Role of Cytokine Hemoadsorption in Cardiopulmonary Bypass-Induced Ventricular Dysfunction in a Porcine Model

Although it has long been established that cardiac surgery routinely provokes a diffuse systemic inflammatory reaction mediated by complement, fibrinolytic, cytokine, and kinnogen/bradykinin pathways (1,2) and that this reaction has the potential to affect virtually every organ system, little is known about the isolated effects of cardiopulmonary bypass (CPB) alone. This is partially explained by the fact that although extracorporeal circulation is an important contributor to systemic inflammation, other aspects of cardiac surgery contribute to the humoral and cellular response including cardiotomy suction, ischemia–reperfusion injury, surgical trauma, and protamine administration, thus confounding clinical attempts to isolate the effects of CPB. In fact, although it is almost an article of faith that “CPB” is responsible for morbidity associated with surgery, almost all of the studies that describe this “postperfusion” effect use the phrase “CPB” as a surrogate for the many aspects of cardiac surgery that contribute to systemic inflammation. To our knowledge, only one study has been published that addresses the isolated effect of CPB on ventricular mechanics; it demonstrated a significant decline in both left ventricular contractility and compliance 15 minutes after separation from CPB in a porcine model but did not examine the duration of this effect or potentially responsible mechanisms (3). Although the systemic response to cardiac surgery is clearly multifaceted, accumulating evidence suggests that surges in inflammatory cytokines may play an important role in postoperative ventricular dysfunction. For example, exogenous cytokine administration has been shown to cause a dose-dependent, reversible injury to ventricular function both in clinical (4) and experimental settings (5). In addition, a correlation between increased tumor necrosis factor (TNF) and interleukin (IL) 6 expression and dysfunctional human donor hearts has been demonstrated (6) and perhaps most relevantly, an association has been demonstrated between proinflammatory cytokines and myocardial dysfunction after cardiac surgery (7). These studies focused our interest on the potential relationship between the effects of CPB on ventricular function and changes in circulating inflammatory cytokine levels. Although it would have been impractical to attempt measurement of all known inflammatory cytokines, the development of a novel cytokine hemoadsorption filter, Cytosorb™ (Cytosorbents Inc, Monmouth Junction, NJ), provides the opportunity to remove virtually all known cytokines from the bloodstream during the period of CPB by incorporating the hemoadsorption filter into the extra-corporeal perfusion apparatus and thus is ideally suited to examine the impact of circulating cytokines on the sequelae of CPB. The Cytosorb™ filter has been shown to significantly reduce cytokine levels both in vitro (8) and in animals with sepsis (9) and the feasibility of hemoadsorption in the organ donor population has already been demonstrated (10). In addition, previous work from our laboratory has demonstrated the use of cytokine hemoadsorption in attenuating brain death-induced ventricular dysfunction in an open-chest porcine model (11). Therefore, we designed this experiment to isolate the effect of CPB on ventricular mechanics and explore the role of inflammatory cytokines by testing the hypothesis that use of a bypass circuit containing a cytokine hemoadsorption filter would attenuate CPB-induced acute organ injury.