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Background The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids.
Methods In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points.
Results The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level,
Conclusions The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473
[ClinicalTrials.gov]
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40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer's lactate.
Source Information
The authors' affiliations are listed in the Appendix. The investigators who participated in the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study are listed in the Supplementary Appendix, available with the full text of this article at www.nejm.org.
Drs. Brunkhorst and Engel contributed equally to the article.
Address reprint requests to Dr. Reinhart at the Department of Anesthesiology and Intensive Care Medicine, Friedrich Schiller University of Jena, Erlanger Allee 101, 07747 Jena, Germany, or at konrad.reinhart{at}med.uni-jena.de.
Related Letters:
Insulin and Pentastarch for Severe Sepsis
Lacherade J.-C., Outin H., De Jonghe B., Bracco D., Schricker T., Carvalho G., Muller L., Jaber S., Lefrant J. Y., Van den Berghe G., Wilmer A., Bouillon R., Ellger B., van den Heuvel I., Poelaert J., Brunkhorst F. M., Reinhart K., Engel C.
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N Engl J Med 2008;
358:2071-2075, May 8, 2008.
Correspondence
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