HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Extract Full Text (PDF) Appendixes Erratum (v27,p1255) Erratum (v27,p856) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clement, S. Articles by Hirsch, I. B. Search for Related Content PubMed PubMed Citation Articles by Clement, S. Articles by Hirsch, I. B. Social Bookmarking                What's this?

Management of Diabetes and Hyperglycemia in Hospitals

¹ Georgetown University Hospital, Washington, DC
² University of North Carolina, Chapel Hill, North Carolina
³ Medstar Research Institute at Washington Hospital Center, Washington, DC
⁴ Oregon Health and Science University, Portland, Oregon
⁵ VA Medical Center, Bay Pines, Florida
⁶ University of Washington, Seattle, Washington

Address correspondence and reprint requests to Dr. Stephen Clement, MD, Georgetown University Hospital, Department of Endocrinology, Bldg. D, Rm. 232, 4000 Reservoir Rd., NW, Washington, DC 20007. E-mail: clements{at}gunet.georgetown.edu

Abbreviations: ADA, American Diabetes Association • AMI, acute myocardial infarction • CDE, certified diabetes educator • CHF, congestive heart failure • CK, creatinine kinase • CQI, continuous quality improvement • CRP, C-reactive protein • CSII, continuous subcutaneous insulin infusion • CVD, cardiovascular disease • DIGAMI, Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction • DSME, diabetes self-management education • DSWI, deep sternal wound infection • FFA, free fatty acid • GIK, glucose-insulin-potassium • ICAM, intercellular adhesion molecule • ICU, intensive care unit • IL, interleukin • IIT, intensive insulin therapy • JCAHO, Joint Commission of Accredited Hospital Organization • LIMP, lysosomal integral membrane protein • MCP, monocyte chemoattractant protein • MI, myocardial infarction • MRI, magnetic resonance imaging • MRS, magnetic resonance spectroscopy • NF, nuclear factor • NPO, nothing by mouth • PAI, plasminogen activator inhibitor • PCU, patient care unit • PKC, protein kinase C • PBMC, peripheral blood mononuclear cell • PMN, polymorphonuclear leukocyte • ROS, reactive oxygen species • TNF, tumor necrosis factor • TPN, total parenteral nutrition • UKPDS, U.K. Prospective Diabetes Study

	INTRODUCTION

TOP INTRODUCTION What is the prevalence... WHAT IS THE LINK... WHAT ARE THE TARGET... HOW ARE TARGET BLOOD... HOW CAN SYSTEM DESIGN... WHAT IS THE ROLE... WHAT IS THE ROLE... WHAT IS THE ROLE... IS IMPROVED DIABETES CARE... SUGGESTIONS FOR FUTURE RESEARCH CONCLUSIONS References

 
Diabetes increases the risk for disorders that predispose individuals to hospitalization, including coronary artery, cerebrovascular and peripheral vascular disease, nephropathy, infection, and lower-extremity amputations. The management of diabetes in the hospital is generally considered secondary in importance compared with the condition that prompted admission. Recent studies (1,2) have focused attention to the possibility that hyperglycemia in the hospital is not necessarily a benign condition and that aggressive treatment of diabetes and hyperglycemia results in reduced mortality and morbidity. The purpose of this technical review is to evaluate the evidence relating to the management of hyperglycemia in hospitals, with particular focus on the issue of glycemic control and its possible impact on hospital outcomes. The scope of this review encompasses adult nonpregnant patients who do not have diabetic ketoacidosis or hyperglycemic crises.

For the purposes of this review, the following terms are defined (adapted from the American Diabetes Association [ADA] Expert Committee on the Diagnosis and Classification of Diabetes Mellitus) (3):

• Medical history of diabetes: diabetes has been previously diagnosed and acknowledged by the patient’s treating physician.
  
• Unrecognized diabetes: hyperglycemia (fasting blood glucose 126 mg/dl or random blood glucose 200 mg/dl) occurring during hospitalization and confirmed as diabetes after hospitalization by standard diagnostic criteria, but unrecognized as diabetes by the treating physician during hospitalization.
  
• Hospital-related hyperglycemia: hyperglycemia (fasting blood glucose 126 mg/dl or random blood glucose 200 mg/dl) occurring during the hospitalization that reverts to normal after hospital discharge.
  

	What is the prevalence of diabetes in hospitals?

