Systemic inflammation and cardiac surgery: an update

Cardiac surgery with cardiopulmonary bypass (CPB) is associated with the development of a systemic inflammatory response that can often lead to dysfunction of major organs. The systemic inflammation can be assessed intra- and postoperatively by measuring concentrations of inflammatory mediators in plasma and tissues. These concentrations, however, do not always correlate with the degree of observed organ dysfunction. Various strategies have been used to reduce inflammatory phenomena in patients undergoing CPB. Cardiac surgery without CPB has been performed increasingly with satisfactory results over the past few years. Attenuation of systemic inflammation and improved outcome in high risk patients are potential benefits of this technique. The emergence and expanding performance of cardiac surgical procedures without the use of CPB has given us an excellent tool to investigate the relative importance of CPB as a cause of systemic inflammation. Aprotinin is a protease inhibitor which is used in cardiac surgical patients for its haemostatic effects. Aprotinin has anti-inflammatory properties, the nature of which have not been completely clarified. This article presents a summary of the published literature investigating inflammatory response and organ dysfunction in patients who have cardiac surgery without CPB. It also presents an overview of recent data on the anti-inflammatory action mechanisms of aprotinin.     

Evaluation of the effect of one large dose of erythropoietin against cardiac and cerebral ischemic injury occurring during cardiac surgery with cardiopulmonary bypass: a randomized double-blind placebo-controlled pilot study

Cardiac surgery and cardiopulmonary bypass (CPB) induce ischemia–reperfusion and subsequent cellular injury with inflammatory reaction. Clinical and experimental studies suggest that recombinant human erythropoietin (EPO) independently of its erythropoietic effect may be used as a cytoprotective agent against ischemic injury. We tested the hypothesis that one large dose of EPO administered shortly before CPB prevents the elevation of cardiac and cerebral ischemic blood markers as well as the systemic inflammatory response induced by cardiac surgery with CBP through this randomized double‐blind placebo‐controlled pilot trial. Fifty patients scheduled for coronary artery bypass graft (CABG) surgery with CPB were randomly allocated to EPO or control groups. EPO (800 IU/kg intravenously) or placebo (saline) was administered before CPB. The primary end point was to study the effect of EPO administration on several blood markers of myocardial and cerebral ischemia in relation to CABG with CPB. In both groups, surgery increased plasma concentrations of cardiac (troponin T, NT‐proBNP, and creatine kinase MB) and cerebral (S100β protein) markers ischemic as well as the pro‐inflammatory marker interleukin‐6. Compared with the placebo, EPO administration before CPB did not prevent an increase of all these markers following CPB. In conclusion, one large dose of EPO, given shortly before CPB, did not protect against cardiac and cerebral ischemia and inflammatory response occurring during CABG surgery with CPB. Although the long‐term clinical implications remain unknown, the findings do not support use of EPO at this dose as a cytoprotective agent in patients undergoing cardiac surgery.     

Treatment of sepsis in cardiac surgery: role of immunoglobulins

Cardiopulmonary bypass (CPB) is associated with an injury that may cause pathophysiological changes such as systemic inflammatory response syndrome, multiple organ dysfunction syndrome, and mediator-induced multiorgan failure. Systemic endotoxinaemia, release of proinflammatory cytokines, and interactions between neutrophils and endothelium have been reported to correlate with a high incidence of organ dysfunction, infection and sepsis following cardiac surgery. This review discusses the dysregulation of the immune response as a major reason for the higher susceptibility to infections following cardiac surgery, various treatment strategies to reduce CPB-induced inflammation, and especially the prophylactic use of immunoglobulins in cardiac surgery.     

