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Virtually all adult medical ICU patients experience at least 1 blood glucose value above the normal fasting level (110 mg/dL).1 The stress of critical illness promotes a state of insulin resistance which is characterized by increased hepatic gluconeogenesis and glycogenolysis, impaired peripheral glucose uptake, and higher circulating concentrations of insulin. There is upregulation of hepatic glucose production triggered by elevated levels of cytokines and counterregulatory hormones such as glucagon, cortisol, growth hormone, and catecholamines. These metabolic disturbances together with common ICU treatments such as corticosteroids, sympathomimetic agents, and glucose-containing infusions explain the frequently observed phenomenon of hyerglycemia irrespective of the disease, diabetes mellitus.

Many practitioners have viewed moderately severe hyperglycemia among critically ill patients to be either an epiphenomenon or an adaptive response, not warranting significant concern or intervention.

Large observational studies in different types of ICU populations reveal a J-shaped relationship between blood glucose levels and mortality of critical illness, with the mortality nadir somewhere between 80 and 140 mg/dL depending on the type of illness and the presence of a history of diabetes mellitus. Observations such as these raised concerns that acute hyperglycemia itself was contributing to poor outcomes, potentially by leaving affected patients susceptible to some of the complications that have long been observed among chronic diabetics, including high infection rates, poor wound healing, and polyneuropathy.


The groundbreaking Leuven I study2 in 2001, conducted in critically ill surgical patients, found a remarkable overall 3.4% ICU mortality reduction, a 9.6% mortality benefit in patients with ICU LOS more than 5 days, and a 34% hospital mortality reduction in the strict normoglycemia group (target glucose 80-110 mg/dL) compared to standard therapy. These beneficial outcomes resulting from the use of intensive insulin therapy targeting normoglycemic levels sparked a strong interest in glycemic management in the ICU. Intensive insulin therapy quickly became the standard of care in both medical and surgical ICUs. However, a follow-up study, done by the same group in 2006,3 demonstrated that in contrast to the earlier study, intensive insulin therapy did not reduce overall morality and was associated with an even higher rate of serious hypoglycemia (18.7%). In the first study, it was speculated that the benefits seen were primarily due to a surgical patient population and the primary use of parenteral nutrition.


Following 4 consecutive negative trials, the most comprehensive landmark NICE-SUGAR trial4 results were reported. They found that the intensive insulin therapy groups achieving normoglycemia had an absolute 2.6% increase in mortality (P = 0.02) and an increased incidence of hypoglycemia (6.8% vs 0.5%). Furthermore, subsequent meta-analyses demonstrated that intensive insulin therapy provided no survival benefit and was associated with increased morbidity secondary to severe hypoglycemic episodes. These findings are also consistent with observational data ...

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