TOP INTRODUCTION What is the prevalence... WHAT IS THE LINK... WHAT ARE THE TARGET... HOW ARE TARGET BLOOD... HOW CAN SYSTEM DESIGN... WHAT IS THE ROLE... WHAT IS THE ROLE... WHAT IS THE ROLE... IS IMPROVED DIABETES CARE... SUGGESTIONS FOR FUTURE RESEARCH CONCLUSIONS References

 
The prevalence of diabetes in hospitalized adult patients is not known. In the year 2000, 12.4% of hospital discharges in the U.S. listed diabetes as a diagnosis. The average length of stay was 5.4 days (4). Diabetes was the principal diagnosis in only 8% of these hospitalizations. The accuracy of using hospital discharge diagnosis codes for identifying patients with previously diagnosed diabetes has been questioned. Discharge diagnosis codes may underestimate the true prevalence of diabetes in hospitalized patients by as much as 40% (5,6). In addition to having a medical history of diabetes, patients presenting to hospitals may have unrecognized diabetes or hospital-related hyperglycemia. Umpierrez et al. (1) reported a 26% prevalence of known diabetes in hospitalized patients in a community teaching hospital. An additional 12% of patients had unrecognized diabetes or hospital-related hyperglycemia as defined above. Levetan et al. (6) reported a 13% prevalence of laboratory-documented hyperglycemia (blood glucose >200 mg/dl (11.1 mmol) in 1,034 consecutively hospitalized adult patients. Based on hospital chart review, 64% of patients with hyperglycemia had preexisting diabetes or were recognized as having new-onset diabetes during hospitalization. Thirty-six percent of the hyperglycemic patients remained unrecognized as having diabetes in the discharge summary, although diabetes or "hyperglycemia" was documented in the progress notes for one-third of these patients.

Norhammar et al. (7) studied 181 consecutive patients admitted to the coronary care units of two hospitals in Sweden with acute myocardial infarction (AMI), no diagnosis of diabetes, and a blood glucose <200 mg/dl (<11.1 mmol/l) on admission. A standard 75-g glucose tolerance test was done at discharge and again 3 months later. The authors found a 31% prevalence of diabetes at the time of hospital discharge and a 25% prevalence of diabetes 3 months after discharge in this group with no previous diagnosis of diabetes.

Using the A1C test may be a valuable case-finding tool for identifying diabetes in hospitalized patients. Greci et al. (8) reported that an A1C >6% was 100% specific and 57% sensitive for identifying persons with diabetes in a small cohort of patients admitted through the emergency department of one hospital with a random blood glucose 126 mg/dl (7 mmol/l) and no prior history of diabetes.

From the patient’s perspective, 24% of adult patients with known diabetes surveyed in 1989 reported being hospitalized at least once in the previous year (9). The risk for hospitalization increased with age, duration of diabetes, and number of diabetes complications. Persons with diabetes reported being hospitalized in the previous year three times more frequently compared with persons without diabetes. In summary, the prevalence of diabetes in hospitalized adults is conservatively estimated at 12.4–25%, depending on the thoroughness used in identifying patients.

	WHAT IS THE LINK BETWEEN HIGH BLOOD GLUCOSE AND POOR OUTCOMES? POSSIBLE MECHANISMS

TOP INTRODUCTION What is the prevalence... WHAT IS THE LINK... WHAT ARE THE TARGET... HOW ARE TARGET BLOOD... HOW CAN SYSTEM DESIGN... WHAT IS THE ROLE... WHAT IS THE ROLE... WHAT IS THE ROLE... IS IMPROVED DIABETES CARE... SUGGESTIONS FOR FUTURE RESEARCH CONCLUSIONS References

 
The mechanism of harm from hyperglycemia on various cells and organ systems has been studied in in vitro systems and animal models. This research has centered on the immune system, mediators of inflammation, vascular responses, and brain cell responses.

Hyperglycemia and immune function
The association of hyperglycemia and infection has long been recognized, although the overall magnitude of the problem is still somewhat unclear (10,11). From a mechanistic point of view, the primary problem has been identified as phagocyte dysfunction. Studies have reported diverse defects in neutrophil and monocyte function, including adherence, chemotaxis, phagocytosis, bacterial killing, and respiratory burst (10–20). Bagdade et al. (14) were among the first to attach a glucose value to improvement in granulocyte function when they demonstrated significant improvement in granulocyte adherence as the mean fasting blood glucose was reduced from 293 ± 20 to 198 ± 29 mg/dl (16.3–11 mmol/l) in 10 poorly controlled patients with diabetes. Other investigators have demonstrated similar improvements in leukocyte function with treatment of hyperglycemia (17,21–23). In vitro trials attempting to define hyperglycemic thresholds found only rough estimates that a mean glucose >200 mg/dl (11.1 mmol/l) causes leukocyte dysfunction (13,14,16,24–26).