Increased plasma levels of soluble triggering receptor expressed on myeloid cells 1 and procalcitonin after cardiac surgery and cardiac arrest without infection

Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) and procalcitonin (PCT) are often considered to be specific markers for infection. We evaluated plasma levels of sTREM-1 and PCT in patients with systemic inflammatory response syndrome but no sepsis. Noninfected patients undergoing elective heart surgery with cardiopulmonary bypass (n = 76) and patients admitted after out-of-hospital cardiac arrest (n = 54) were followed up for 3 days. Patients with severe sepsis (n = 55) and healthy volunteers (n = 31) were included as positive and negative controls, respectively. Plasma levels of PCT were higher in sepsis patients than in patients who survived after cardiac arrest or after heart surgery. In contrast, peak plasma levels of sTREM-1 in heart surgery and in cardiac arrest patients overlapped with those measured in patients with sepsis. Both sTREM-1 and PCT were significantly higher in cardiac arrest patients who died of refractory shock than in those who died of neurological failure or survived without major neurological damage. In the cardiac arrest patients with refractory shock, sTREM-1 and PCT levels were similar to those in the patients with severe sepsis. In conclusion, sTREM-1 and PCT are not specific for infection and can increase markedly in acute inflammation without infection.     

Adiponectin as an anti-inflammatory factor

Obesity is characterized by low-grade systemic inflammation. Adiponectin is an adipose tissue-derived hormone, which is downregulated in obesity. Adiponectin displays protective actions on the development of various obesity-linked diseases. Several clinical studies demonstrate the inverse relationship between plasma adiponectin levels and several inflammatory markers including C-reactive protein. Adiponectin attenuates inflammatory responses to multiple stimuli by modulating signaling pathways in a variety of cell types. The anti-inflammatory properties of adiponectin may be a major component of its beneficial effects on cardiovascular and metabolic disorders including atherosclerosis and insulin resistance. In this review, we focus on the role of adiponectin in regulation of inflammatory response and discuss its potential as an anti-inflammatory marker.     

Early postoperative monocyte deactivation predicts systemic inflammation and prolonged stay in pediatric cardiac intensive care

OBJECTIVE: Sepsis and systemic inflammatory response syndrome (SIRS) are major causes of morbidity and mortality after cardiopulmonary bypass. Attempts to suppress proinflammatory mediators have failed to improve outcomes in sepsis or in patients undergoing cardiopulmonary bypass. Recent work in adult patients has suggested that the balance between pro- and anti-inflammatory mediators is more important than the level of proinflammatory response alone. This balance may be reflected by the expression of monocyte human lymphocyte antigen (HLA)-DR, with low concentrations indicating an excess of anti-inflammatory stimuli and relative immunodeficiency. We investigated the relationship between monocyte HLA-DR expression and the subsequent development of sepsis/SIRS in children undergoing cardiopulmonary bypass. DESIGN: A prospective, observational, clinical study. SETTING: A tertiary pediatric cardiac center. PATIENTS: Eighty-two infants and children undergoing elective cardiac surgery between March and December 1999. MEASUREMENTS AND MAIN RESULTS: Monocyte HLA-DR expression was assessed before and after surgery and was found to be related to the length of hospital stay and the development of complications including sepsis/SIRS. The inflammatory insult of cardiopulmonary bypass decreased monocyte HLA-DR expression in all children. Lowest concentrations were seen within 72 hrs of surgery and were significantly lower in cases that subsequently required prolonged intensive care support (p <.0001, Mann-Whitney). HLA-DR expression on <60% of circulating monocytes was associated with a greatly increased risk of later (minimum 4 days) development of sepsis/SIRS (odds ratio, 12.9; 95% confidence interval, 3.4-47.5). Low HLA-DR was an independent predictor for the development of sepsis/SIRS after correction for age, bypass time, complexity of surgery, Paediatric Index of Mortality, and surgeon on multiple logistic regression analysis. CONCLUSIONS: Patients with decreased HLA-DR in the early postoperative period represent a subpopulation at greatly increased risk of later sepsis/SIRS. Such patients may benefit from strategies aimed to reduce this risk.     

