Moreover, many of the glycemia data from several of thecenters included dilution calculator in this study were derived from capillary blood measured onpoint-of-care devices, a method associated with increased analytic inaccuracy [38-41]. Nevertheless, any degree of measurement imprecision would only serve todampen the observed relations between glycemia and diabetic status.Finally, we acknowledge that the observational nature of this investigation mandatesthat its conclusions must be considered to be hypothesis generating, rather thanproof of causality. Nevertheless, it would be unethical to randomize patients toinduced hyperglycemia, hypoglycemia, or increased glycemic variability.Biological plausibilityConsiderable evidence suggests that diabetes may alter the relation between glycemiaand mortality in critically ill patients [28].

Diabetes patients may develop a tolerance to hyperglycemia, and amoderate degree of hyperglycemia that might exert toxicity in a patient withoutdiabetes may be well tolerated in a patient with diabetes. This may explain thestrong relation seen between increasing mean BG levels and mortality in patientswithout diabetes, detailed in several large observational studies, but not amongthose with diabetes [3,29-31,36,42]. In a recent study [43], diabetes patients with poor preadmission glycemic control, reflected byhigh HgbA1c levels, had higher mortality when mean BG was tightly controlled duringICU stay compared with patients with high premorbid HgbA1c levels who had a highermean BG during ICU stay.

These intriguing data parallel the results of largeinterventional studies in outpatient populations with type II diabetes [44,45]. An extensive body of literature has explored the physiological basis ofthe deleterious impact of hypoglycemia [46-51] demonstrated in interventional [4,6,11,25] and observational [12-17] studies; none of these has focused explicitly on the different impact thathypoglycemia may exert on patients with diabetes compared with those withoutdiabetes. Similarly, although various physiological mechanisms underlying the harmfuleffect of increased glycemic variability detailed in interventional [4,6,25] and observational [18-24] studies have been proposed [52-56], the reasons that glycemic variability has no or a muted independentassociation with risk of mortality in patients with diabetes compared with thestriking relation seen in patients without diabetes requires furtherclarification.

Clinical implicationsThe central findings of the current investigation have important implications for thecare of critically ill patients. Hyperglycemia does Carfilzomib not have the same associationwith mortality among critically ill patients without diabetes compared with thosewith diabetes. The euglycemic range was independently associated with the lowest riskof mortality among patients without diabetes but with higher mortality among patientswith diabetes.