For many cardiothoracic operations, the use of an extracorporeal circulation (ECC) is required. However, because of the exposure of blood to foreign material and surfaces as well as ischemia-reperfusion of the heart and other tissues, a systemic inflammatory response often occurs in response to the employment of the ECC circuit. Off-pump coronary artery bypass graft (CABG) surgery was first described in the 1960s. In the 1990s, first studies reported a reduced inflammatory response and, hence, organ protection when the usage of ECC was avoided during cardiac operations. Since then, there has been an ongoing debate as to whether surgery performed off-pump is more protective compared with on-pump surgery. Despite a multitude of studies having aimed to proof that one technique is superior to the other, a Cochrane Database Systematic Review in 2012 concluded that there is “not any significant benefit of off-pump compared with on-pump CABG regarding mortality, stroke, or myocardial infarction.” As a result, Moeller et al. (1) suggested that on-pump CABG should be recognized as the standard surgical treatment.
In the current issue of Shock, Jongman et al. (2) add further fuel to the debate by providing evidence for a decreased inflammatory reaction as well as decreased endothelial activation in patients having undergone CABG off-pump compared with patients receiving surgery with ECC. Immediately after surgery, a more pronounced increase in the concentrations of tumor necrosis factor α, interleukin 10, and leukocyte-derived myeloperoxidase was detected in plasma of patients in the on-pump CABG group compared with the off-pump group. However, these differences in inflammatory reaction between groups did not persist to the first observation time point at 6 hours after surgery, suggesting that a variety of other modulators of the overall inflammatory response may disguise a sustained aggravated inflammatory reaction in response to ECC. For example, on-pump surgery requires a more intensive anticoagulation regimen with heparin. Heparin, however, influences systemic inflammation by reducing cytokine levels primarily by interacting with nuclear factor κB (3). Thus, differences in cytokine levels in on-pump patients may be lower than expected. Also, the use of cell savers in the off-pump group might alter the immune and inflammatory response, although the literature in this regard is not consistent. While Damgaard et al. (4) observed a decrease in inflammatory response after the use of cell savers, Takayama et al. (5) showed an increase in inflammation after reinfusion of processed cell-saver blood. Additional confounders may be involved in modulating an individual patient’s inflammatory response. For example, estrogens have been shown to influence the inflammatory reaction, and this phenomenon has been extensively investigated following trauma and sepsis (6). In the study by Jongman et al. (2), the study population comprised only 10% of female participants, but premenopausal hormonal status could still render the results heterogeneous.
When comparing on-pump with off-pump surgery, the major question that remains unanswered is where the inflammatory stimulus comes from. Is the ECC really the cause of inflammation? Franke et al. (7) compared immune reactions after cardiac operations with those after thoracic surgery. They proved that local trauma, ECC, and pulmonary and myocardial reperfusion contributed to substantial changes in the immune system. They further concluded that surgical trauma and reperfusion injury appear to represent the predominant factors resulting in immunologic changes after cardiac surgery. In comparison, cardiopulmonary bypass surgery appeared to be a less potent inductor of immune responses, thus rendering the dissection of the culprits for inflammation difficult to identify.
As a consequence of the increased synthesis of proinflammatory cytokines, endothelial cells become activated and interact with inflammatory cells that in turn trigger an increase of vascular permeability. Soluble adhesion molecules such as E-selectin, vascular adhesion molecule 1, and intercellular adhesion molecule 1 are considered as reliable serological markers to reflect endothelial cell activation and the severity of inflammation (8). Although tumor necrosis factor α alone suffices to induce endothelial cell activation, the time of exposure of the endothelial lining to increased concentrations of the cytokine may have been too limited (e.g., only within the first hours after surgery) in the study by Jongman et al. Hence, the authors could not detect any changes in plasma concentrations of soluble surrogate parameters for endothelial activation. However, the induction of a more pronounced gene transcription and protein synthesis of parameters of endothelial activation could have been possibly identified in on-pump patients if there had been the possibility to perform molecular analysis from tissue samples—a limitation all clinical studies have to deal with. Furthermore, endothelial integrity is modulated by a variety of factors, including patients’ medication. In this regard, a variety of drugs exerting effects on the cardiovascular system have been suggested to alter endothelial cell function and therefore vascular homeostasis. Statins, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers have been shown to exert pleiotropic effects that result in stabilization of the endothelial lining (9).
Finally, we have no idea from which organ specific endothelial tissue markers of endothelial activation or damage are released, i.e., heart, lungs, or other tissues. We have learned so far that there is heterogeneity between endothelial tissues with organ-specific phenotypes and site-specific properties (10). Looking at on- versus off-pump surgery, we deal with different sites of ischemia-reperfusion phenomena. In on-pump surgery, there is ischemia-reperfusion in the myocardium and lungs, which is absent in off-pump surgery. However, in off-pump surgery, there are repetitive phases of myocardial ischemia-reperfusion injury when myocardial tissue is immobilized for surgery.
In the future, studies using large study cohorts will have to tell whether off-pump CABG not only results in less inflammatory stress to the vasculature but will also have to provide evidence of a beneficial alteration of mortality or morbidity in patients having to undergo cardiac surgery.
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2. Jongman RM, Zijlstra JG, Kok WF, et al.: Off pump CABG surgery reduces systemic inflammation compared with on pump surgery but does not change systemic endothelial responses: a prospective randomized study. Shock 42: 384–393, 2014.
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