The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial recruited 6,104 intensive care unit (ICU) patients in 24 hospitals. In this post hoc analysis of the trial’s database, the NICE-SUGAR investigators explored the association between different levels of hypoglycemia and death. Findings were published in the September 20 issue of The New England Journal of Medicine.

Patients in the NICE-SUGAR trial were randomly assigned to either intensive blood glucose control, targeting a glucose range of 81-108 mg/dL (4.5-6.0 mmol/L), or conventional glucose control, targeting a glucose <180 mg/dL (<10.0 mmol/L). Severe hypoglycemia was defined as a glucose value <40 mg/dL (2.2 mmol/L); values between 41 and 70 mg/dL (2.3-3.9 mmol/L) were considered moderate hypoglycemia. Each group contained 3,013 patients. Cox regression was used to calculate hazard ratios for death, adjusted for treatment assignment, baseline characteristics and time-dependent factors.

Forty-five percent of patients had moderate hypoglycemia, including 74.2% of patients in the intensive glucose control group. In the intensive glucose control group, 6.9% of patients had severe hypoglycemia (n=208/3013). Patients with moderate hypoglycemia were more likely to have severe sepsis, trauma, diabetes, and cardiovascular failure. When adjusted for treatment assignment, patients in the intensive glucose control group had a statistically significantly higher risk of death when they had severe hypoglycemia (hazard ratio 3.21; 95% confidence interval, 2.49-4.15; P<0.001). The risk of death remained statistically increased when adjustments for baseline characteristics and post-randomization factors were taken into account; both moderate and severe hypoglycemia was associated with an increased risk of death. Patients with hypoglycemia for more than 1 day were found to have an increased risk of death (>1 day vs. 1 day, P=0.01).

This post hoc analysis offers further insight into the mechanisms of increased mortality when ICU patients are treated with intensive glucose control. Because the original NICE-SUGAR trial included a wide range of ICU patients (i.e., postsurgical vs. medical), it is unclear if the association between hypoglycemia and death is valid across all patient populations. As the authors correctly point out, the results from this study cannot demonstrate a casual relationship between hypoglycemia and death. Instead, the authors rightly surmise that hypoglycemia may be a marker of severe underlying disease processes. Based on the results of this trial and additional observational data, the current American Diabetes Association guidelines, which stress avoidance of hypoglycemia and targeting of glucose values in the range of 140-180 mg/dL (8–10 mmol/L), appear reasonable for critically ill patients.

Concise Critical Appraisal is a regular feature authored by SCCM member Samuel M. Galvagno Jr., DO, PhD. Each installment highlights journal articles most relevant to the critical care practitioner.