Related Measures
Glycemic Control Goal
Background:
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/hour) 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:
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.
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 (relative risk 0.85, 95 percent confidence interval 0.75-0.97) but did not include any studies of insulin therapy in medical ICUs. [4]
A multi-center randomized control trial (VISEP) focusing on patients with severe sepsis 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 per deciliter [6.2 mmol per liter]) than in the conventional therapy group (151 mg per deciliter [8.4 mmol per liter], 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, < or = 40 mg per deciliter [2.2 mmol per liter]) 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 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.
Grading the Evidence: [See Ranking the Evidence]
The Grade 1 recommendations are based on strong evidence for care based on a number of qualitative considerations. “B” level evidence generally derives from randomized control trials with certain limitations or very well-done observational or cohort studies. “C” level evidence reflects well-done observational or cohort studies with controls. “D” level evidence generally reflects case series data or expert opinion.
The Surviving Sepsis Campaign formerly recommended in the 2008 Surviving Sepsis Campaign Guidelines 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 (Evidence Grade 1B).
The Surviving Sepsis Campaign reviewed its specific recommendations and ranges for glucose control after publication of NICE-SUGAR and issued a statement on glucose control ranges for severely septic patients in June 2009:
“There is insufficient information from randomized controlled trials to determine the optimal target range of blood glucose in the severely septic patient. [6] The NICE-SUGAR trial is the largest most compelling study to date on glucose control in ICU patients given its inclusion of multiple ICUs and hospitals, and a more general patient population. [1] Based on the results of this trial, we recommend against intravenous insulin therapy titrated to keep blood glucose in the normal range (80-110 mg/dl) in patients with severe sepsis. It is clear that attempts to normalize blood glucose with IV insulin during critical illness results in higher rates of hypoglycemia. [6,7] Until additional information is available, teams seeking to implement glucose control should consider initiating insulin therapy when blood glucose levels exceed 180 mg/dL with a goal blood glucose approximating 150 mg/dl as was observed in the beneficial arm of the NICE-SUGAR trial.”
Similarly, IHI advocates for a target threshold less than <180 for criticially ill patients based on the NICE-SUGAR trial data.
References:
- 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.
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- 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.
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Pittas, AG, Siegel RD, Lau, J. Insulin therapy for critically ill hospitalized patients. Archives of Internal Medicine. 2004;164:2005-2011.
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Brunkhorst FM, Engel C, Bloos F, et al; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. New England Journal of Medicine. 2008 Jan 10;358(2):125-139.
- Griesdale DE, de Souza RJ, van Dam RM, et al. Intensive insulin therapy and mortality among critically ill patients: A meta-analysis including NICE-SUGAR study data. Canadian Medical Association Journal. 2009 Apr 14;180(8):799-800.
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Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: A meta-analysis. Journal of the American Medical Association. 2008;300:933-944.
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