UCSF Resident Sara Epstein discusses the landmark NICE-SUGAR trial

December 3, 2014

Sara Epstein UCSF Resident

Name: Sara Epstein, PGY 1 (Internal Medicine)
Institution: University of California-San Francisco

Trial: Intensive versus conventional glucose control in critically ill patients
Authors: NICE-SUGAR Investigators
Journal: New England Journal of Medicine
Date: March 2009
URL: https://www.docphin.com/articledetail.aspx?articleID=216133

At our most recent internal medicine intern teaching session, the topic of the hour was the incredibly sexy “Inpatient Glycemic Control.” Inpatient glycemic control has been protocoled at many institutions, either because these institutions want to protect their patients, skeptical physicians can consistently to come up with appropriate insulin regimens on their own, or because these institutions want to protect their physicians from the mundane detailed insulin orders needed on nearly every patient every time the patient has a change in diet orders. Somehow, I think patient safety is what has been driving these protocols rather than physician tedium. 

Despite these standardization efforts, the world of glycemic control continues to be quite nebulous. In the intern teaching session I attended, I was struck by how few times there was a “right answer” in designing an insulin regimen for the case patients we discussed. When is the optimal time to switch a patient from an insulin drip to subcutaneous insulin? A multitude of answers were validated by our expert endocrinologist and diabetes pharmacist. What is the best way to dose insulin in a patient who is NPO after midnight for a procedure that may happen as early as 7:30 in the morning or as late as 4:30 in the afternoon? Again, several approaches seemed reasonable. What is a target blood glucose in this patient in the ICU who has undergone a Whipple procedure? If only there was a landmark study that could answer this question…

When the NICE-SUGAR trial was published in the New England Journal of Medicine in March 2009, the momentum had already been gaining to liberalize glycemic control in critically ill patients. The “landmark” Leuven Trial published in 2001 had shown marked decreased mortality in critically ill patients with tight glycemic control. This led to a wave of enthusiasm in developing protocols for and pushing clinicians to aim for tight glycemic control. Several smaller studies that followed failed to replicate the Leuven Trial’s findings, but the arrival of the NICE-SUGAR trial seriously called into question the role of universal tight glycemic control in critically ill patients. A swath of analyses and review articles arose attempting to reconcile the disparate outcomes between these two significant studies, citing the difference in methodology (single-center study in the surgical ICU for the Leuven Trial vs. multi-center study in medical and surgical ICU in the NICE-SUGAR Trial)  and the fact that many of the subjects in the Leuven trial were being fed parenterally versus enterally in the NICE-SUGAR trial. 

Since I have been active on the wards, the backlash against tight glycemic control that followed NICE-SUGAR is quite evident. At UCSF, fear of hypoglycemia is palpable, and we are much more comfortable with blood glucose levels in the 200+ range than in the 75-90 range. My sense is that NICE-SUGAR and similar trials have made us feel more comfortable with “permissive hyperglycemia.” Although we know from these trials that target glucose is not in the 200-range, we shy away from ramping up intensive insulin therapy for fear that people will “go low.” We can blame mild hyperglycemia on the patient’s physiology, but we can only blame ourselves if the patient becomes acutely hypoglycemic. 

To counter the fear of hypoglycemia let’s take a hard look in the evidence, to remind ourselves what our targets for “liberal glycemic control” actually are. A blood glucose value above 180 should trigger the same call to action that a blood glucose of 70 does.

Important Takeaways:
1) There was increased mortality in adults in the ICU who were randomized to the tight glycemic control group (81-108 mg/dl)
2) Subjects received majority of nutrition enterally
3) These results applied to both surgical and medical patients

Although very tight glycemic control has fallen out of favor in the setting of NICE-SUGAR, it is important to remember that even though the trial sought to have “tight glycemic control” between 81-108 mg/dl, it failed to achieve these goals and had an average blood glucose of 115 mg/dl in the group randomized to stricter glycemic control. The average blood glucose in the other group was 145 mg/dl. It is difficult to interpret how this should be incorporated into clinical practice. As clinicians or as hospital protocol writers, what should our true target value be?


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