Alexiewicz et al. (17) demonstrated elevated basal levels of cytosolic calcium in the polymorphonuclear leukocytes (PMNs) of patients with type 2 diabetes relative to control subjects. Elevated cytosolic calcium was associated with reduced ATP content and impaired phagocytosis. There was a direct correlation between PMN cytosolic calcium and fasting serum glucose. These were both inversely proportional to phagocytic activity. Glucose reduction with glyburide resulted in reduced cytosolic calcium, increased ATP content, and improved phagocytosis.

Classic microvascular complications of diabetes are caused by alterations in the aldose reductase pathway, AGE pathway, reactive oxygen species pathway, and the protein kinase C (PKC) pathway (rev. in 27). Several of these pathways may contribute to immune dysfunction. PKC may mediate the effect of hyperglycemia on neutrophil dysfunction (28). Liu et al. (29) found that decreased phagocytic activity in diabetic mice correlated inversely with the formation of AGEs, although a direct cause-and-effect relationship was not proven. Ortmeyer and Mohsenin (30) found that hyperglycemia caused impaired superoxide formation along with suppressed activation of phospholipase D. Reduced superoxide formation has been linked to leukocyte dysfunction. Another recent study found a link among hyperglycemia, inhibition of glucose-6-phosphate dehydrogenase, and reduced superoxide production in isolated human neutrophils (31). Sato and colleagues (32–34) used chemiluminescence to evaluate neutrophil bactericidal function. The authors confirmed a relationship between hyperglycemia and reduced superoxide formation in neutrophils. This defect was improved after treatment with an aldose reductase inhibitor. This finding suggests that increased activity of the aldose reductase pathway makes a significant contribution to the incidence of diabetes-related bacterial infections.

Laboratory evidence of the effect of hyperglycemia on the immune system goes beyond the granulocyte. Nonenzymatic glycation of immunoglobulins has been reported (35). Normal individuals exposed to transient glucose elevation show rapid reduction in lymphocytes, including all lymphocyte subsets (36). In patients with diabetes, hyperglycemia is similarly associated with reduced T-cell populations for both CD-4 and CD-8 subsets. These abnormalities are reversed when glucose is lowered (37).

In summary, studies evaluating the effect of hyperglycemia on the immune system comprise small groups of normal individuals, patients with diabetes of various duration and types, and animal studies. These studies consistently show that hyperglycemia causes immunosuppression. Reduction of glucose by a variety of means reverses the immune function defects.

Hyperglycemia and the cardiovascular system
Acute hyperglycemia has numerous effects on the cardiovascular system. Hyperglycemia impairs ischemic preconditioning, a protective mechanism for ischemic insult (38). Concomitantly, infarct size increases in the setting of hyperglycemia. The same investigators demonstrated reduced coronary collateral blood flow in the setting of moderately severe hyperglycemia (39). Acute hyperglycemia may induce cardiac myocyte death through apoptosis (40) or by exaggerating ischemia-reperfusion cellular injury (41).

Other vascular consequences of acute hyperglycemia relevant to inpatient outcomes include blood pressure changes, catecholamine elevations, platelet abnormalities, and electrophysiologic changes. Streptozotocin-induced diabetes in rats results in significant hemodynamic changes as well as QT prolongation (42). These changes were reversed with correction of hyperglycemia. In humans, Marfella et al. (43) reported increased systolic and diastolic blood pressure and increased endothelin levels with acute hyperglycemia in patients with type 2 diabetes. The same researchers also induced acute hyperglycemia (270 mg/dl or 15 mmol/l) over 2 h in healthy men. This produced elevated systolic and diastolic blood pressure, increased pulse, elevation of catecholamine levels, and QTc prolongation (44). Other investigators have demonstrated an association between acute hyperglycemia and increased viscosity, blood pressure (45), and natiuretic peptide levels (46).

Hyperglycemia and thrombosis
Multiple studies have identified a variety of hyperglycemia-related abnormalities in hemostasis, favoring thrombosis (47–51). For example, hyperglycemic changes in rats rapidly reduce plasma fibrinolytic activity and tissue plasminogen activator activity while increasing plasminogen activator inhibitor (PAI)-1 activity (52). Human studies in patients with type 2 diabetes have shown platelet hyperactivity indicated by increased thromboxane biosynthesis (47). Thromboxane biosynthesis decreases with reduction in blood glucose. Hyperglycemia-induced elevations of interleukin (IL)-6 levels have been linked to elevated plasma fibrinogen concentrations and fibrinogen mRNA (53,54).

