Survival Benefits of Intensive Insulin Therapy in Critical Illness

Abstract

Tight blood glucose control with insulin reduces morbidity and mortality of critically ill patients. However, the relative impact of maintaining normoglycemia and of glycemiaindependent 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. Diabetes 55:1096 -1105, 2006 H yperglycemia in critically ill patients is brought about by hepatic and peripheral insulin resistance and by concomitant relative insulin deficiency due to limited compensatory ability of pancreatic ␤-cells, largely independent of the underlying disease (1). Hyperglycemia during critical illness has long been considered essential to provide fuel for vital organ systems and hence was interpreted as a beneficial adaptation. Evidence is now growing against this notion as hyperglycemia is identified as an independent risk factor for adverse outcome of numerous surgical and medical conditions (2-4), and avoiding hyperglycemia with intensive insulin therapy has been shown to improve outcome (5,6). The risks of hyperglycemia comprise increased vulnerability to infectious complications, impaired recovery of organ failure, myocardial dysfunction, and neuromuscular weakness (7-12). The cardiovascular and immune systems thus emerge as two important target systems of glycemic control in the critically ill (7,10,13).It remains unclear, however, to what extent maintaining normoglycemia and glycemia-independent actions of insulin account for the different clinical benefits of intensive insulin therapy in the critically ill. A post hoc analysis of the randomized controlled study of intensive insulin therapy in surgical intensive care patients suggested that blood glucose control best explains the clinical benefits of the intervention (14). In contrast, insulin-induced promotion of glycolysis in cardiomyocytes and a diversion of fatty acids...

Telmisartan Shows an Equivalent Effect of Vitamin C in Further Improving Endothelial Dysfunction After Glycemia Normalization in Type 1 Diabetes

“…However, very recently, Ellger et al (26) demonstrated in an animal model that the reduction of glucose toxicity, more than the action of insulin, improves endothelial function.…”

Multivariate analysis of hyperglycemia in extremely low birth weight infants

“…A laboratory study manipulating insulin and glucose independently showed that the observed benefits of intensive insulin therapy required maintenance of normoglycemia. 15 Both studies in this issue of Journal of Perinatology 4,5 found a strong association between hyperglycemia and low gestational age, whereas the association between hyperglycemia and low birth weight was either less strong 4 or not significant. 5 Kao et al 4 found a significant association between their primary outcome variable, that is, a composite outcome of either mortality or late-onset culture-proven infection (odds ratio (OR) 5.07, 95% confidence interval (CI) 1.06 to 24.3) and early (the first 3 days) severe hyperglycemia (defined as mean morning glucose equal to or greater than 180 mg/dl) after adjusting for gestational age.…”

Perioperative glucose control: living in uncertain times—Continuing Professional Development

“…Plusieurs auteurs ont proposé qu'un maintien strict de la normoglycémie était en soi responsable de ces bienfaits impressionnants, et non pas l'administration d'insuline. 7,8 En 2006, le même groupe a utilisé une stratégie semblable de contrôle strict de la glycémie chez des patients médicaux de l'USI mais n'a pas pu démontrer d'effet sur la mortalité intra-hospitalière. Un taux plus élevé d'épisodes d'hypoglycémie grave (glucose \ 2,2 mmolÁL -1 ) pourrait avoir contrecarré les bienfaits potentiels d'un contrôle strict de la glycémie au niveau de la survie chez cette population de patients.…”

“…Several authors proposed that strict maintenance of normoglycemia per se was responsible for these impressive benefits, not the administration of insulin. 7,8 In 2006, the same group applied a similar strict glucose control strategy to medical ICU patients but failed to demonstrate any effect on in-hospital mortality. A higher rate of severe hypoglycemic episodes (glucose \ 2.2 mmolÁL -1 ) may have offset the potential survival benefits of strict glucose control in this patient population.…”