108] and reduced synthesis of other proteins (e.g., albumin). This may alter protein binding ratios for drugs (e.g., lidocaine) [157] with potential changes in drug effect in the hours to days after CPB.
Changes in Distribution
The myocardial depression [92] and changes in vascular permeability attributed to cytokines [120] may alter drug volumes of distribution with potential changes in pharmacokinetics.
Central Nervous System Depression
The febrile response to inflammation mediated by TNF-alpha [107], IL-1 beta [97], and IL-6 [107] is associated clinically with a reduced level of consciousness [158]. The potential additive or anesthetic-sparing effect of such a response has not been investigated but could represent an important potential pharmacodynamic interaction.
Opioids
Endogenous opioids interact with the immune system to promote leukocyte chemotaxis, and adherence and changes in cellular opioid receptors may influence the leukocyte immune function during cardiac surgery [141]. Exogenous administration of opioids such as morphine may reduce cytokine release [159], and the use of anesthetic techniques using large doses of opioids during cardiac surgery to promote a "stress-free" anesthetic has been popular and variably successful in the past [160]. The choice of opioid and/or the timing of administration may influence the degree and magnitude of the subsequent inflammatory response and its consequences [161], although there are no definitive data to verify or refute this postulate.
Conclusions
Our understanding of the systemic inflammatory response to CPB has progressed considerably in the last two decades. As further research continues to define the roles of the various cytokines and their receptors, the potential for therapeutic advances that might attenuate deleterious effects becomes a real possibility. In addition, it has become apparent that the effects of the systemic inflammatory response on pharmacokinetics and pharmacodynamics have important potential implications for the anesthetic management of patients undergoing CPB.
The authors thank Ms. Polly Moores for secretarial assistance in the preparation of this manuscript and Dr. Tom Coonan for reviewing the manuscript.
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