Increased platelet activation as shown by shear-induced platelet adhesion and aggregation on extracellular matrix has been demonstrated in patients with diabetes (48). As little as 4 h of acute hyperglycemia enhances platelet activation in patients with type 2 diabetes (51). In this crossover, double-blind study, 12 patients were subjected to hyperglycemic (250 mg/dl, 13.9 mmol/l) and euglycemic (100 mg/dl, 5.55 mmol/l) clamps. Hyperglycemia precipitated stress-induced platelet activation as well as platelet P-selectin and lysosomal integral membrane protein (LIMP) expression. Hyperglycemia also caused increased plasma von Willebrand factor antigen, von Willebrand factor activity, and urinary 11-dehydro-thromboxane B₂ (a measure of thromboxane A₂ production). These changes were not seen in the euglycemic state.

If hyperglycemia-induced platelet hyperreactivity is particularly evident with high–shear stress conditions, as suggested in the above studies, this finding may explain the increased thrombotic events commonly seen in hospitalized patients with diabetes.

Hyperglycemia and inflammation
The connection between acute hyperglycemia and vascular changes likely involves inflammatory changes. Cultured human peripheral blood mononuclear cells (PBMCs), when incubated in high glucose medium (594 mg/dl, 33 mmol/l) for 6 h produce increased levels of IL-6 and tumor necrosis factor (TNF)- (53). TNF- is apparently involved in IL-6 production. Blocking TNF- activity with anti-TNF monoclonal antibody blocks the stimulatory effect of glucose on IL-6 production by these cells. Other in vitro studies suggest that glucose-induced elevations in IL-6, TNF-, and other factors may cause acute inflammation. This inflammatory response to glucose has been seen in adipose tissue, 3T3-L1 adipocyte cell lines, vascular smooth muscle cells, PBMCs, and other tissues or cell types (55–61).

In humans, moderate elevation of glucose to 270 mg/dl (15 mmol/l) for 5 h has been associated with increased IL-6, IL-18, and TNF- (62). Elevations of these various inflammatory factors have been linked to detrimental vascular effects. For example, TNF- extends the area of necrosis following left anterior descending coronary artery ligation in rabbits (63). In humans, TNF- levels are elevated in the setting of AMI and correlate with severity of cardiac dysfunction (63,64). TNF- may also play a role in some cases of ischemic renal injury and in congestive heart failure (CHF) (57,65). Ischemic preconditioning is associated with decreased postischemic myocardial TNF- production (66). IL-18 has been proposed to destabilize atherosclerotic plaques, leading to acute ischemic syndromes (67).

One of the most commonly demonstrated relationships between hyperglycemia and inflammatory markers is the in vitro induction of the proinflammatory transcriptional factor, nuclear factor (NF)-B by exposure of various cell types to 1–8 days of hyperglycemia (58,59,68–71). In patients with type 1 diabetes, activation of NF-B in PBMCs was positively correlated to HbA_1c level (r = 0.67, P < 0.005) (72). A recent study by Schiefkofer et al. (73) demonstrated in vivo exposure to hyperglycemia (180 mg/dl, 10 mmol/l) for 2 h caused NF-B activation.

Hyperglycemia and endothelial cell dysfunction
One proposed link between hyperglycemia and poor cardiovascular outcomes is the effect of acute hyperglycemia on the vascular endothelium. In addition to serving as a barrier between blood and tissues, vascular endothelial cells play a critical role in overall homeostasis. In the healthy state, the vascular endothelium maintains the vasculature in a quiescent, relaxant, antithrombotic, antioxidant, and antiadhesive state (rev. in 74,75). During illness the vascular endothelium is subject to dysregulation, dysfunction, insufficiency, and failure (76). Endothelial cell dysfunction is linked to increased cellular adhesion, perturbed angiogenesis, increased cell permeability, inflammation, and thrombosis. Commonly, endothelial function is evaluated by measuring endothelial-dependent vasodilatation, looking most often at the brachial artery. Human in vivo studies utilizing this parameter confirm that acute hyperglycemia to the levels commonly seen in the hospital setting (142–300 mg/dl or 7.9–16.7 mmol/l) causes endothelial dysfunction (77–82). Only one study failed to show evidence of endothelial cell dysfunction induced by short-term hyperglycemia (83). The degree of endothelial cell dysfunction after an oral glucose challenge was positively associated with the peak glucose level, ranging from 100 to 300 mg/dl (5.5–16.7 mmol/l) (78,79). Hyperglycemia may directly alter endothelial cell function by promoting chemical inactivation of nitric oxide (84). Other mechanisms include triggering production of reactive oxygen species (ROS) or activating other pathways (rev. in 27). Despite compelling experimental data, studies examining a possible association among hyperglycemia, endothelial function, and outcomes have not to date been done in hospitalized patients.

