Intensive insulin therapy does not change the inflammatory response in non-diabetic patients undergoing elective coronary artery bypass grafting

Introduction

Strict control of plasma glucose in diabetic and non-diabetic patients has been shown to improve outcome in several clinical settings. A large randomized trial in critically ill patients treated with intensive insulin therapy resulted in a 42% reduction in mortality compared with conventional treatment. In patients with acute myocardial infarction, maintenance of blood glucose levels below 11.9 mmol/l has been shown to increase the success rate of thrombolysis, to preserve myocardial function and to improve long-term outcome. There is extensive evidence that glucose can stimulate the production of proinflammatory cytokines such as tumour necrosis factor (TNF) and IL-6, with no effect on the anti-inflammatory cytokine IL-10. We hypothesized that strict glucose regulation results in modulation of cytokine production, resulting in a change in cytokine balance from a proinflammatory state to a more balanced anti-inflammatory condition.

Methods

We performed a randomized, controlled study in 20 non-diabetic patients undergoing elective coronary bypass surgery. Cardiopulmonary bypass increases proinflammatory and anti-inflammatory cytokines and is associated with the development of SIRS. After surgery patients were randomly assigned to intensive insulin therapy (to maintain blood glucose between 4.4 and 6.1 mmol/l) or conventional insulin therapy (only instituted when blood glucose exceeded 11.1 mmol/l). At 0, 1, 2, 4, 8, 12, 16, and 24 hours after admission to the intensive care unit, plasma samples and samples from the tubes draining the mediastinal cavity were drawn. In these samples levels of the proinflammatory cytokines TNF and IL-6 and the anti-inflammatory cytokine IL-10 were measured by ELISA.

Results

Both patient groups were comparable with respect to demographics, clinical characteristics and operative data. In the intensive treatment group glucose levels were significantly lower compared with the conventionally treated group. The cumulative insulin dose was significantly higher in the intensive therapy group. No differences were found in levels of TNF, IL-6 and IL-10 in plasma samples or in fluid draining the mediastinal cavity between both groups. Levels of IL-6 and IL-10 were significantly higher in mediastinal fluid samples compared with plasma samples, suggesting a compartmentalized production of cytokines. No differences in TNF levels between plasma and mediastinal fluids were found.

Conclusions

The protective effect of intensive insulin therapy in critically ill patients is not related to a change in cytokine balance from a proinflammatory to an anti-inflammatory pattern. Systemic cytokine levels are not representative measures for local inflammatory processes.