Hypoglycemia was the second of the three domains to be associated with increased riskof mortality in critically ill patients. Although most of the literature hasdescribed an independent association of severe hypoglycemia (minimum BG <40 mg/dl)with mortality [12-15,22], recent observational obviously studies [16,17] and prospective trial data [11] have identified mild hypoglycemia (minimum BG <70 mg/dl) as beingindependently associated with increased risk of mortality. Our findings confirm theseobservations for patients with and without diabetes.Glycemic variability was the third of the three domains to be independentlyassociated with mortality in the critically ill [18-25]. One observational study suggested that glycemic variability wasindependently associated with mortality only among critically ill patients withoutdiabetes [24]; our study confirms these findings.

Finally, the independent impact of diabetic status, without reference to glycemiccontrol, on the mortality of critically ill patients has been the subject of recentobservational studies that concluded that patients with diabetes did not experiencehigher mortality, and diabetes may, in fact, be protective [30-36]. We demonstrated here that diabetes is independently associated withdecreased risk of mortality.Strengths and weaknessesThe clearest strength of this study is its size. The 44,964 patients include patientsadmitted with a large array of medical, surgical, and trauma diagnoses, treated witha variety of glycemic-control protocols, substantially enhancing the generalizabilityof the investigation.

Moreover, this is a modern cohort of patients treated in an eracharacterized by attention to glycemic control. Each of the nine centers maintained arobust database characterized by prospective data collection, creating an additionalimportant strength of this investigation: the breadth of demographic, clinicaloutcome, and glycemic data available for analysis. The absence of information aboutinsulin therapy is an important limitation. It is likely that important differencesexist between insulin-treated and insulin-naive patients regarding the relation ofthe three domains of glycemic control to mortality.Another potential limitation is that the identification of diabetic status was madeon clinical grounds, based on all information available at the time of ICU admission.

It is likely that some patients designated as without diabetes may actually have haddiabetes; HgbA1c levels were not obtained routinely, and, of course,glucose-tolerance testing could not be performed. Furthermore, we are unable todetermine whether the diabetes patients were categorized as type I or type II.Although most were likely type II, important Batimastat differences may exist between the twogroups in their response to derangements in the domains of glycemic control.