Hyperglycemia and the brain
Acute hyperglycemia is associated with enhanced neuronal damage following induced brain ischemia (85–98). Exploration of general mechanisms of hyperglycemic damage has used various models of ischemia and various measures of outcomes. Models differ according to transient versus permanent ischemia as well as global versus localized ischemia. There is some indication from animal studies that irreversible ischemia or end arterial ischemia is not affected by hyperglycemia (87,99,100). The major portion of the brain that is sensitive to injury from hyperglycemia is the ischemic penumbra. This area surrounds the ischemic core. During evolution of the stroke, the ischemic penumbra may evolve into infarcted tissue or may recover as viable tissue (87,99,101,102). One of the primary mechanistic links between hyperglycemia and enhanced cerebral ischemic damage appears to be increased tissue acidosis and lactate levels associated with elevated glucose concentrations. This has been shown in various animal models with rare exception (94,102–108). Lactate has been associated with damage to neurons, astrocytes, and endothelial cells (104). In humans, Parsons et al. (109) demonstrated that the lactate-to-choline ratio determined by proton magnetic resonance spectroscopy (MRS) had value in predicting clinical outcomes and final infarct size in acute stroke. More recently, the same investigators used this method to demonstrate a positive correlation between glucose elevations and lactate production (110). Through this mechanism, hyperglycemia appears to cause hypoperfused at-risk tissue to progress to infarction.

Animal studies have shown additional association of hyperglycemia with various acute consequences that likely serve as intermediaries of adverse outcomes. For example, hyperglycemia causes accumulation of extracellular glutamate in the neocortex. Increased glutamate levels predict ensuing neuronal damage (95). A unique hippocampal cell culture model of "in vitro ischemia" demonstrated a similar relationship between hyperglycemia, glutamate activity, and increased intracellular calcium with enhanced cell death (98). Hyperglycemia has also been associated with DNA fragmentation, disruption of the blood-brain barrier, more rapid repolarization in severely hypoperfused penumbral tissue, ß-amyloid precursor protein elevation, as well as elevated superoxide levels in neuronal tissue (111–115).

Many of the same factors noted earlier, linking hyperglycemia to cardiovascular event outcomes, likely contribute to acute cerebrovascular outcomes. Specifically, in brain ischemia models exposed to hyperglycemia, hydroxyl free radicals are elevated and positively correlate with tissue damage (116). Likewise, antioxidants have a neuroprotective effect (117). Elevated glucose levels have also been linked to inhibition of nitric oxide generation, increased IL-6 mRNA, decreased cerebral blood flow, and evidence of vascular endothelial injury (90,92,118,119). Again, the composite of evidence supports scientifically viable mechanisms of central nervous system injury from hyperglycemia in the acute setting.

Hyperglycemia and oxidative stress
Oxidative stress occurs when the formation of ROS exceeds the body’s ability to metabolize them. Attempts to identify a unifying basic mechanism for many of the diverse effects of acute hyperglycemia point to the ability of hyperglycemia to produce oxidative stress (58,69,120). Acute experimental hyperglycemia to levels commonly seen in hospitalized patients induces ROS generation. Endothelial cells exposed to hyperglycemia in vitro switch from producing nitric oxide to superoxide anion (84). Increased ROS generation causes activation of transcriptional factors, growth factors, and secondary mediators. Through direct tissue injury or via activation of these secondary mediators, hyperglycemia-induced oxidative stress causes cell and tissue injury (58,59,62,70,72,74,80,121–127). In all cases studied, abnormalities were reversed by antioxidants or by restoring euglycemia (58,59,70,72,80,122,127).

Is insulin per se therapeutic?
Two large, well-done prospective studies support the relationship between insulin therapy and improved inpatient outcomes (2,128). The prevalent assumption has been that insulin attained this benefit indirectly by controlling blood glucose. However, a growing body of literature raises the question of whether insulin may have direct beneficial effects independent of its effect on blood glucose (121,129–132).

