Relationship Between Blood Glucose Levels and Variability and Infections Development in Critically Ill Patient

INTRODUCTION High blood glucose levels and insulin resistance are frequently registered in critically ill patients. In the past, hyperglycemia due to stress was considered as an adaptive body reaction to satisfy higher energetic requests. This theory has been re-discussed after Leuven's study in 2001, which demonstrated that a strict glycemic control, by means of intensive insulin administration, may reduce mortality in critically ill patients. However, more recent randomized controlled studies cannot confirm these results, showing how an intensive insulinic therapy can be associated to an higher risk of hypoglycemia and death.

Recently, the attention has been shifted on the issue of glycemic variability in the Intensive Care Units (ICU), that seems to be a better mortality predictor than the simple blood glucose level. A relationship between lower glycemic variability, normal glucose levels (range 72-125 mg/dl) and outcome improving has been investigated. An high glycemic variability it's been associated to an increased in-hospital mortality, also in patients having total parenteral nutrition (TPN) independently from the presence of episodes of hypo or hyperglycemia. Furthermore, an intensive insulinic therapy itself may lead to excessive blood glucose levels fluctuations as it brings to an increased risk of hypoglycemia, usually treated in an "aggressive" way. A recent retrospective study has evaluated the impact of glycemic variability and hypoglycemia on outcome in non critically ill patients (undergone insulin administration during the hospitalization), showing a strong correlation between hypoglycemia and an increasing of mortality rate. A recent work of Arnold and coll. showed that the application of a treatment protocol for hypoglycemia (using administration of 50% dextrose) in critically ill patients was able to obtain a reduction of glycemic variability, remaining safe in avoiding dangerous hypoglycemia.

However, the real causal relationship between glycemic variability and mortality has not yet been demonstrated. The increased oxydative stress due to wide glycemic fluctuations seems to play a leading role.

The altered glucidic homeostasis in the critically ill patient may also cause a disfunction of immune cells with an increased risk of infections: Hirshberg et al. have found an association between glycemic variability an the risk of nosocomial infections development in a population of pediatric critically ill patients, studied retrospectively. A correlation between high glycemic variability, development of sepsis and risk of nosocomial infections in burn patients has also been demonstrated. Recently, a study by Krinsley and Preiser has highlighted how keeping blood glucose levels in a range between 70 and 140 mg/dl is strongly associated with an increased surviving rate in non diabetic patients, independently from ICU length of stay and from the severity of the clinical conditions. Donati et al. have demonstrated, in a retrospective study, the relationship between glycemic variability and infections; however, it's not yet clear if the glycemic variability is a cause of an effect of infections. Indeed, "relationship" is not equivalent to "causality" and it's yet to be elucidated if an higher glycemic variability just represents a sign of a worse clinical condition or, conversely, really leads to an increased risk of nosocomial infections. In this last case, dedicated protocols should be mandatory, not only to normalize blood glucose levels but also to minimize excessive glycemic fluctuations.

STUDY PURPOSE Primary endpoint of this multicenter prospective observational study is to evaluate the relationship between blood glucose levels and glycemic variability and the development of nosocomial infection during ICU stay.