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142 PART 2: General Management of the Patient

stress hyperglycemia and poor outcome is largely established. This asso- TOXICITY ASSOCIATED WITH HIGH
ciation reflects the validity of blood glucose concentration as a marker GLUCOSE CONCENTRATIONS
of illness severity. However, the correction of a moderate stress hypergly-
cemia may improve the prognosis. Indeed, in 2001, a large randomized Because glucose is the preferential substrate during critically ill condi-
controlled trial in critically ill surgical patients demonstrated that tight tions, stress hyperglycemia was considered for a long time as a ben-
glucose control (TGC) (defined as the restoration and maintenance of eficial response allowing an adequate provision of energy to tissues.
blood glucose between 80 and 110 mg/dL) by intensive insulin therapy However, in stress conditions, an overall massive glucose overload
(IIT) was associated with a decreased mortality and rate of complica- happens in NIMGU tissues under the influence of proinflammatory
tions. However, subsequent studies performed in other intensive care mediators, counterregulatory hormones, and hypoxia. A wide range of
2
units (ICU) failed to reproduce the beneficial effects of IIT titrated to tissues, including hepatocytes, endothelial cells, neurons, nephrons, and
3-8
achieve TGC. immune cells may be susceptible to enhanced glucose toxicity as a result
These conflicting results raise the clinically relevant question: How of acute illness. In these tissues, several deleterious effects have been
to control glycemia in ICUs? This chapter intends to summarize the associated with these high glucose concentrations in cells. Damages
1,9
current understanding of the physiological regulation of glycemia, to mitochondrial proteins occur and the formation of reactive oxygen
the toxicity of hyperglycemia, the mechanisms and consequences of species (ROS) is increased as a consequence of the shift from glycolysis
stress hyperglycemia, and the available clinical data from observational toward accessory metabolic pathways (pentose phosphate, hexosamines,
and interventional studies and to discuss the unsolved issues and the polyols). Other effects of excess glucose concentrations include the
10
implications for the daily clinical practice. Updated formal recom- exacerbation of inflammatory pathways, decreased complement activity,
mendations will be suggested for glucose control in critically ill and modifications in the innate immune system, impairment in endothelial
postoperative patients. and hepatic mitochondrial functions, abolishment of the ischemic pre-
conditioning, and protein glycosylation. Acute complications attributed
PHYSIOLOGICAL REGULATION OF BLOOD GLUCOSE to stress hyperglycemia include renal failure, increased susceptibility to
infections, polyneuropathy, and impaired microcirculation. 1
Blood glucose concentration (BG) is tightly regulated by two types of
mechanisms : 1 MECHANISMS OF STRESS HYPERGLYCEMIA
• The hormonal system consists in a balance between insulin, which
will induce the entrance and utilization of glucose into tissues, and Although sharing some similarities, the pathogenetic mechanisms of
the so-called “hyperglycemic” counterregulatory hormones (gluca- type 2 diabetes and stress hyperglycemia are different. In diabetes,
gon, epinephrine, cortisol). the cause of hyperglycemia is a combination of insulin resistance and
• The neural mechanism consists in an activation of messages issued defective secretion of insulin by pancreatic β-cells. During stress hyper-
glycemia, complex interactions between counterregulatory hormones
from glucose sensors of various organs. (catecholamines, growth hormone, and cortisol) and cytokines lead to
These hormonal and neural signals modulate carbohydrate metabo- an excessive hepatic glucose production and peripheral insulin resistance
lism by controlling glucose fluxes, including endogenous production (Fig. 21-2). This highly complex interplay is largely variable over time. 1,11
and the entrance of glucose into the cells. The translocation of glucose The stress-related increase in hepatic output of glucose results from glu-
transporters (GLUT) is the prominent mechanism for the modulation of coneogenesis and to a lesser extent from glycogenolysis. Gluconeogenesis
glucose transport across the cell membranes. Among those transporters, is triggered to a larger extent by glucagon than by epinephrine and cortisol.
9
GLUT-1 is the predominant transporter for noninsulin-mediated glucose Glycogenolysis is primarily triggered by catecholamines and perpe tuated
uptake (NIMGU) (Fig. 21-1). GLUT-2 regulates the flow of glucose under the influence of epinephrine and cortisol. Tumor necrosis factor-α
32
across liver cell membranes. GLUT-4 is the main insulin-responsive (TNFα) might promote gluconeogenesis by stimulating glucagon
glucose transporter and therefore modulates the insulin-mediated glucose production. The increase in peripheral resistance is characterized by the
uptake (IMGU) in adipose tissue, cardiac and skeletal muscles. inability of skeletal muscles and adipocytes to take up glucose, related to

Study name Statistics for each study Odds ratio and 95% CI
Odds Lower Upper
ratio limit limit z Value p Value
Van den Berghe, 2001 1.572 1.102 2.242 2.498 0.012
Van den Berghe, 2006 1.057 0.826 1.353 0.441 0.659
Glucotrol, 2006 0.788 0.573 1.085 –1.460 0.144
VISEP, 2008 1.064 0.720 1.572 0.310 0.757
De La Rosa, 2008 0.830 0.574 1.199 –0.994 0.320
Arabi, 2008 0.781 0.484 1.262 –1.009 0.313
NICE-SUGAR 2009 0.918 0.812 1.038 –1.361 0.173
0.954 0.871 1.046 –0.995 0.320
0.5 1 2
Favors Control Favors IIT

Meta-analysis
FIGURE 21-1. Insulin and glucose uptake by tissues in physiological conditions. Insulin promotes insulin-mediated glucose uptake (IMGU) in adipose tissues, skeletal and cardiac muscles
by activating GLUT-4 transporters. Simultaneously, insulin activates GLUT-2 transporters in the liver, which decrease the endogenous glucose production. The global effect is a decrease in blood
glucose level (insulin is a hypoglycemic hormone). As a consequence, noninsulin-mediated glucose uptake (NIMGU) by GLUT-1 transporters decreases. (Adapted with permission from Lena D,
Kalfon P, Preiser JC, Ichai C. Glycemic control in the intensive care unit and during the postoperative period. Anesthesiology. February 2011;114(2):438-444.)

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