Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis

N Engl J Med. 2008 Jan 10;358(2):125-39. doi: 10.1056/NEJMoa070716.

Abstract

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, < or = 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.

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.)

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / etiology*
  • Aged
  • Combined Modality Therapy
  • Critical Illness
  • Dose-Response Relationship, Drug
  • Female
  • Fluid Therapy*
  • Humans
  • Hydroxyethyl Starch Derivatives / administration & dosage
  • Hydroxyethyl Starch Derivatives / adverse effects*
  • Hydroxyethyl Starch Derivatives / therapeutic use
  • Hypoglycemia / chemically induced*
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects
  • Infusions, Intravenous
  • Insulin / administration & dosage*
  • Insulin / adverse effects
  • Isotonic Solutions / adverse effects
  • Isotonic Solutions / therapeutic use
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Ringer's Solution
  • Risk Factors
  • Sepsis / drug therapy
  • Sepsis / mortality
  • Sepsis / therapy*
  • Treatment Failure

Substances

  • Hydroxyethyl Starch Derivatives
  • Hypoglycemic Agents
  • Insulin
  • Isotonic Solutions
  • Ringer's Solution

Associated data

  • ClinicalTrials.gov/NCT00135473