Investigation of Inflammatory Parameters in a Perioperative Closed-meshed Standard Progress in CPB Patients

Overview

Similar to poly-trauma, acute myocardial infarction, or stroke, the speed and appropriateness of therapy administered in the initial hours after severe sepsis develops are likely to influence outcome. However, the crux of matter is the "early diagnosis" lacking of high sensitive and specific test, in contrary to, for instance, the acute coronary syndrome, where the highly sensitive Troponin T is measured and increased values are fix component of the diagnosis and definition of acute myocardial infarction. Cardiac surgery can initiate a systemic inflammatory response syndrome (SIRS) induced by extrinsic and intrinsic factors, which are associated in the pathogenesis of postoperative complications. SIRS is closely related to sepsis, but in contrast sepsis is induced by infection. This strong inflammatory response induces malfunction of the peripheral circulation with increased lactate levels, pronounced fluid accumulation and increased need of vasopressors. The investigators want to assess the timing dynamic of release of IL-6 apart from established markers like CRP, leukocytes, PCT. Target of this is to estimate the time-scope and -advance of an "IL-6 axis panel" toward the measurement of standard inflammation parameters in inflammatory response to surgical trauma as a pre-figuration of non-infectious SIRS and to search for a eligible "cut-off" of IL-6.

Similarly for early detection of SIRS/Sepsis, interleukin 6 (IL-6) assays have been brought up for discussion and have been studied extensively over last years. IL-6 is pro-and anti-inflammatory cytokine with multimodal functions in physiology and patho- physiology: As a major regulator of hepatic acute phase response, IL-6 induces the expression of C- reactive protein, fibrinogen and serum amyloid-A protein among others. However, along with pro-inflammatory effects IL-6 is described as an anti- inflammatory agent. Especially in systemic inflammatory response syndrome (SIRS) and sepsis the pro-inflammatory impact of IL-6 is of paramount interest: Via trans-signaling using the soluble IL-6 receptor (sIL-6R) pathway adherent junctions of endothelial VE-cadherin are disconnected causing a loss of barrier function. Increased endothelial permeability results in trans-endothelial flow of fluid and interstitial oedema with consecutive impairment of tissue oxygenation and increased blood viscosity. Recent publications suggest, that regenerative or anti-inflammatory activities of IL-6 are mediated by classic signalling via a membrane bound IL-6 receptor, whereas pro-inflammatory responses of interleukin-6 are rather mediated by trans-signalling using soluble IL-6. The IL-6, sIL-6R, soluble glycoprotein 130- buffer: Since all cells in body express glycoprotein (gp) 130, one of the crucial molecules in signal-transduction of IL-6, they all are susceptible to activation by the complex of IL-6 and sIL-6-Receptor. Thus, under steady state conditions there must be a control mechanism, which prevents IL-6/sIL-6R trans-signalling and hence unbounded activation of pro- inflammatory axis conterminously with a kind of "buffer system" for the IL-6 activity. For such a buffer, at least three different molecules have been taken into account: IL-6 itself, the -above mentioned- sIL-6Receptor and the soluble form of gp130 (sgp130). Under steady-state and non- inflammatory conditions levels of sIL-6R and sgp130 are almost 1000 fold higher than IL-6, meaning IL-6 is once secreted, it will form a complex with sIL-6R and consecutively will be neutralized by association to sgp130. The immunological impact of circulating IL-6 is a function of the serum IL-6, sIL-6R and sgp130 concentration, respectively of the proportion of the proteins to each other. Kinetic of IL-6 and the impact of procalcitonin: In the early nineties, the use of procalcitonin (PCT) has been described by Assicot et al. for the diagnosis of, in particular, bacterial sepsis. However, for discrimination of the acute inflammatory pattern of sepsis from other causes of generalized inflammation (e.g., postoperative, other forms of shock) no recommendation has been given for the use PCT to distinguish between severe infection and other acute inflammatory states in the actual guidelines. Nevertheless, conflicting to this reference, a recent high impact meta-analysis concluded that PCT can differentiate effectively between sepsis and systemic inflammatory response syndrome (SIRS) of non- infectious origin with a cut-off of between 1·0 and 2·0 ng/mL. The drawback of PCT and e.g. C-reactive Protein (CRP) in relation to members of the IL-6 axis is, that these molecules are downstream of the IL-6 axis and therefore the increase caused by endotoxin or for instance by surgical trauma is delayed.