Latest Evidence:
Due to IHI's commitment to adjust recommendations based on emerging evidence-based medicine, we are updating our glucose control recommendations following the publication of the NICE-SUGAR study in the New England Journal of Medicine in March 2009. [1] We will continue to adjust recommendations as new evidence emerges. The updated recommendation follows.
Introduction:
Effective glucose control in the intensive care unit (ICU) has been shown to decrease morbidity across a large range of conditions and also to decrease mortality.
Hyperglycemia, caused by insulin resistance in the liver and muscle, is a common finding in ICU patients. Some have considered it to be an adaptive response, providing glucose for the brain, red blood cells, and wound healing. Traditionally, hyperglycemia has only been treated when blood glucose increases to >215 mg/dL (>12 mmol/L). Conventional wisdom in the ICU has been that some degree of hyperglycemia is beneficial and that hypoglycemia is dangerous and should be avoided. The extent of appropriate glucose control has been evaluated in recent years.
Initial Investigations — Intensive Insulin Therapy:
An initial investigation by Van den Berghe and colleagues [2] suggested that controlling blood glucose levels by intensive insulin therapy decreased mortality and morbidity in surgical critically ill patients. The trial was a large single-center study of postoperative surgical patients. The design employed a continuous infusion of insulin to maintain glucose between 80 and 110 mg/dL (4.4–6.1 mmol/L). Exogenous glucose was begun simultaneously with insulin, with frequent monitoring of glucose (every 1 hour) and intensity of monitoring was greatest at the time of initiation of insulin. This protocol called for implementing a strategy to maintain normoglycemia with an insulin infusion while providing for normal intake of glucose (9 g/hr) and calories (19 kcal·kg-1·day-1).
A total of 35 of 765 patients (4.6 percent) in the intensive insulin group died in the ICU in Van den Berghe et al., compared with 63 patients (8.0 percent) in the conventional therapy group.
Intensive insulin therapy halved the prevalence of:
- Bloodstream infections
- Prolonged inflammation
- ARF requiring dialysis or hemofiltration
- Critical illness polyneuropathy
- Transfusion requirements
Patients receiving intensive insulin therapy were also less likely to require prolonged mechanical ventilation and intensive care. Rigorous insulin treatment reduced the number of deaths from multiple-organ failure with sepsis, regardless of whether there was a history of diabetes or hyperglycemia.
Surgical vs. Medical Patients:
The same protocol used in the first Van den Berghe trial for surgical patients was subsequently tested in medical patients. [3]
Patients who were considered to need intensive care for at least three days were enrolled in a prospective, randomized, single-center, controlled study. On admission, patients were randomly assigned to strict normalization of blood glucose levels (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) with the use of insulin infusion or conventional therapy (i.e., insulin administered when the blood glucose level exceeded 215 mg per deciliter [12 mmol per liter], with the infusion tapered when the level fell below 180 mg per deciliter [10 mmol per liter]).
Intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality (40.0 percent in the conventional-treatment group vs. 37.3 percent 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.
Although length of stay in the ICU could not be predicted on admission, among 433 patients who stayed in the ICU for less than three days, mortality was greater among those receiving intensive insulin therapy. 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 percent (P=0.009) and morbidity was also reduced.
The authors concluded that intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy.
NICE-SUGAR Study:
Based on the foregoing studies, most clinicians believed that there was a benefit to glucose control in terms of mortality and morbidity. However, the optimal target range for blood glucose in critically ill patients remained unclear.
The NICE-SUGAR study investigators [1] chose to evaluate whether there was a difference in mortality between subjects randomly assigned to either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter). To be considered, patients were expected to require treatment in the ICU on 3 or more consecutive days.
Of the 6,104 patients who underwent randomization, 3,054 were assigned to undergo intensive control and 3,050 to undergo conventional control. A total of 829 patients (27.5 percent) in the intensive-control group and 751 (24.9 percent) in the conventional-control group died. Thus, the odds of dying with intensive control were 1.14 times greater than with conventional control (P=0.02). In addition, severe hypoglycemia (blood glucose level of 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3,016 patients (6.8 percent) in the intensive-control group and in 15 of 3,014 patients (0.5 percent) in the conventional-control group (P<0.001). Thus, the incidence of hypoglycemia was lower in the conventional group.
With regard to morbidity and length of stay, NICE-SUGAR demonstrated that there was no significant difference between the two treatment groups in the median number of days in the ICU or hospital, or the median number of days of mechanical ventilation or renal-replacement therapy.
The NICE-SUGAR investigators concluded that that intensive glucose control increased mortality among adults in the ICU and that a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter.
Overall Recommendation:
Evaluating the evidence, it is clear that the NICE-SUGAR trial is the most complete study on glucose control in ICU patients given its inclusion of multiple sites, a more general patient population, a much larger number of patients, etc., compared to other trials. As such, we recommend teams seeking to implement glucose control set a goal of less than 180 mg/dL for critically ill patients.
Nevertheless, there is not great clarity about lower guidelines following the NICE-SUGAR study, given that ranges such as 100 to 140 mg/dL were not studied. Hospitals can review and adapt existing protocols (including the protocol in the NICE-SUGAR study) and take into account their own feeding regimens and local expertise and experience with glucose control and avoidance of hypoglycemia. Hospitals can consider settings goal ranges such as 60 to 180, 100 to 140, 100 to 180, or 140 to 180 as needed to avoid severe (less than 40 mg/dl) hypoglycemia. The effort should be to avoid hypoglycemia in at least 99 percent of patients.
Clinical Evidence:
- NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. New England Journal Medicine. 2009 Mar 26;360(13):1283-1297.
- Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. New England Journal of Medicine. 2001 Nov 8;345(19):1359-1367.
- Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. New England Journal of Medicine. 2006 Feb 2;354(5):449-461.
