In 2001, the same researchers here showed that intensive insulin therapy to control hyperglycemia significantly reduce both morbidity and mortality among patients in surgical intensive care units.
But this new study suggested that among patients in medical ICUs, tight glycemic control reduces morbidity, but only reduces the death rate among patients treated for three days or more, reported Greet Van den Berghe, M.D., of the Catholic University of Leuven, and colleagues in the Feb. 2 issue of the New England Journal of Medicine.
In fact, intensive insulin therapy may be associated with a higher mortality rate among patients treated in the medical ICU for less than 72 hours, and there is no reliable way to predict which patients might benefit or, possibly be harmed by the focus on glycemic control, they wrote.
The researchers were at a loss to explain why only patients with longer ICU stays had lower death rates when treated with intensive insulin therapy.
"In our previous study, brief exposure to insulin therapy had no significant effect on the risk of death," they wrote. "Why 48 hours or less of insulin therapy would cause harm, whereas sustained treatment would be beneficial, is unclear."
An intensive care specialist who was not involved in the study said that while the study data make it hard to draw inferences about when intensive insulin therapy should be used in ICU patients, one message comes through clearly.
"No matter how you take this specific article, it contributes to the growing body of evidence that supports that hyperglycemia should be controlled in the acutely ill and severely ill, " said Renee Y. Meadows, M.D., a hospital-based internist at the Ochsner Clinic in New Orleans.
"The days of just letting glucoses go above 250 and hang there, because we're presuming it's of some physiologic benefit, are over," Dr. Meadows said in an interview.
Pending the outcome of two large-scale randomized trials exploring the benefits or drawbacks of glycemic control in the ICU, intensive care physicians might try the middle ground, suggested Atul Malhotra, M.D., of Boston's Brigham and Women's Hospital, in an accompanying editorial.
"In my opinion, a reasonable approach would be to provide adequate exogenous insulin to achieve target glucose values of less than 150 mg/dL (8.3 mmol/L), at least during the first three days in the ICU," he wrote. "If critical illness persists beyond three days despite the provision of other proven therapies and resuscitation, a goal of normoglycemia (80 to 110 mg/dL [4.4 to 6.1 mmol/L]) could then be considered, to maximize the potential benefits."
The Belgian researchers conducted a prospective, randomized, controlled study of adult patients admitted to the medical ICU. The patients in the study were judged to need at least three days of intensive care.
Patients were randomly assigned on admission to either intensive insulin therapy with the goal of normoglycemia (glucose 80 to 110 mg/dL [4.4 to 6.1 mmol/L]), or to conventional therapy, in which insulin would be administered only when the blood glucose level exceeded 215 mg/dL [12 mmol/L], with the infusion tapered when the level fell below 180 mg/dL [10 mmol/L]).
A total of 1,200 patients were enrolled, of whom 16.9% had diabetes. Analysis was by intention-to-treat.
The investigators found that intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality among all patients (40.0% in the conventional-treatment group vs. 37.3% in the intensive-treatment group, P = 0.33).
"However, morbidity was significantly reduced by the prevention of newly acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital," Dr. Van den Berghe and colleagues wrote.
Among 433 patients whose ICU stays were less than three days, the mortality rate was higher in those receiving intensive insulin therapy. There were 56 deaths among the intensive-treatment group, compared with 42 in the conventional treatment group, but the statistical significance of this finding depended on the test used, the authors noted.
In contrast, among 767 patients who stayed in the ICU for three or more days, in-hospital mortality in the 386 who received intensive insulin therapy was reduced from 52.5% to 43.0%, and this difference was statistically significant (P = 0.009). Morbidity was also in these patients, the authors noted.
The investigators acknowledged that the study results were limited by the fact that it was a single-center study and that it was not strictly blinded because the presence of patients with diabetes required clinician awareness of glycemic status for some patients.
"Because patients who will have a prolonged stay in the ICU cannot be identified with certainty on admission, adequately powered trials are needed to address his important issue," they wrote.
- Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine
New England Journal of MedicineSource Reference: Van den Berghe et al. Intensive Insulin Therapy in the Medical ICU. N Engl J Med 2006;354:449-61.
New England Journal of MedicineSource Reference: Malhotra A. Intensive Insulin in Intensive Care. N Engl J Med 2006;354:516-18.