Cortisol antiinflammatory effects are maximal at postoperative plasma concentrations

OBJECTIVE: To determine the plasma concentration of cortisol that is needed for maximal suppression of the systemic inflammatory response to cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective, randomized, double-blind clinical study of cardiac surgical patients. SETTING: Operating room and inpatient care facility of a university medical center. SUBJECTS: Sixty elective cardiac surgical patients scheduled for coronary artery bypass graft, cardiac valve replacement, or both. INTERVENTIONS: Patients were randomized to receive one of three different hydrocortisone doses, by intravenous infusion, for 6 hrs before, during, and immediately after surgery while also receiving etomidate to suppress endogenous cortisol production. MEASUREMENTS AND MAIN RESULTS: Serial determinations of plasma interleukin-6 were studied as a marker of systemic inflammation. Measurements of interleukin-10 were used as a marker of the compensatory antiinflammatory response. Plasma cortisol concentrations in an untreated control group rose from 17 microg/dL before surgery to a mean of 43 microg/dL by 4 hrs after surgery. A dose of hydrocortisone (4 microg/kg/min for 6 hrs) that maintained plasma cortisol between 40 and 50 microg/dL, starting 60-90 mins before surgery, significantly suppressed plasma interleukin-6 after surgery compared with control while significantly increasing plasma interleukin-10 during surgery. Plasma interleukin-6 after surgery was not suppressed further by increasing the dose of hydrocortisone to 8 microg/kg/min, although the mean peak plasma interleukin-10 concentration increased further compared with the group that received the 4 microg/kg/min hydrocortisone dose. CONCLUSIONS: At the doses studied, cortisol-induced suppression of plasma interleukin-6 during and after cardiac surgery appears to be a saturable phenomenon at the concentration of plasma cortisol that is normally achieved after surgery in untreated patients.     

Inflammatory response to coronary stent implantation in patients with unstable angina.

Previous evidence has shown that coronary angioplasty leads to the release of inflammatory mediators. In this study, we sought to characterize the systemic inflammatory response after coronary stent implantation in patients with unstable angina by measuring different protein markers. Peripheral blood samples were taken before and 24 h, 48 h, and 7 days after successful coronary stenting in 58 patients. Several markers of acute-phase response were determined: C-reactive protein (CRP), alpha2-macroglobulin, haptoglobin, acid alpha1-glycoprotein, prealbumin and albumin. Besides, proinflammatory cytokines (tumor necrosis factor-alpha, IL-6, IL-8) and the anti-inflammatory cytokine IL-10 were also measured. We have found that coronary angioplasty with stent implantation produces a systemic inflammatory response with a rise in inflammation markers concentration. CRP plasma levels declined 1 week after the intervention, but the other marker levels were even higher after 7 days. IL-6 was the only cytokine whose plasma levels significantly increased in peripheral blood after stenting, with a rise after 24 h, maintained after 48 h, and decreased to near-basal levels after 1 week. There was a good correlation between CRP and IL-6 plasma levels (r=0.5, p<0.001). IL-10 levels were slightly decreased after 24 h. Although no significant differences in the means at different time points were found, there was a decrease in IL-10 in most patients 24 h after the intervention. These results indicate that coronary stent implantation induces a systemic inflammatory reaction, with a temporal increase in the concentration of the inflammation markers, especially CRP and IL-6. Since these markers had been previously used as prognostic markers, this needs to be taken into account in patients undergoing stent implantation.     

Pathophysiology and diagnostic value of urinary trypsin inhibitors.

Inflammation is an important indicator of tissue injury. In the acute form, there is usually accumulation of fluids and plasma components in the affected tissues. Platelet activation and the appearance in blood of abnormally increased numbers of polymorphonucleocytes, lymphocytes, plasma cells and macrophages usually occur. Infectious disorders such as sepsis, meningitis, respiratory infection, urinary tract infection, viral infection, and bacterial infection usually induce an inflammatory response. Chronic inflammation is often associated with diabetes mellitus, acute myocardial infarction, coronary artery disease, kidney diseases, and certain auto-immune disorders, such as rheumatoid arthritis, organ failures and other disorders with an inflammatory component or etiology. The disorder may occur before inflammation is apparent. Markers of inflammation such as C-reactive protein (CRP) and urinary trypsin inhibitors have changed our appraisal of acute events such as myocardial infarction; the infarct may be a response to acute infection and (or) inflammation. We describe here the pathophysiology of an anti-inflammatory agent termed urinary trypsin inhibitor (uTi). It is an important anti-inflammatory substance that is present in urine, blood and all organs. We also describe the anti-inflammatory agent bikunin, a selective inhibitor of serine proteases. The latter are important in modulating inflammatory events and even shutting them down.     

