Intensive insulin therapy does not alter the inflammatory response in patients undergoing coronary artery bypass grafting : a randomized controlled trial [ ISRCTN 95608630 ]

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)-α 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-α and IL6 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-α, 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 proinflammatory to an anti-inflammatory pattern. Systemic cytokine levels are not representative of the local inflammatory response. Introduction Strict glycemic control is increasingly recognized as an important goal in a broad spectrum of critically ill patients, even in the absence of pre-existing diabetes. After myocardial infarction, stress hyperglycemia is associated with an increased risk of in-hospital mortality in both diabetic and non-diabetic patients and increases the risk of congestive heart failure or cardiogenic shock in patients without diabetes [1]. The DIGAMI study demonstrated that rapid improvement of metabolic control in diabetic patients with myocardial infarction improves short-term and long-term outcome [2,3]. Intensive insulin therapy is thought to increase the success rate of thrombolysis and preserves myocardial function [4,5]. The recently published DIGAMI 2 trial failed to support the hypothesis that insulin treatment improves survival and morbidity in diabetic patients after myocardial infarction, possibly because the target blood glucose levels in the treatment group were never reached [6]. However, this trial confirmed that glucose is a R790 CABG = coronary artery bypass grafting; ICU = intensive care unit; IL = interleukin; NF = nuclear factor; TNF = tumor necrosis factor. Critical Care Vol 9 No 6 Hoedemaekers et al. R791 strong and independent factor of long-term mortality in these patients. In cardiac surgery patients, hyperglycemia was found to be an independent post-operative risk factor for the development of hyperlactatemia and associated with increased morbidity and mortality [7,8]. A meta-analysis of all randomized studies using glucose-insulin-potassium therapy in cardiac surgery patients indicated that such therapy might considerably improve post-operative recovery of contractile function and reduce the incidence of atrial arrhythmias [9]. Some studies even show a survival benefit [10]. In critically ill patients in a surgical intensive care unit (ICU), maintenance of blood glucose levels between 80 and 110 mg/dl resulted in a 42% reduction in mortality compared with conventional treatment aiming at blood glucose levels between 180 and 200 mg/dl [11]. More than 60% of the patients in this study had also recently had cardiac surgery. How strict control of blood glucose reduces morbidity and mortality is unknown, but the mechanism may be related either to a direct effect of normalization of hyperglycemia or to the concomitantly higher insulin levels. Post hoc multivariate logistic regression analysis of the study by van den Berghe et al. suggests that the lowered blood glucose level rather than the insulin dose is related to the reduction in mortality [12,13]. In this study [11] septic patients showed the largest reduction in mortality, suggesting that strict glucose regulation might influence the inflammatory response. Hyperglycemia has a strong impact on host defense. Acute, short-term hyperglycemia affects all major components of innate immunity [14]. Neutrophil activity is reduced, leading to decreased chemotaxis, decreased phagocytosis, decreased bacterial killing and overproduction of free radicals [15-17]. In addition to changes in cellular function, other components of the innate immune response contribute to the pro-inflammatory state in hyperglycemia. In vitro, human monocytes show a glucose-dependent increase in tumor necrosis factor (TNF)-α and IL-6 production [18-20]. Healthy volunteers have an increase in the pro-inflammatory cytokines IL-6, TNF-α and IL18 when the plasma glucose level is acutely raised by glucose infusion while endogenous insulin secretion is blocked with octreotide [21]. Patients with hyperglycemia on admission to the ICU had increased levels of IL-6 and IL-10, although after multivariate analysis only IL-6 was associated with hyperglycemia [22]. Studies of cytokine responses in critically ill patients are potentially confounded by the absence of a well-defined time of onset and differences in the etiology and severity of the disease. Cardiac surgery is associated with the development of a systemic inflammatory reaction with increased cytokine concentrations. Inflammation after cardiac surgery is believed to be caused mainly by contact of blood with the artificial surface of the extracorporeal circuit, and also by ischemia-reperfusion injury, and the operative trauma [23,24]. It has been suggested that the release of pro-inflammatory cytokines into the circulation is important in the pathogenesis of post-operative myocardial dysfunction [25-28]. We studied the effect of strict glycemic control on the local and systemic pro-inflammatory and anti-inflammatory cytokine balance in cardiac surgery patients after cardiopulmonary bypass. We considered cardiac surgery with cardiopulmonary bypass to be a suitable clinical model of inflammation with a well-defined preset time of onset and etiology of the insult, in contrast to other clinical models of inflammation such as sepsis. We hypothesized that strict glucose regulation modulates cytokine production in these patients, leading to a shift toward a more anti-inflammatory pattern [29]. Methods Study population We performed a randomized controlled trial in non-diabetic patients undergoing elective coronary artery bypass grafting (CABG). The local Institutional Review Board approved the protocol. Written informed consent was obtained from each patient on the day before surgery. All patients aged 18 years or older scheduled for elective CABG were eligible for the study. Patients were excluded if they had a history of diabetes, fasting blood glucose levels above 100 mg/dl on the day before surgery, myocardial infarction within 4 weeks before surgery, cardiogenic shock or renal failure (serum creatinine level above 1.7 mg/dl). Patients were also excluded if they had used any medication within 4 weeks before surgery known to modulate the inflammatory response (for example non-steroidal anti-inflammatory drugs or steroids) or when there were clinical signs of infection or inflammatory disease. The use of low-dose salicylates was allowed. Patients undergoing offpump cardiac surgery were excluded. During surgery no blood glucose concentrations were measured, and none of the patients received insulin before admission to the ICU. Cardiopulmonary bypass was performed with a priming solution containing gelatin (Gelofusine®), mannitol, albumin, NaHCO3, CaCl2 and heparin. After weaning from cardiopulmonary bypass, patients were given protamine to neutralize the heparin. Heparin antagonization was identical in both groups.