Dynamic characteristics of blood glucose time series during the course of critical illness: Effects of intensive insulin therapy and relative association with mortality

Objectives: To assess the effect of intensive insulin therapy on blood glucose amplitude variation and pattern irregularity in critically ill patients. To assess the association of these blood glucose signal characteristics with hospital mortality, independent of blood glucose level. Design: Retrospective analysis of the databases of two previously published randomized controlled trials. Setting: University hospital, 56-bed adult surgical intensive care unit and 17-bed medical intensive care unit. PATIENTS: One thousand five-hundred forty-eight surgical intensive care unit patients, admitted between February 2000 and January 2001, and 1200 medical intensive care unit patients, admitted between March 2002 and May 2005. Interventions: In the two randomized controlled trials, patients were randomized to receive either intensive insulin therapy (targeting normoglycemia, between 4.4 and 6.1mmol/L) or conventional insulin therapy (infusing insulin when blood glucose levels were >12 mmol/L and stopping at 10 mmol/L). Measurements and Main Results: Intensive insulin therapy significantly lowered mean blood glucose (5.8 vs. 8.4 mmol/L), hyperglycemic index (0.8 vs. 3.2 mmol/L), and glycemic penalty index (26 vs. 53), but it increased the mean daily difference between minimum and maximum blood glucose (mean daily δ blood glucose; 4.0 vs. 3.3 mmol/L). There was no significant effect on the standard deviation of the blood glucose measurements or on jack-knifed approximate entropy. In multivariable logistic regression analysis, corrected for baseline risk factors, blood glucose levels outside the normoglycemic range, higher mean daily δ blood glucose, higher standard deviation blood glucose, and higher jack-knifed approximate entropy were independently associated with hospital mortality. Conclusions: The Leuven intensive insulin therapy strategy increased mean daily δ blood glucose while not affecting standard deviation blood glucose and jack-knifed approximate entropy. Increased blood glucose amplitude variation and pattern irregularity were associated with mortality, irrespective of blood glucose level. The reduced mortality observed with intensive insulin therapy in the Leuven trials cannot be attributed to an effect on blood glucose amplitude variation or entropy. Reducing amplitude variation and entropy of the blood glucose signal, irrespective of blood glucose concentration, may produce clinical benefits.