Cortisol metabolism in critical illness: effects of intensive insulin therapy

An appropriate activation of the hypothalamic–pituitary–adrenal axis and cortisol response to critical illness is essential for survival. Indeed, both high and low cortisol levels are associated with increased mortality. We investigated the effect of intensive insulin therapy (IIT), a treatment recently shown to reduce mortality and morbidity of surgical ICU patients [1], on the cortisol response versus conventional insulin therapy (CIT).

All patients included in the large randomized trial [1] who were dependent on intensive care for more than 5 days (n = 451) were selected for this study. Serum levels of total cortisol and cortisol-binding globulin (CBG) were measured upon ICU admission, day 5, day 15 and the last day of intensive care. Free cortisol levels were calculated from these data. Baseline characteristics were similar for both patient groups. The two levels of blood glucose control were well maintained throughout the study.

Total cortisol, CBG and free cortisol levels were comparable in both groups on admission to the ICU. On day 5, day 15 and the last day, IIT significantly lowered total cortisol levels. CBG levels were similar except for slightly lower levels in the IIT group on the last day. IIT thus significantly decreased free cortisol on day 5 and day 15. Multivariate logistic regression analysis revealed that reducing cortisol at least in part explained the survival benefit of IIT [1]. Total and free cortisol levels were several-fold higher in critically ill patients receiving exogenous hydrocortisone in so-called 'replacement dose' as compared with patients who did not require such a therapy. IIT appeared to largely exert similar effects in patients with or without hydrocortisone therapy.

In conclusion, by reducing serum cortisol levels, intensive insulin therapy beneficially affected outcome of critically ill patients. Studies are ongoing to elucidate the mechanisms underlying this effect.