Xenon triggers pro-inflammatory effects and suppresses the anti-inflammatory response compared to sevoflurane in patients undergoing cardiac surgery

Abstract

Introduction: Cardiac surgery encompasses various stimuli that trigger pro-inflammatory mediators, reactive oxygen species and mobilization of leucocytes. The aim of this study was to evaluate the effect of xenon on the inflammatory response during cardiac surgery.

Methods: This randomized trial enrolled 30 patients who underwent elective on-pump coronary-artery bypass grafting in balanced anaesthesia of either xenon or sevoflurane. For this secondary analysis, blood samples were drawn prior to the operation, intra-operatively and on the first post-operative day to measure the pro- and anti-inflammatory cytokines interleukin-6 (IL-6), interleukin-8/C-X-C motif ligand 8 (IL-8/CXCL8), and interleukin-10 (IL-10). Chemokines such as C-X-C motif ligand 12/ stromal cell-derived factor-1α (CXCL12/SDF-1α) and macrophage migration inhibitory factor (MIF) were measured to characterize xenon's perioperative inflammatory profile and its impact on migration of peripheral blood mononuclear cells (PBMC).

Results: Xenon enhanced the postoperative increase of IL-6 compared to sevoflurane (Xenon: 90.7 versus sevoflurane: 33.7 pg/ml; p = 0.035) and attenuated the increase of IL-10 (Xenon: 127.9 versus sevoflurane: 548.3 pg/ml; p = 0.028). Both groups demonstrated a comparable intraoperative increase of oxidative stress (intra-OP: p = 0.29; post-OP: p = 0.65). While both groups showed an intraoperative increase of the cardioprotective mediators MIF and CXCL12/SDF-1α, only MIF levels decreased in the xenon group on the first postoperative day (50.0 ng/ml compared to 23.3 ng/ml; p = 0.012), whereas it remained elevated after sevoflurane anaesthesia (58.3 ng/ml to 53.6 ng/ml). Effects of patients' serum on chemotactic migration of peripheral mononuclear blood cells taken from healthy volunteers indicated a tendency towards enhanced migration after sevoflurane anaesthesia (p = 0.07).

Conclusions: Compared to sevoflurane, balanced xenon anaesthesia triggers pro-inflammatory effects and suppresses the anti-inflammatory response in cardiac surgery patients even though the clinical significance remains unknown.

Trial registration: This clinical trial was approved by the European Medicines Agency (EudraCT-number: 2010-023942-63) and at ClinicalTrials.gov ( NCT01285271 ; first received: January 24, 2011).

Figures

Fig. 1

Perioperative time course of interleukin (IL)-6 (IL-6) (a), IL-8 (b) and IL-10 (c). Circulating serum levels of IL-6, IL-8, and IL-10 were measured perioperatively in serum samples of patients who underwent cardiac surgery. Values are depicted in pg/ml. IL-6, IL-8 and IL-10 increased during the surgical intervention. While IL-6 levels increased postoperatively in the xenon group compared to the sevoflurane group, IL-10 levels only increased significantly in the sevoflurane group during surgery. Serum levels of IL-8 levels did not differ between both groups during the observation. Data are shown as boxplots with means and maximal to minimal values (p values are indicated within the figure). Pre-OP baseline, before induction of anaesthesia, intra-op immediately before termination of surgery, post-OP 24 h after surgery

Fig. 2

a Perioperative time course of CXCL12/stromal cell-derived factor 1α (SDF-1α) serum concentrations. Measurement of CXCL12/SDF-1α levels in the serum of patients who underwent cardiac surgery. Values are depicted in pg/ml. CXCL12 levels increased in both groups during surgical intervention. However, there were no significant differences between groups. Shown as boxplots with means and maximal to minimal values (p values are indicated). Pre-OP baseline, before induction of anaesthesia, intra-op immediately before termination of surgery, post-OP 24 h after surgery. b Perioperative time course of macrophage migration inhibitory factor (MIF) serum concentrations. The measurement of perioperative circulating MIF levels in cardiac surgery patients was performed as described previously [25]. Values are depicted in ng/ml. There was a strong intraoperative increase in serum MIF levels in both groups, which decreased again postoperatively. Postoperative measured MIF levels were significantly reduced after xenon anaesthesia compared to sevoflurane. Data are shown as interleaved boxes with means and maximal to minimal values (p values are indicated)

Fig. 3

Migration assay of peripheral blood mononuclear cells (PBMCs) in serum samples of cardiac surgery patients after xenon or sevoflurane anaesthesia. a In vitro migration of PBMCs is increased by serum samples of patients after sevoflurane anaesthesia. Extent of PBMC migration (received from healthy volunteers) towards serum samples from cardiac surgery patients is demonstrated in both groups. While PBMC migration towards serum samples was increased during surgery in the sevoflurane group, PBMC migration was not affected in serum samples from the xenon group. Data are shown in boxplots with means and maximal to minimal values (p values are indicated). Pre-OP baseline, before induction of anaesthesia, intra-op immediately before termination of surgery, post-OP 24 h after surgery. b Serum samples from patients after xenon anaesthesia show no chemokinetic effect on PBMCs. Migration of PBMCs from healthy volunteers, which were pre-incubated in serum samples elicited by recombinant CCL2/monocyte chemoattractant protein-1 (MCP-1), is demonstrated. No significant difference was measured between the groups during surgery. Data are shown as boxplots with means and maximal to minimal values (p values are indicated)