Although the precise cause of these glucose elevations has not been comprehensively defined, it has been postulated that they are the result of increased levels of cortisol, glucagons, and epinephrine associated with critical illness [12,13]. The action of these hormones results in increased gluconeogenesis in vivo. As a result of these hormones’ actions, there is also a decrease in peripheral uptake of glucose to insure substrate availability. These combined effects result in high circulating levels of glucose during the physiologic response to critical illness or trauma.

There are several effects of hyperglycemia that have the potential to contribute to associated adverse outcomes observed after acute illness or trauma [7,14–17]. It has been suggested that hyperglycemia may be acutely toxic in critically ill patients because of accentuated cellular glucose overload and associated pronounced side effects of glycolysis and oxidative phosphorylation [18]. Additionally, it has been hypothesized that after trauma or critical illness, the expression of glucose transporters on the membranes of several cell types may be up-regulated. During reperfusion after ischemia, this up-regulation may allow high circulating glucose levels to overload cellular metabolism and cause irreversible damage to cellular function and structure. Other proposed mechanisms of injury include increased generation and deficient scavenging systems for reactive oxygen species produced by the activated glycolysis and oxidative phosphorylation associated with glucose toxicity [17]. All of these proposed mechanisms may contribute to the observed dysfunctions of liver, renal, cardiac, endothelial, and cellular immune functions associated with hyperglycemia in the setting of critical illness [19].

As understanding of the adverse effects of hyperglycemia has expanded, considerable recent attention has been focused on the role of glycemic control in mitigating the risks associated with this consequence of critical illness or trauma.

In 2001, the first of 2 landmark randomized trials examining the effects of insulin therapy on outcome was reported by Van den Berghe and colleagues [8,20]. In the initial examination, reported in 2001, the investigators enrolled 1548 patients requiring surgical ICU admission and mechanical ventilation. On admission, these patients were randomly assigned to receive intensive insulin therapy (maintenance blood glucose goal 80–110 mg/dL) or conventional glucose control therapy (infusion of insulin only if blood glucose exceeded 215 mg/dL). At 12 months, they found that intensive insulin therapy was associated with reduced overall mortality (4.6% vs 8.0% for the conventional therapy group; P <.04). The researchers also found that the benefit of intensive insulin therapy was most attributable to its effect on mortality in patients who remained in an ICU for more than 5 days. The greatest reduction in mortality involved deaths due to multiple-organ failure with a proved septic focus, with associated overall reductions in infections and renal failure requiring dialysis [20].

A subsequent study conducted by the Leuven group examined the impact of intensive glucose therapy in a population of medical ICU patients using the same glucose control cohort arms [8]. In this study of 1200 patients, the investigators found that the use of intensive insulin therapy significantly reduced blood glucose levels but did not significantly reduce in-hospital mortality (37.3% in the intensive therapy group and 40.0% in the conventional therapy group; P = .33). They did find, however, that for those patients staying in an ICU for more than 3 days, there was a reduction of in-hospital mortality (52.5% to 43.0%; P = .009), with an associated reduction in all-cause morbidity. For those patients who required less than 3 days of admission, however, there was an increased mortality associated with intensive insulin therapy use. Based on these and subsequent post hoc analyses, the Leuven group concluded that intensive insulin therapy was beneficial for ICU patients, with the maximal benefit appreciated by surgical patients. The results of these 2 studies prompted a significant shift in emphasis toward tight glucose control practices among ICU practitioners and were widely promoted as a standard of care practice by such groups as the Institute for Healthcare Improvement.

In the wake of the Leuven group findings, subsequent randomized controlled trials were conducted in heterogeneous populations of ICU patients. The studies failed to achieve the same degree of glucose control as Van den Berghe and colleagues and also failed to support the subsequent benefit of these intensive glucose control practices in this environment [21–24]. One of the largest studies reported was conducted by the Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study group [23].

This multi-institutional, multinational collection of investigators conducted a study of 6104 patients from various ICU populations. These patients were randomized to target glucose ranges of 81 to 108 mg/dL versus less than 180 mg/dL using insulin therapy, with the primary endpoint death from any cause within 90 days after randomization. They failed to achieve the glucose control success demonstrated by the initial studies of the Leuven group. The 2 treatment groups had no differences in the median number of hospital or ICU days, number of mechanical ventilation days, and the need for renal replacement therapy. The use of intensive insulin therapy was associated with increased mortality (27.5% vs 24.9%; P = .02). There were, however, important methodologic differences between NICE-SUGAR and the original Van den Berghe studies, including the use of different target ranges for blood glucose in the control and intervention groups, different routes for insulin administration, and types of infusion systems used. Additionally, there were differences in sampling sites, glucometer devices used, nutritional strategies, and levels of expertise that may have contributed significantly to the observed differences between these investigations.

Meta-analyses of available prospective randomized controlled trials examining intensive insulin therapy in the critical care environment have attempted to provide answers regarding the role of this intervention in the setting of critical illness [25,26]. In the largest meta-analysis of available data to date, Greisdale and colleagues [26] evaluated 26 randomized controlled trials comparing intensive insulin therapy to conventional glucose control therapies, including the NICE-SUGAR study. They found that patients treated in a surgical ICU were the only patients who seemed to benefit from intensive insulin therapy compared with those in the control group of patients undergoing conventional insulin therapy (P = .02). Among all of these studies, however, there has been limited examination of the effect of glycemic control specifically on patients who have required hospitalization or ICU admission after trauma.

The largest studies of hyperglycemic effects and glucose control specifically for dedicated populations of critically ill trauma patients have been conducted at the University of Maryland R Adams Cowley Shock Trauma Center. The earliest of these investigations demonstrated that early hyperglycemia might contribute significantly to adverse outcome after trauma. In 2005, Sung and colleagues [1]