Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis
Frank M. Brunkhorst, M.D., Christoph Engel, M.D., Frank Bloos, M.D., Ph.D., Andreas Meier-Hellmann, M.D., Max Ragaller, M.D., Norbert Weiler, M.D., Onnen Moerer, M.D., Matthias Gruendling, M.D., Michael Oppert, M.D., Stefan Grond, M.D., Derk Olthoff, M.D., Ulrich Jaschinski, M.D., Stefan John, M.D., Rolf Rossaint, M.D., Tobias Welte, M.D., Martin Schaefer, M.D., Peter Kern, M.D., Evelyn Kuhnt, M.Sc., Michael Kiehntopf, M.D., Christiane Hartog, M.D., Charles Natanson, M.D., Markus Loeffler, M.D., Ph.D., Konrad Reinhart, M.D., for the German Competence Network Sepsis (SepNet)
Background The role of intensive insulin therapy in patientswith severe sepsis is uncertain. Fluid resuscitation improvessurvival among patients with septic shock, but evidence is lackingto support the choice of either crystalloids or colloids.
Methods In a multicenter, two-by-two factorial trial, we randomlyassigned patients with severe sepsis to receive either intensiveinsulin therapy to maintain euglycemia or conventional insulintherapy and either 10% pentastarch, a low-molecular-weight hydroxyethylstarch (HES 200/0.5), or modified Ringer's lactate for fluidresuscitation. The rate of death at 28 days and the mean scorefor organ failure were coprimary end points.
Results The trial was stopped early for safety reasons. Among537 patients who could be evaluated, the mean morning bloodglucose level was lower in the intensive-therapy group (112mg per deciliter [6.2 mmol per liter]) than in the conventional-therapygroup (151 mg per deciliter [8.4 mmol per liter], P<0.001).However, at 28 days, there was no significant difference betweenthe two groups in the rate of death or the mean score for organfailure. The rate of severe hypoglycemia (glucose level, 40mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapygroup 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 ratesof acute renal failure and renal-replacement therapy than wasRinger's lactate.
Conclusions The use of intensive insulin therapy placed criticallyill patients with sepsis at increased risk for serious adverseevents related to hypoglycemia. As used in this study, HES washarmful, and its toxicity increased with accumulating doses.(ClinicalTrials.gov number, NCT00135473
[ClinicalTrials.gov]
.)
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.
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.
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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. 
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