Insulin Therapy During Critical Illness Protects Endothelium Against Inflammatio

Evidence suggests that insulin helps to control nitric oxide levels, which may represent a prognostic marker in the ICU.

Maintenance of normoglycemia prevents organ failure and reduces mortality in critically ill patients, apparently by protecting the endothelium from the proinflammatory effects of glucose, investigators report.

Previously reported studies have demonstrated the protective effects of intensive insulin therapy during acute illness.
In the current article, reported in the August issue of The Journal of Clinical Investigation, Dr. Greet Van den Berghe and colleagues analyzed levels of inflammatory markers in 405 mechanically ventilated patients treated in ICUs for at least 7 days.
Patients randomly assigned to conventional insulin therapy (n = 224) were treated if glucose concentrations rose above 215 mg/dL, with the goal of maintaining levels between 180 and 200 mg/dL. The remaining 181 patients were treated with insulin to maintain glucose levels between 80 and 100 mg/dL.

Deaths in the ICU occurred in 21% of conventional therapy patients and 12% of intensive insulin patients (p = 0.01). Maintaining euglycemia also significantly reduced the incidence of bacteremia, the risk of acute renal failure, duration of mechanical ventilation and length of stay in the ICU.

Dr. Van den Berghe, from Katholieke Universiteit Leuven in Belgium, and her associates found that both adhesion molecules were present at significantly lower concentrations in survivors compared with nonsurvivors.

Concentrations of nitric oxide were significantly elevated in both groups at admission. Only those in the intensive insulin therapy group had significant decreases in nitric oxide at day 7 compared with baseline (p = 0.02), the result of a downward shift in levels of the two upper quartiles. Furthermore, the authors note, nitric oxide levels explained a significant part of improved survival in multivariate logistic regression analysis.

In biopsies of liver and muscle tissue from the patients who died, gene expression of inducible nitric oxide synthase was decreased in those treated intensively, which may be the mechanism mediating lower nitric oxide levels.

"The demonstration of (insulin’s) anti-inflammatory action…is a major advance," Dr. Paresh Dandona, from the State University of New York at Buffalo, and colleagues write in a related editorial.

The editorialists also point out that "these data offer us the opportunity to use nitric oxide concentration as a prognostic marker and as an important mediator of the pathological process in ICU patients."
J Clin Invest 2005;115:2069-2072,2277-2286.