Does intensive insulin therapy affect the cortisol response of critically ill patients?

BACKGROUND Activation of the hypothalamic - pituitary - adrenal (HPA) axis is an important biologic response to critical illness; however, in appropriate cortisol levels can lead to increased mortality. OBJECTIVE To assess the effect of intensive insulin therapy on the cortisol response in critically ill patients. DESIGN AND INTERVENTION This was a randomized, controlled study of adult patients admitted to a single surgical intensive care unit in Belgium. Eligible participants had been in intensive care for > 5 days and were dependent on mechanical ventilation. Insulin was administered to patients in the conventional insulin therapy group when blood glucose levels exceeded 11.9 mmol/l. The aim of insulin treatment in this group was to maintain blood glucose levels of 10.0 - 11.1 mmol/l. For patients in the intensive insulin therapy group, insulin was administered to maintain blood glucose levels of 4.4 - 6.1 mmol/l. A subgroup of patients with a diagnosis of adrenal insufficiency also received hydro cortisone. An initial dose of 300 mg hydrocortisone was given by continuous infusion for 24 h, after which the dose was reduced incrementally to 90 mg daily. Assessment was at admission, on day 5 and on day 15. Patients who required > 15 days of intensive care were also assessed on their final day in the intensive care unit. Blood samples were drawn at 0600 h and the levels of blood glucose, total cortisol, free cortisol, corticosteroid-binding globulin (CBG), albumin, and various cytokines were measured. OUTCOME MEASURES The main outcome measures were the levels of total cortisol, free cortisol and CBG. RESULTS Conventional and intensive insulin therapies were used to manage 243 and 208 patients, respectively. Compared with conventional insulin therapy, blood glucose levels were lower at all time points after admission in the intensive insulin therapy group ( P < 0.0001); however, this effect was only achieved with high doses of insulin. Intensive insulin therapy also improved patient survival ( P = 0.005) and reduced the incidence of morbidities, which included bacteremia ( P = 0.01) and poly neuropathy ( P < 0.0001). Although total cortisol levels remained elevated throughout the study, they were lower in the intensive insulin therapy group than in the conventional insulin therapy group ( P = 0.0001). A similar effect was observed for free cortisol levels ( P = 0.03); however, there was no significant difference between groups for the levels of CBG and cytokines. Among survivors, intensive insulin therapy correlated with low total and free cortisol levels ( P = 0.004) and the risk of death was decreased in patients with low total and free cortisol levels ( P < 0.0001). In patients who received a 'replacement' dose of hydrocortisone, total and free cortisol levels remained elevated, whereas CBG levels were reduced. CONCLUSION Intensive insulin therapy reduced cortisol levels in critically ill patients, an effect that might correlate with improved clinical outcomes in this treatment group.