Acute pancreatitis: models, markers, and mediators

Acute pancreatitis has an incidence of approximately 40 cases per year per 100,000 adults. Although usually self-limiting, 10% to 20% of afflicted patients will progress to severe pancreatitis. The mortality rate among patients with severe pancreatitis may approach 30% when they progress to multisystem organ failure. The development of acute pancreatitis illustrates the requirement for understanding the basic mechanisms of disease progression to drive the exploration of therapeutic options. The pathogenesis of acute pancreatitis involves the interplay of local and systemic immune responses that are often difficult to characterize, particularly when results from animal models are used as a foundation for human trials. Experimental studies suggest that the prognosis for acute pancreatitis depends upon the degree of pancreatic necrosis and the intensity of multisystem organ failure generated by the systemic inflammatory response. This suggests an intricate balance between localized tissue damage with proinflammatory cytokine production and a systemic, anti-inflammatory response that restricts the inappropriate movement of proinflammatory agents into the circulation. The critical players of this interaction include the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, IL-8, and platelet activating factor (PAF). The anti-inflammatory cytokines IL-10, as well as TNF-soluble receptors and IL-1 receptor antagonist, have also been shown to be intimately involved in the inflammatory response to acute pancreatitis. Other compounds implicated in disease pathogenesis in experimental models include complement, bradykinin, nitric oxide, reactive oxygen intermediates, substance P, and higher polyamines. Several of these mediators have been documented to be present at increased concentrations in the plasma of patients with severe, acute pancreatitis. Preclinical work has shown that some of these mediators are markers for disease activity, whereas other inflammatory components may actually drive the disease process as important mediators. Implication of such mediators suggests that interruption or blunting of an inappropriate immune response has the potential to improve outcome. Although the manipulations of specific mediators in animal models may be promising, they may not transition well to the human clinical setting. However, continued reliance on experimental animal models of acute pancreatitis may be necessary to determine the underlying causes of disease. Full understanding of these basic mechanisms involves determining not only which mediators are present, but also closely documenting the kinetics of their appearance. Measurement of the inflammatory response may also serve to identify diagnostic markers for the presence of acute pancreatitis and provide insight into prognosis. Understanding the models, documenting the markers, and deciphering the mediators have the potential to improve treatment of acute pancreatitis.     

Equivalence of the acute cytokine surge and myocardial injury after coronary artery bypass grafting with and without a novel extracorporeal circulation system

Cardiopulmonary bypass (CPB) contributes to a morbidity-inducing systemic inflammatory response after cardiac surgery. We compared this response in patients receiving coronary artery bypass grafting (CABG) with (CPB group; n = 7) or without (off-pump group; n = 8) the Minimal Extracorporeal Circulation (MECC) system. Serum concentrations of tumour necrosis factor (TNF)-alpha, soluble TNF receptors, pro- and anti-inflammatory interleukins (ILs) and other myocardial injury markers were measured after anaesthetic induction, at 1 h, 4 h and 24 h after completing all anastomoses or serially. Soluble TNF receptor type I (sTNFRI) and IL-8 peaked early after CABG in both groups and did not decline. Serum sTNFRI was significantly higher in the CPB compared with the off-pump group at 1 h, whereas IL-8 was significantly lower in the CPB group throughout. The MECC system, therefore, produces an equivalent acute cytokine response and degree of myocardial injury to off-pump CABG, and may be useful when CABG cannot be performed without CPB.     

Markers of inflammation in sepsis

Pathophysiology of sepsis is characterised by a whole body inflammatory reaction and concurrent activation of the host's anti-inflammatory mechanisms. The balance between pro- and anti-inflammatory reactions is critical for the outcome of the patient. Strongly activated phagocytes and high levels of proinflammatory cytokines occur in patients who are at risk of developing circulatory shock and multiple organ dysfunction. Extensive anti-inflammatory reaction, which is characterised by the presence of high levels of circulating anti-inflammatory cytokines and impaired innate and adaptive immune functions, renders critically ill patients prone to secondary infections. Evaluation of the immune-inflammatory status on admission to the hospital may be helpful in the early identification of patients who are bound to develop organ dysfunction. Such patients could possibly benefit from a mode of therapy aimed at modifying the course of inflammatory response. The use of inflammatory markers may also improve diagnosis of severe infection. The present review summarises the studies on markers of inflammation and immune suppression used, first, as predictors of organ dysfunction in patients with systemic inflammation, and, second, as indicators of infection in adults and neonates.     

