Intensive insulin therapy does not alter the inflammatory response in patients undergoing coronary artery bypass grafting: a randomized controlled trial [ISRCTN95608630]

Abstract

Introduction: Strict control of plasma glucose in diabetic and non-diabetic patients has been shown to improve outcome in several clinical settings. There is extensive evidence that glucose can stimulate the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and IL-6, with no effect on the anti-inflammatory cytokine IL-10. We hypothesized that strict glucose regulation results in a change in cytokine balance from a pro-inflammatory state to a more balanced anti-inflammatory condition. In a randomized controlled trial we studied the effect of strict glycemic control on the local and systemic pro-inflammatory and anti-inflammatory balance in non-diabetic patients undergoing elective coronary artery bypass grafting with cardiopulmonary bypass.

Methods: After surgery patients were randomly assigned to intensive insulin therapy (blood glucose between 80 and 110 mg/dl) or conventional insulin therapy (blood glucose less than 200 mg/dl). At 0, 1, 2, 4, 8, 12, 16 and 24 hours after admission to the intensive care unit, plasma samples and samples from the mediastinal drains were obtained. We measured the concentrations of the pro-inflammatory cytokines TNF-alpha and IL-6 and the anti-inflammatory cytokine IL-10 by enzyme-linked immunosorbent assay.

Results: Both patient groups were comparable in demographics, clinical characteristics and peri-operative data. In the intensive treatment group, glucose levels were significantly lower than in the conventionally treated group. No differences were found between both groups in the concentrations of TNF-alpha, IL-6 and IL-10 in plasma samples or in fluid draining the mediastinal cavity. Levels of IL-6 and IL-10 were significantly higher in mediastinal fluid samples than in plasma samples, suggesting a compartmentalized production of cytokines.

Conclusion: The protective effect of intensive insulin therapy in patients after cardiac surgery with cardiopulmonary bypass is not related to a change in cytokine balance from a pro-inflammatory to an anti-inflammatory pattern. Systemic cytokine levels are not representative of the local inflammatory response.

Figure 1

Insulin dosage and glucose concentration are significantly different between the treatment groups. Insulin dosage per hour (a) and glucose concentration in serum (b) in the intensive and conventional treatment group after admission to the intensive care unit. Points are median values.

Figure 2

Systemic cytokine concentrations are comparable between the treatment groups. Concentration of IL-6 (a) and IL-10 (b) at different time points after admission to the intensive care unit. (c) The ratio of IL-6 to IL-10 in serum is expressed as arbitrary units. No significant differences are found between both treatment groups. Points are median values.

Figure 3

Cytokine production is highly compartmentalized. Concentration of IL-6 (a) and IL-10 (b) in mediastinal fluid at different time points after admission to the intensive care unit. (c) The ratio of IL-6 to IL-10 in mediastinal fluid is expressed as arbitrary units. No significant differences are found between both treatment groups. IL-6 and IL-10 levels are significantly higher in the mediastinal fluid samples than in plasma samples, indicating local production. Points are median values.