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 study by 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/dL [4.4 to 6.1 mmol/L]) with the use of insulin infusion or conventional therapy (i.e., insulin administered when the blood glucose level exceeded 215 mg/dL [12 mmol/L], with the infusion tapered when the level fell below 180 mg/dL [10 mmol/L]).
 
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.

Meta-analyses and Severe Sepsis Specific Inquires

A meta-analysis of 35 trials on insulin therapy in critically ill patients, including 12 randomized trials, demonstrated a 15 percent reduction in short-term mortality (RR 0.85, 95% confidence interval 0.75-0.97) but did not include any studies of insulin therapy in medical ICUs [4].
 
A multi-center randomized controlled trial focusing on patients with severe sepsis (VISEP) failed to demonstrate improvement in mortality [5].  In VISEP, the investigators randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy.  Of the 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg/dL [6.2 mmol/L]) than in the conventional-therapy group (151 mg/dL [8.4 mmol/L], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure.

Further, the VISEP investigators found that the rate of severe hypoglycemia (glucose level, < 40 mg/dL [2.2 mmol/L]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0 percent vs. 4.1 percent, P<0.001), as was the rate of serious adverse events (10.9 percent vs. 5.2 percent, P=0.01).  The trial was stopped earlier than planned for these reasons.

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/dL (4.5 to 6.0 mmol/L), or conventional glucose control, with a target of < 180 mg/dL (< 10.0 mmol/L). To be considered, patients were expected to require treatment in the ICU on three 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/dL [2.2 mmol/L]) 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/dL resulted in lower mortality than did a target of 81 to 108 mg/dL.
 

Grading the Evidence

The Surviving Sepsis Campaign recommends that, following initial stabilization, patients with severe sepsis and hyperglycemia who are admitted to the ICU receive IV insulin therapy to reduce blood glucose levels (Grade 1B). 

Rationale: The Surviving Sepsis Campaign is reviewing specific recommendations and ranges for glucose control shortly.  Presently, IHI also advocates for a target threshold less than <180 mg/dL for criticially ill patients based on the NICE-SUGAR trial data.

Category 1 recommendations are strong recommendations for care basd on qualitative considerations. "B" level evidence generally derives from randomized control trails with certain limitations or very well-done observational or cohort studlies.   “C” level evidence  reflects well-done observational or cohort studies with controls.  “D” level evidence generally reflects case series data or expert opinion.