Cytokine balance and immunosuppressive changes at cardiac surgery: contrasting response between patients and isolated CPB circuits

Abstract

In vitro work suggests that IL-10 plays a pivotal role in controlling the balance of pro- and anti-inflammatory cytokines and monocyte HLA-DR expression. In 20 patients undergoing cardiac surgery, we investigated elaboration of interleukin 10 (IL-10) and its relationship to pro- and anti-inflammatory cytokines and leucocyte expression of HLA-DR and adhesion molecules. There were small increases in pro-inflammatory cytokines (IL-1, IL-8 and tumour necrosis factor (TNF) after induction, returning to baseline on induction of cardiopulmonary bypass (CPB). After CPB another transient increase in IL-8 occurred (P < 0.05). The anti-inflammatory response began with elevated IL-10 during CPB (P < 0.001), which peaked early in recovery (P < 0.001), by which time IL-1 receptor antagonist (IL-1ra) and the TNF soluble receptors (TNFsr) had also increased (P < 0.01). The next day IL-10 and IL-1ra were decreasing but TNFsr continued to increase. Induction of anaesthesia caused HLA-DR downregulation. The IL-10 peak was associated with further monocyte HLA-DR downregulation (P < 0.001) and return towards baseline of granulocyte adhesion molecule expression which transiently increased during CPB (P < 0.001). To determine which aspects of the immune response arose from the interaction of blood with the CPB apparatus, the above variables were studied within an isolated CPB circuit and the influence of fentanyl on the magnitude of any such changes determined. Five healthy volunteers donated two, 250-ml samples of blood to which was added either fentanyl 175 micrograms with heparin 1050 u. or heparin alone 1050 u. These were used to prime two identical isolated CPB circuits and circulation was conducted under identical conditions for 90 min. Of the pro-inflammatory cytokines, only IL-8 was elevated at 90 min CPB (P < 0.05). There was no increase in anti-inflammatory cytokines and TNFsr decreased (P < 0.001). Granulocyte adhesion molecules were increased during CPB. In the fentanyl group, the CD11b increase was greater and preceded CPB. The reduction in lymphocyte HLA-DR expression, observed throughout the study period (P < 0.01), was greater with fentanyl (P < 0.05). Monocyte HLA-DR expression increased (P < 0.05), but to a lesser extent with fentanyl (P > 0.05). In contrast with the in vivo response where there was a phased anti-inflammatory response beginning with IL-10, in the isolated CPB model no anti-inflammatory cytokine response occurred.

The effect of anaesthesia and surgery on plasma cytokine production

“…The current study showed that the cytokine response to open cholecystectomy stimulated both the pro-inflammatory (IL-1, IL-6 and TNF-a) and anti-inflammatory (IL-4) components, while this response was absent in laparoscopic cholecystectomy. This pro-and anti-inflammatory cytokine response has been reported by Gilliland et al during abdominal surgery [15] and by McBride et al during cardiac surgery [16].…”

An investigation of the effects of heparin, low molecular weight heparin, protamine, and fentanyl on the balance of pro‐ and anti‐inflammatory cytokines in in‐vitro monocyte cultures

“…Following administration of fentanyl and heparin during cardiac surgery, no immediate increases were observed in plasma levels of the anti-inflammatory cytokines suggesting perhaps that the drugs did not directly induce an anti-inflammatory response [6]. This present study also looked at the effect of these drugs on the IL-Ira and TNFsr response.…”

“…Furthermore, there is in uitro evidence that administration of TNFcl may induce a later anti-inflammatory IL-I0 response [20]. In this context, it may be significant that the pro-inflammatory response prior to cardiopulmonary bypass is followed by a phased plasma anti-inflammatory response which commences before the termination of bypass [6]. Such a concept of pro-inflammatory cytokine priming is consistent with the present report of fentanyl administration to the monocyte cultures not only leading to a n increase in pro-inflammatory cytokines, but also a significant increase in IL-I ra production.…”

“…This is further confirmed by observations of pro-and anti-inflammatory cytokine changes within an isolated cardiopulmonary bypass system, where institution of the bypass led to a significant pro-inflammatory response mainly characterised by interleukin-8 (IL-8), and upregulation of granulocyte adhesion molecules [6, 71. However, the possibility that peri-operatively administered drugs may induce a pro-inflammatory response was suggested by the demonstration that addition of fentanyl to the isolated cardiopulmonary bypass system led to increased granulocyte CDI l b expression and an enhanced plasma IL-8 response [6,7]. Furthermore, in patients undergoing elective coronary artery bypass graft surgery, 10 min after induction of anaesthesia with high dose fentanyl, small but statistically significant increases in interleukin-I beta (IL-lfl), tumour necrosis factor alpha (TNFa) and IL-8 were observed.…”

Systemic inflammatory response syndrome is reduced by preoperative plasma-thrombo-leukocyte aphaeresis in a pig model of cardiopulmonary bypass

“…Neutrophils play a key effector role in systemic inflammation because their activation leads to the production of cytotoxic hydroxyl radicals and proteolytic enzymes 17 . The level of cytokines produced by monocytes increases during and after extracorporeal circulation and orchestrated pro-anti-inflammatory responses 18 . endothelial cells, with their surface of 100 square metres, are effective excretion organs that are closely involved in inflammatory processes 19 .…”