This association is typically present in hyperglycemic patients whether they have a diagnosis of diabetes or not, and the association is often even stronger in those lacking a pre-existing diagnosis. Dysfunction typically is detectable at only modest elevations of blood glucose and becomes more marked in a dose response relationship.
Uncontrolled Interventional Studies
The Portland Diabetic Project is a prospective, non-randomized, observational study of 5,510 consecutive diabetic cardiac surgery patients.14-15 The three-day blood glucose average (3-BG) has been progressively reduced for the population through the use of continuous insulin infusion (CII).
The last reported glycemic target is less than 130 mg/dL, and the current glycemic target is less than 110 mg/dL. Both CII for three days and a favorable 3-BG were independently associated with improved mortality, deep sternal-wound infection rates, and length of stay. Mortality and deep sternal-wound infection rates for diabetic patients with well-controlled glucose levels are equal to patients without diabetes.
Another study compared 800 mixed medical-surgical ICU patients with tight glycemic control (mean BG 130.7 mg/dL) to historical controls with a mean glucose of 152.3 mg/dL. The insulin infusion group had associated significant reductions in mortality and median length of ICU stay.16
Randomized Controlled Trials and Meta-Analyses
In the first Diabetes and Insulin-Glucose study (DIGAMI 1), patients with acute MI received IV insulin therapy for 24 hours, followed by multiple daily injections for three months or longer. The insulin group had lower glucose values and a 29% reduction in mortality at one year and 28% reduction at 3.4 years compared with the control group.17-18
In the most influential study to date, van den Berghe, et al., randomized 1,548 surgical intensive-care unit (ICU) patients to either intensive (IT) or conventional (CT) insulin therapy.19 The glycemic target in the IT arm was 80 to 110 mg/dL (mean glucose attained was 103 mg/dL), while the CT arm had a mean glucose level of 153 mg/dL. The IT group enjoyed substantial reductions in both ICU and total in-hospital mortality, as well as reductions in blood stream infections, acute renal failure, transfusions and the duration of mechanical ventilation (p<0.01 for all).
While a similar study in a medical ICU did not achieve statistical significance in the overall intention-to-treat analysis for mortality, it did demonstrate reductions in mortality in patients with at least three days of ICU treatment and significant reductions in morbidity.20
A meta-analysis of these two studies demonstrated a relative risk reduction in mortality (23.6 to 20.4%) and morbidity in all patients treated with intensive insulin therapy.21
A separate meta-analysis of 35 clinical trials evaluating the effect of intensive insulin infusion therapy on mortality in critically ill inpatients revealed a 15% reduction in short-term mortality.22
Noncritical Care Settings
There are no randomized controlled trials establishing the optimal glycemic target for noncritical care inpatients. There are a number of observational and pilot studies that reinforce the studies performed in critical care settings.
In a retrospective review of almost 1,900 general medical-surgical admissions, Umpierrez, et al., reported an 18-fold increase in mortality in hyperglycemic patients without prior history of diabetes and a 2.5-fold increase in mortality in patients with known diabetes compared to controls. These associations persisted with adjustment for severity of illness.23
A variety of observational and pilot studies associate hyperglycemia with poor outcomes in community acquired pneumonia, renal transplant, and the durability of remission in acute lymphocytic leukemia.24-25
Guidelines and Recommendations
Spurred by the emerging controlled trial evidence, the American Association of Clinical Endocrinologists (AACE) convened a consensus conference involving nine organizations, including SHM. Recommendations for the management of inpatient hyperglycemia included stringent glycemic targets for critical care and noncritical care areas.26 The American Diabetes Association (ADA) produced an excellent technical review on inpatient diabetes that provided the basis for ADA Clinical Practice Guideline glycemic targets.27 The glycemic targets recommended are shown in Table 1 (above).