2. Understanding Cardiopulmonary Bypass Induced Inflammation and the Role of Steriods; A Post-Hoc Analysis of the SIRS Trial

Background: Cardiopulmonary bypass (CPB) initiates a systemic inflammatory response syndrome (SIRS) that is associated with the development of post-operative complications including thrombosis, myocardial injury and infarction, respiratory failure, renal and neurological dysfunction, bleeding disorders, altered liver function and ultimately, multiple organ failure. At the 2005 AAS conference, we presented our randomized controlled trial SIRS 1 that demonstrated that 500 mg of methylprednisolone (MP) attenuates IL-6 release and possibly results in better hemodynamics, shorter mechanical ventilation times, less blood loss, less hyperthermia, and ultimately shorter ICU length of stay. To further assess the inflammation initiated by CPB and the effect of methylprednisolone, our group utilized Randox’s Evidence Investigator platform to measure multiple inflammatory mediators not previously examined. We now present a post-hoc analysis of the SIRS 1 study examining the effect of CPB and methylprednisolone on a broad array of cytokines. Methods: Randox’s Evidence Investigator platform allows for multiple samples to be analyzed for different mediators simultaneously (IL-1-alpha, IL-1-beta, IL-2, IL-4, IL-6, IL-8, IL-10, INF-gamma, TNF-alpha, MCP1). Twenty-four patients (12 MP and 12 Placebo) were analyzed at 5 different time points. The table below presents the data for IL-10, MCP1, INF-gamma and TNF-alpha. Results: IL-10 concentrations were significantly higher in the steroid group at four hours post-operatively (P=0.002). The steroid group exhibited significantly lower concentrations in the following: MCP1 upon cessation of CPB (P=0.001) and at four hours post-operatively (P=0.003); INF-gamma upon cessation of CPB (P=0.001) and at four hours post-operatively (P=0.02); IL-6 upon cessation of CPB (P=0.0002), and at four, eight and 24 hours post-operatively (P=0.0002, P=0.001, P=0.003, respectively); IL-8 upon cessation of CPB (P=0.006), and at four, eight and 24 hours post-operatively (P=0.01, P=0.003, P=0.007, respectively); and TNF-alpha upon cessation of CPB (P=0.001), and at four, eight and 24 hours post-operatively (P=0.008, P=0.01, P=0.01, respectively). Conclusions: To our knowledge, this study marks the first time that microarray technology has been employed to measure a broad array of cytokines in patients who have undergone a cardiac surgery requiring CPB. 500 mg of methylprednisolone has the ability to attenuate many pro-inflammatory mediators that are released peri-CPB. The data further demonstrates that reducing the levels of pro-inflammatory mediators with this protocol increases the concentration of an anti-inflammatory mediator (IL-10) to a greater-than-normal level. Thus, a low dose steroid protocol, at the molecular level, is efficacious in reducing the SIRS response to CPB. All concentrations are presented in pg/mL; data are presented as median (25th percentile, 75th percentile); Steroid versus control comparison: