Organ dysfunction in critical illness: impact of maintaining normoglycemia and glycemia-independent insulin actions

Introduction

Tight glycemic control by intensive insulin therapy (IIT) reduces mortality and risk of organ failure in critically ill patients. The relative impact of maintaining normoglycemia and of glycemia-independent actions of insulin in explaining these clinical benefits remains unknown.

Methods

In a TPN-fed rabbit model of prolonged (7 days) critical illness we assessed the impact of normoglycemia/normoinsulin-emia, normoglycemia/hyperinsulinemia, hyperglycemia/normoinsulin-emia and hyperglycemia/hyperinsulinemia on survival and organ function. Assessment of myocardial function (dp/dtmax) was performed under mechanical ventilation on day 7. Aortic rings were isolated to quantify endothelium-dependent relaxation by relaxation to cumulative doses of acetylcholine (Ach), Ach + L-nitro-arginine-methyl-ester and nitroprusside, respectively, of norepinephrine (NE)-induced vasoconstriction. Leukocyte function and plasma markers of kidney and liver function were measured.

Results

Both normoglycemic groups revealed a mortality rate of 11%, whereas mortality was 36% in the HG/NI group and 47% in the HG/HI group (P = 0.03). Left ventricular contractility was increased by high insulin levels exclusively when normoglycemia was maintained (P < 0.05). The two normoglycemic groups revealed largely sustained endothelium-dependent vasorelaxation, as compared with both hyperglycemic groups (P < 0.05), independently of insulinemia. Nitroprusside-induced relaxation was not affected. Leukocyte function as well as kidney and liver function were protected only in both normoglycemic groups and deteriorated in both hyperglycemic groups (P < 0.05).

Conclusion

Survival benefits and prevention of organ dysfunction by IIT largely depend on glycemic control rather than on glycemia-independent actions of insulin. When normoglycemia is maintained, insulin might exert a glycemia-independent effect on myocardial contractility.