Glucose control in the critically ill patient is an area of current debate. While avoidance of uncontrolled hyperglycemia is desirable to prevent poor clinical outcomes,1 the preferred blood glucose target is unknown and data from randomized trials has failed to provide a consensus. Recent data has revealed that hypoglycemia is associated with an increased incidence of mortality among critically ill patients.2,3 While data is still conflicting, current guidelines recommend treating to a blood glucose goal of 144 to 180 mg/dL,4 or alternately to <180 mg/dL,5 to reduce the risk of hypoglycemia while avoiding hyperglycemia.
Post hoc analysis has been performed on results from the NICE-SUGAR trial (Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation) to better describe a relationship between hypoglycemia and mortality. The NICE-SUGAR trial, originally published in 2009, is the largest trial to compare intensive and conventional glucose control. NICE-SUGAR sought to determine whether intensive glucose control led to decreased mortality in critically ill patients, and randomly assigned 6104 patients to one of two treatment groups: 3054 to intensive glucose control (target blood glucose range 81 to 108 mg/dL; 4.5 to 6 mmol/L) and 3050 to conventional glucose control (target blood glucose range <180 mg/dL; <10 mmol/L).2
Results of this trial reported an increased incidence of severe hypoglycemia (blood glucose <40mg/dL [2.2 mmol/L]) in the intensive control group (6.8% versus 0.5% in conventional group; odds ratio 14.7; 95% confidence interval 9 to 25.9; P<0.001). The 90-day mortality was also significantly higher in the intensive control group, with 829 (27.5%) patient deaths compared with 751 (24.9%) patient deaths in the conventional glucose control group (odds ratio 1.14; 95% CI 1.02-1.28; P=0.02). Based on this data, authors suggested that an intensive glucose control target of 81-108 mg/dL leads to increased mortality among critically ill patients in the ICU setting compared to a glucose control target of <180 mg/dL.2 A causal relationship, however, could not be determined.
Post-hoc analysis of the NICE-SUGAR trial was performed to investigate associations between moderate hypoglycemia (blood glucose 41 to 70 mg/dL; 2.3 to 3.9 mmol/L), severe hypoglycemia (blood glucose <40 mg/dL; 2.2 mmol/L), and death and to determine if a causal relationship exists. Of the 6104 patients randomized, follow-up data was available for 6026 patients. After adjustment for baseline characteristics and post-randomization factors, both moderate and severe hypoglycemia resulted in a significantly increased risk for death compared to patients who did not experience hypoglycemia (moderate hypoglycemia, hazard ratio 1.41; 95% CI 1.21 to 1.62; P<0.001; severe hypoglycemia, HR 2.10; 95% CI 1.59 to 2.77; P<0.001).6
The risk of death was not significantly different between patients who received conventional or intensive glucose control (P=0.22), or between patients with or without a previous history of diabetes (P=0.42). Associations between hypoglycemia and death were greatest among patients who experienced severe hypoglycemia (P<0.001), postoperative patients (P=0.03), patients who experienced moderate hypoglycemia on more than one day (P=0.01), and patients who were not on insulin therapy prior to hypoglycemia (P=0.007 for moderate hypoglycemia, P=0.003 for severe hypoglycemia).6
Cause-specific mortality was also analyzed. Data showed that patients who experienced moderate or severe hypoglycemia were at increased risk for death from distributive shock (P<0.001). Patients who experienced severe hypoglycemia were also shown to have an increased risk for death from causes other than cardiovascular, neurologic, or respiratory causes (P=0.002).6
Authors were unable to prove a causal relationship between moderate and severe hypoglycemia and mortality in this critically ill population. While a strong association is seen, authors suggest more data is needed to determine if hypoglycemia is a cause of death or a marker of underlying disease processes. Current guidelines, however, should continue to recommend appropriate glucose control for avoidance of hypoglycemia.
1. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogenous population of critically ill patients. May Clin Proc 2003;78:1471-1478.
2. The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283-97.
3. Preiser JC, Devos P, Ruiz-Santana S, et al. A prospective randomized multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med 2009;35:1738-1748.
4. American Diabetes Association. Standards of ...