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Survival Benefits of Intensive Insulin Therapy in Critical Illness

Impact of Maintaining Normoglycemia Versus Glycemia-Independent Actions of Insulin

¹ Department of Intensive Care Medicine, Catholic University of Leuven, Leuven, Belgium
² Department of Anesthesiology and Intensive Care Medicine, University Hospital, Muenster, Germany
³ Laboratory for Experimental Medicine and Endocrinology, Catholic University of Leuven, Leuven, Belgium
⁴ Cardiovascular Research Unit, Centre for Experimental Surgery and Anesthesiology, Catholic University of Leuven, Leuven, Belgium

Address correspondence and reprint requests to Prof. Dr. Greet Van den Berghe, Department of Intensive Care Medicine, Catholic University of Leuven, B-3000 Leuven, Belgium. E-mail: greta.vandenberghe{at}med.kuleuven.be

Abbreviations: ACh, acetylcholine; CVP, central venous pressure; dp/dt, first derivative of left and right ventricular pressure over time; GIK, insulin infused together with glucose and potassium; L-NAME, L-nitro-arginine-methyl-ester; MAP, mean arterial pressure; SVRI, systemic vascular resistance index

Tight blood glucose control with insulin reduces morbidity and mortality of critically ill patients. However, the relative impact of maintaining normoglycemia and of glycemia-independent actions of insulin remains unknown. We therefore independently manipulated blood glucose and plasma insulin levels in burn-injured, parentally fed rabbits over 7 days to obtain four study groups: two normoglycemic groups with either normal or elevated insulin levels and two hyperglycemic groups with either normal or elevated insulin levels. We studied the relative impact of glycemia and glycemia-independent effects of insulin on survival; myocardial contractility in an open chest preparation; endothelial function in isolated aortic rings; and liver, kidney, and leukocyte function in a rabbit model of critical illness. Mortality was significantly lower in the two normoglycemic groups independent of insulin levels. Maintaining normoglycemia, independent of insulin levels, prevented endothelial dysfunction as well as liver and kidney injury. To increase myocardial systolic function, elevated insulin levels and prevention of hyperglycemia were required concomitantly. Leukocyte dysfunction was present in the two hyperglycemic groups, which could in part be rescued by insulin. The results suggest that the observed benefits of intensive insulin therapy required mainly maintenance of normoglycemia; whereas glycemia-independent actions of insulin exerted only minor, organ-specific impact.

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