Anti-inflammatory pre-treatment and the resultant effects of interleukin-10: adjuncts to multi-therapeutical strategies

With the advent of off-pump coronary bypass surgery, there is increasing demand for research in attenuating the deleterious effects of cardiopulmonary bypass (CPB). An improved understanding of the systemic inflammatory response syndrome (SIRS) has distinguished which areas of components have the most adverse effects and which are, in fact, anti-inflammatory. This classification of inflammatory components allows strategic treatment for those likely to cause the most clinically significant 'effect', suitably termed 'effectors'. This article will identify current methods in treating 'effectors', as well as those components having anti-inflammatory effects. This article selectively features certain inflammatory components by: (1) grouping them as being 'mediators' or 'effectors'; (2) relating them to interleukin-10 (IL-10) and treatments potentiating anti-inflammatory effects; (3) summarizing their mechanisms of action; (4) recognizing the time periods during bypass exhibiting peak levels; and (5) investigating current treatment. methods and identifying their significance to 'effectors'. A literature search in MEDLINE was performed, featuring articles of the English-language within the past 5 years. Because of the characteristic of having interlinked multi-component cascades, it is evident that treating SIRS with a one-dimensional method would be inadequate. This article not only confirms the importance of a multi-factorial therapeutic approach, but also targets the inflammatory components having the highest potential for causing direct tissue damage, known as 'effectors'. In addition, previous studies have found IL-10 to have 'regulatory effects' during periods of excessive pro-inflammatory stimuli. These findings may arouse new ideas in exploring the area of anti-inflammatory cytokines. In fact, future treatments may suggest a new classification featuring 'mediators', 'effectors', and 'regulators'.     

A physiological model for autonomic heart rate regulation in human endotoxemia

The systemic inflammatory response syndrome often accompanies critical illnesses and can be an important cause of morbidity and mortality. Marked abnormalities in cardiovascular function accompany acute illnesses manifested as sustained tachyarrhythmias, which are but one component of systemic dysregulation. The realization that cardiac pacemaker activity is under control of the autonomic nervous system has promoted the analysis of heart rate (HR) variation for assessing autonomic activities. In acute illnesses, autonomic imbalance manifesting in part as parasympathetic attenuation is associated with increased morbidity in patients who manifest systemic inflammatory response syndrome phenotype. Driven by the premise that biological phenotypes emerge as the outcome of the coordinated action of network elements across the host, a multiscale model of human endotoxemia, as a prototype model of systemic inflammation in humans, is developed that quantifies critical aspects of the complex relationship between inflammation and autonomic HR regulation. In the present study, changes in HR response to acute injury, phenotypically expressed as tachycardia, are simulated as a result of autonomic imbalance that reflects sympathetic activity excess and parasympathetic attenuation. The proposed model assesses both the anti-inflammatory and cardiovascular effects of antecedent stresses upon the systemic inflammatory manifestations of human endotoxemia as well as a series of nonlinear inflammatory relevant scenarios. Such a modeling approach provides a comprehensive conceptual framework linking inflammation and physiological complexity via a multiscale model that may advance the translational potential of systems modeling in clinical research.     

The compromised inflammatory response to bacterial components after pediatric cardiac surgery is associated with cardiopulmonary bypass–suppressed Toll-like receptor signal transduction pathways

Purpose

Cardiopulmonary bypass (CPB) during pediatric cardiac surgery often elicits a systemic inflammatory response followed by a compromised immune response, which has been attributed to the morbidity of postoperative infection; however, the underlying mechanism(s) has not yet been fully elucidated. We hypothesized that CPB inhibits the activation of Toll-like receptor (TLR) signal transduction pathways, thereby causing an immunosuppressive state after pediatric cardiac surgery.

Methods

We examined 20 children with congenital heart disease undergoing pediatric cardiac surgery.

