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The American Diabetes Association (ADA) defines inpatient hyperglycemia as a fasting blood glucose (BG) >126 mg/dL or a random BG >200 mg/dL that reverts to normal after discharge.1 The prevalence of hyperglycemia in the acutely ill patient in the intensive care unit (ICU) has been shown to be as high as 83%.2 Hyperglycemia in critical illness may occur due to stress-related surges in counterregulatory hormones, preexisting diabetes, impaired glucose tolerance, and insulin resistance. Whether it is a condition necessitating intervention or a marker of disease severity, hyperglycemia has been shown to be an independent risk factor for increased mortality in the ICU.3 Despite this association, tight glycemic control (TGC) has not been shown to consistently improve patient outcomes and surprisingly may, in some subgroups, cause more harm than good. This chapter examines the historical background, essential pathophysiology, associations, key clinical studies, current protocols, and recommendations regarding hyperglycemia in the critically ill.

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Hyperglycemia was first detected as glucosuria in ether-anesthetized patients 150 years ago, and in 1877, Bernard described hyperglycemia in a canine model of hemorrhagic shock.4 For many years, hyperglycemia in the critically ill was considered an adaptation to stress and was not treated. In fact, some early ICU practitioners recognized insulin resistance and believed that elevated glucose levels (160–200 mg/dL) would promote cellular glucose uptake. In 2001, Van den Berghe demonstrated a statistically significant mortality benefit with TGC in surgical ICU patients. Subsequently, many professional societies including the Surviving Sepsis Campaign (SSC) in 2004 endorsed TGC.5 The Leuven (Van den Berghe et al) medical trial in 2006, Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP, Brunkhorst et al) trial in 2008, and Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation (NICE-SUGAR, Finfer et al) and Glucontrol (Preiser et al) trials published in 2009 have contributed most to the continuously evolving issue of glucose management in the critically ill patient.

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Risk factors for the development of hyperglycemia include preexisting diabetes mellitus, advanced age, infusion of catecholamine pressors, glucocorticoids, obesity, excessive dextrose resuscitation, sepsis, hypothermia, hypoxia, uremia, and cirrhosis.6 These proven risk factors highlight the multifactorial pathophysiologic mechanisms underlying ICU hyperglycemia.

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In the critically ill patient, hyperglycemia can be explained by increased glucose production (glycogenolysis and gluconeogenesis) and decreased peripheral uptake (insulin resistance) (Figure 32-1):

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  • Increased glucose production: Counterregulatory hormones and catecholamines such as glucagon, growth hormone, cortisol, and epinephrine increase adipose tissue lipolysis and skeletal muscle proteolysis. The end products from this process (glycerol, alanine, and lactate) then fuel hepatic gluconeogenesis. By directly enhancing hepatic glycogenolysis, the above hormones simultaneously further raise glucose levels. Impairment of cellular glycogen synthesis is another important pathway leading to increased glucose levels.
  • Decreased peripheral uptake: In a healthy subject, insulin binds to its receptor triggering a signaling pathway that ultimately leads to the translocation of the intracellular Glut4 protein to the plasma membrane where it ...

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