These findings call into question the “one size fits all”strategy for glycemic control of critically except ill patients. It may be most appropriateto establish lower glycemic target ranges for medical patients without diabetes thanfor patients with diabetes or for surgical patients without diabetes.In addition, our observations call into question the appropriateness of recentlypublished glycemic-control guidelines that recommend a glycemic target range of 140to 180 mg/dl [57] or 140 to 200 mg/dl [58] for all critically ill patients. Furthermore, premorbid glycemic controlin diabetes may have an important impact on the consequences of glycemic control inthe ICU [43]. The optimal glycemic-control protocol may result not only fromstratifying patients by diabetic status, but also by additionally stratifyingpatients with diabetes based on the degree of preadmission glycemic control.

Incontrast, the deleterious association of hypoglycemia with mortality, even atthreshold levels of <70 mg/dl, was observed in patients with diabetes and in thosewithout diabetes. Because hypoglycemia can never be the subject of a randomizedtrial, the data from this investigation, when combined with the findings fromprevious interventional [4,6,10,11,25] and observational [12-17] studies, provide the strongest evidence basis for the goal of avoidinghypoglycemia in all critically ill patients.Finally, increased glycemic variability, defined as CV >20%, was identifiedin the current study as having a strong independent association with increased riskof mortality in patients without diabetes.

These data provide strong impetus for thecreation of insulin-dosing strategies and the development of new technologies [59] for accurate continuous or near-continuous BG monitoring, with the goal ofreducing glycemic variability in critically ill patients. Further investigationshould stratify patient outcomes by specific admitting diagnosis; importantdifferences may be found within the broad medical and surgical categories that thecurrent investigation was underpowered to assess.The design of future trials of IIT should include consideration of all three domainsof glycemic control as well as recognition of the differences in their associationwith mortality based on premorbid diabetes status.ConclusionsThis large international cohort study evaluated the relation of diabetic status to theassociation of hyperglycemia, hypoglycemia, and increased glycemic variability in aheterogeneous population of critically ill patients. We found that diabetic statusmodulates the relation between the three domains of glycemic control and mortality inclinically important ways. Our findings suggest that patients with diabetes may benefitfrom higher glucose Anacetrapib target ranges than those without diabetes.