Insulin Therapy and Pentastarch in Sepsis
Brunkhorst FM, Engel C, Bloos F, et al
N Engl J Med. 2008;358:125-139

Despite major clinical trials attempting to definitively determine the optimal management of sepsis, 2 controversial questions remain unanswered: (1) How tightly should we control blood glucose? and (2) What type of intravenous solution works best for fluid resuscitation? In a 2-by-2 factorial trial, the authors of this study sought to inform both questions by randomizing patients with severe sepsis or septic shock to tight glycemic control (80-110 mg/dL) vs regular glycemic control (180-200 mg/dL) and fluid resuscitation with pentastarch vs Ringer's lactate solution. The trial was stopped early after enrollment of 537 patients because the rate of severe hypoglycemia (blood glucose ≤ 40 mg/dL) was higher in the tight glycemic control group than in the conventional-therapy group (17% vs 4.1%, P <.001), and pentastarch therapy was associated with higher rates of acute renal failure and need for renal replacement therapy compared with Ringer's lactate therapy. At 28 days, there were no significant differences between the 2 groups in the rate of death or the mean score for organ failure.

Viewpoint

This well-conducted study addresses 2 important aspects of care for patients with severe sepsis or septic shock. First, it challenges the recent notion that tight glycemic control (maintaining blood glucose between 80 and 110 mg/dL) is an important strategy for improving outcomes. This concept initially grew out of a trial of surgical intensive care unit (ICU) patients that showed improved outcomes with tight glycemic control, and the idea persisted despite a second trial that showed no consistent benefit for medical ICU patients who were managed this way. Hypoglycemic events in the medical ICU trial were sufficiently common and concerning that the Surviving Sepsis Campaign guidelines were revised to recommend controlling blood glucose levels to < 150 mg/dL rather than < 110 mg/dL. The current study will likely not change that recommendation, but the implementation of glycemic control in protocols around the world will now be scrutinized to ensure that whatever form of glycemic control is chosen can be safely achieved without adverse events.

The second major finding of this study is that acute renal failure developed at higher rates in patients with severe sepsis and septic shock who were treated with pentastarch than in patients who received Ringer's lactate solution. This appeared to be a very clinically significant finding, with pentastarch-treated patients also requiring renal replacement therapy (ie, dialysis) more frequently. This finding has been previously suggested in a study in which a different form of hydroxyethyl starch solution was compared with a colloidal gelatin solution. Whether different hydroxyethyl starch solutions or different timing of administration (ie, not for early resuscitation) may result in a better safety profile is not known. On the basis of the findings of the current study, it is reasonable to conclude that patients with severe sepsis or septic shock should not be given pentastarch for fluid resuscitation.

Abstract