Can Tight Glucose Control Increase Mortality in Critically Ill Patients?

Ninety-day mortality was 14% higher in hyperglycemic patients in general intensive-care units (ICUs) who received insulin to meet intensive vs. conventional blood glucose targets, in a large, multinational trial.

Dr Simon Finfer (the George Institute for International Health, Sydney, Australia) stated that the study showed that "intensively lowering blood glucose to a target of 81 to 108 mg/dL does not benefit critically ill patients and may well increase their risk of dying…. There is no benefit to be gained beyond a target of less than 180 mg/dL."

Cardiovascular failure was seen in 57% of patients at study entry, and cardiovascular causes accounted for most of the increased mortality in the intensive glucose control group, he noted. "This raises the possibility that intensive glucose control has adverse effects on the cardiovascular system, but our study was not designed to study this in detail," he said.

Patients in ICU commonly have hyperglycemia, which is associated with increased morbidity and mortality, the authors write. In 2001, Van den Berghe et al reported that in a study of over 1,500 surgical-ICU patients, intensive glucose control reduced mortality. However, three subsequent studies in medical- and general-ICU patients did not demonstrate a mortality benefit with tight glucose control.

Intensive glucose control has been recommended by the American Diabetes Association (ADA), the American Society of Clinical Endocrinologists (ASCE), and the Institute for Healthcare Improvement, and it is widely practiced in ICUs, said Finfer.

To test the hypothesis that intensive blood glucose control lowers 90-day mortality, the researchers randomized 6,104 patients to intensive glucose control with a target of 81 to 108 mg/dL or conventional glucose control with a target of 180 mg/dL or less.

Average blood glucose was 115 mg/dL with intensive control and 144 mg/dL with conventional control. Among patients who received intensive vs. conventional blood glucose control, 90-day mortality was higher (27.5% vs. 24.9%; odds ratio 1.14; p=0.02), as was severe hypoglycemia (6.8% vs. 0.5%). Length of stay in the ICU or hospital, time spent on mechanical ventilation, and the need for dialysis were similar in the two groups.

In an accompanying editorial, Dr. Silvio E. Inzucchi and Dr. Mark D. Siegel (Yale University School of Medicine, CT) stress, "We would caution against any overreaction to the NICE-SUGAR findings."

The study showed that lowering blood glucose levels below about 140 to 180 mg/dL for patients in a general ICU did not provide added benefit, and levels below this may cause harm, they note. This does not imply that efforts to optimize glucose control should be abandoned.

"Until further evidence becomes available, it would seem reasonable to continue our attempts to optimize the management of blood glucose in our hospitalized patients, especially to avert the extremes of hyperglycemia (which have acute effects on renal function, hemodynamics, and immune defenses) and also hypoglycemia (with its own, often more immediate and serious, consequences)," they write.

Similarly, in a joint statement, the ADA and the ASCE caution that the NICE-SUGAR results "should not lead to an abandonment of the concept of good glucose management in the hospital setting," since uncontrolled blood glucose can lead to serious problems such as dehydration and increased risk of infection.

The two organizations are preparing joint recommendations for treating hyperglycemia in inpatients, to be published this spring. "Until more information is available, it seems reasonable for clinicians to treat critical-care patients with less intensive--yet good--glucose control strategies used in the conventional arm of the NICE-SUGAR trial," they write.

The findings appear to strongly support the American Heart Association position paper published in Circulation in February 2008, which "dramatically backtracked from zeal in recommending [tight] glucose control in ACS patients and recommended that it would be reasonable to have a blood glucose target of less than 180 mg/dL--coincidentally, the conservative-management arm in this trial," he said.

It is noteworthy that the bulk of the mortality difference in this study is driven by cardiovascular events, McGuire added.
"This supports a position that we should not be treating toward normal glycemic control in cardiovascular patients. Although we don’t understand why, it simply is not working, and it appears to be putting people at risk."

• The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360:1283-1297.
• Inzucchi SE and Siegel MD. Glycemic control in the ICU--How tight is too tight? N Engl J Med 2009; 360:1346-1349.

Findings from the Normoglycemia in Intensive Care Evaluation--Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study are published in the March 26, 2009 issue of the New England Journal of Medicine.