Results

Cardiopulmonary bypass differentially affected lipopolysaccharide (LPS)- or bacterial lipoprotein (BLP)–stimulated ex vivo production of proinflammatory and anti-inflammatory cytokines, with significantly diminished tumor necrosis factor α, interleukin (IL) 1β, IL-6, and IL-8, but substantially enhanced IL-10 production. Consistent with the reduced inflammatory response, CPB strongly inhibited LPS- or BLP-activated TLR signal transduction pathways in monocytes with down-regulated expression of CD14, TLR4, and TLR2 and with suppressed phosphorylation of nuclear factor κB p65, p38, and extracellular signal-regulated kinase 1/2.

Conclusions

These results indicate that CPB during pediatric cardiac surgery causes substantially reduced production of inflammatory cytokines in response to bacterial component LPS or BLP stimulation, which is associated with CPB-induced suppression of TLR-mediated signal transduction pathways. This reduced inflammatory response after CPB in children with congenital heart disease may predispose them to an increased risk of postoperative infection.     

Postoperative analgesia in abdominal surgery: a new look at an old problem

Analgesia in abdominal surgery is a sufficiently complicated problem. The extensive surgeries in the abdominal cavity are concomitant with massive tissue damages and are associated the systematic tissue inflammatory response to an intensity of the pain syndrome and of other postoperative complications. The modern understanding of surgical-trauma pathophysiology is indicative of the necessity to modulate the systemic inflammatory response whose severity is preconditioned not only by postoperative pain intensity but also by surgical results. With respect to the above stated, multi-model analgesia can be regarded as an optimal technique since it presupposes the long-term administration of local anesthetics (preferably 0.2% ropivakain) concurrently with non-steroid anti-inflammatory drugs used preoperatively (the most effective one is lornoxicam).     

Markers of inflammation in sepsis

Pathophysiology of sepsis is characterised by a whole body inflammatory reaction and concurrent activation of the host's anti-inflammatory mechanisms. The balance between pro- and anti-inflammatory reactions is critical for the outcome of the patient. Strongly activated phagocytes and high levels of proinflammatory cytokines occur in patients who are at risk of developing circulatory shock and multiple organ dysfunction. Extensive anti-inflammatory reaction, which is characterised by the presence of high levels of circulating anti-inflammatory cytokines and impaired innate and adaptive immune functions, renders critically ill patients prone to secondary infections. Evaluation of the immune-inflammatory status on admission to the hospital may be helpful in the early identification of patients who are bound to develop organ dysfunction. Such patients could possibly benefit from a mode of therapy aimed at modifying the course of inflammatory response. The use of inflammatory markers may also improve diagnosis of severe infection. The present review summarises the studies on markers of inflammation and immune suppression used, first, as predictors of organ dysfunction in patients with systemic inflammation, and, second, as indicators of infection in adults and neonates.     

Does modified ultrafiltration reduce the systemic inflammatory response to cardiac surgery with cardiopulmonary bypass?

Cardiopulmonary bypass (CPB) is associated with an accumulation of total body water and a systemic inflammatory response syndrome (SIRS), which, in turn, is associated with organ dysfunction and postoperative morbidity. It has been suggested that modified ultrafiltration (MUF) may be capable of reducing SIRS and improving clinical outcome by filtering out the inflammatory mediators generated during CPB. This paper reviews the data regarding the use of MUF in paediatric and adult settings. Specifically, three issues will be considered: 1) Does MUF improve clinical outcome? 2) Does MUF reduce the systemic inflammatory response to cardiac surgery with CPB? 3) Is MUF more effective than conventional ultrafiltration in improving clinical outcome?     

Dextran-70 to modulate inflammatory response after cardiopulmonary bypass: potential for a novel approach?

Potential deleterious effects of cardiopulmonary bypass (CPB) and cardioplegic cardiac arrest are known to influence outcome. The inflammatory response after CPB may have unfavourable effects especially in high-risk patients, for example, the very elderly. Thus, to blunt the release of pro-inflammatory mediators seems to be a promising approach. So far, numerous attempts at immune modulation have been performed. However, the management of cardiac surgery patients needs further improvement. In this context, Gombocz and colleagues investigated the potential anti-inflammatory effect of dextran-70. Their results suggest that compared to gelatine, dextran-70 reduces the inflammatory response in patients after CPB.