Multiple studies suggest cardiac and neurological benefits of glucose-insulin-potassium (GIK) infusions (133–154). One may propose that such therapy supports a direct effect of the insulin since blood glucose control is not the goal of these infusions and the benefits have been displayed in normal humans and animals. Although the direct effect of insulin may play a significant role in benefits of GIK therapy, other metabolic factors are likely to be major contributors to the mechanism of this therapy. The theory promoting this form of therapy centers on the imbalance between low glycolytic substrate in the hypoperfused tissue and elevated free fatty acids (FFAs) mobilized through catecholamine-induced lipolysis (41,155–159). In ischemic cardiac tissue, there is decreased ATP and increased inorganic phosphate production (148,156,159). Adequate glycolytic ATP is important for maintaining cellular membranes, myocardial contractility, and avoidance of the negative effect of fatty acids as substrate for ischemic myocardium (155,158–161). FFAs are associated with cardiac sympathetic overactivity, worsened ischemic damage, and possibly arrhythmias. Accordingly, using a model of 60-min low-flow ischemia followed by 30 min of reperfusion in rat hearts, investigators have demonstrated the ability of GIK infusion to increase glycolysis, decrease ATP depletion, and maintain lower inorganic phosphate levels in the affected tissue (148). These effects extrapolated to improved systolic and diastolic function in this model. In other animal models, GIK infusion in improved left ventricular contractility, decreased tissue acidosis, and decreased infarct size (144,152,162).

In small studies of individuals with or without diabetes undergoing coronary artery bypass surgery, GIK therapy is associated with shorter length of intubation and shorter length of stay (142,143,163). As therapy for patients with an AMI, GIK therapy is associated with the expected decrease in FFAs, decreased heart failure, and a suggestion of improved short-term survival (133–135,139,164). In follow-up of a first myocardial infarction (MI), individuals who received GIK therapy reported better stress tolerance, an elevated ischemic threshold, and improved myocardial perfusion by 99 m-Tc-tetrofosmin–gated single photon emission computed tomography (SPECT) compared with those receiving saline infusion (149). These studies of classic GIK therapy with emphasis on glucose delivery have been small and more suggestive than conclusive. No large, randomized, placebo-controlled studies have been reported. Even less information is available regarding the use of GIK therapy in strokes or cerebral ischemia. Limited studies have demonstrated safety of GIK therapy in the acute stroke patient, with a trend to reduced mortality, and a decrease in blood pressure (147,150). However, the data are clearly inadequate to make any conclusions of benefit.

Beyond GIK therapy, one finds increasing support for a direct effect of insulin on many of the abnormalities that underlie inpatient complications. Insulin treatment, ranging in duration from brief euglycemic-hyperinsulinemic clamps to 2 months of ongoing therapy, improves endothelial cell function (165–171). There are rare exceptions to this finding (172). Insulin also has vasodilatory properties in the internal carotid and femoral arteries (165,167). The vasodilatory properties of insulin appear to be mediated at least in part by stimulating nitric oxide release (165,166). Aortic endothelial cell cultures have also demonstrated insulin-induced nitric oxide synthase activity and increased nitric oxide levels (172,173). In a rat model, insulin inhibits the upregulation of the endothelial adhesion molecule P-selectin expression seen as a consequence of elevated glucose levels (121).

Insulin infusion has anti-inflammatory effects (129,174,175). In a large study of intensive insulin infusion therapy in the intensive care unit, investigators found decreased C-reactive protein (CRP) levels in insulin-treated patients (176). Cell culture studies have shown the ability of insulin incubation to reduce oxidative stress and its associated apoptosis in cardiomyocytes (177). In addition to the induction of endothelial-derived nitric oxide, human aorta cell and human mononuclear cell culture studies have shown dose-dependent reductions in ROS, the proinflammatory transcription factor NF-B, intercellular adhesion molecule (ICAM)-1, and the chemokine monocyte chemoattractant protein (MCP)-1 (173,178–180). Insulin also inhibits the production TNF- and the proinflammatory transcription factor early growth response gene (Egr)-1 (181). These effects suggest a general anti-inflammatory action of insulin.

In an animal model of myocardial ischemia, insulin given early in the acute insult reduced infarct size by >45% (182). This effect was mediated through the Akt and p70s6 kinase–dependent signaling pathway and was independent of glucose. There is preliminary evidence of insulin’s ability to improve pulmonary diffusion and CHF in humans (183). Studies have also suggested that insulin protects from ischemic damage in the brain, kidney, and lung (184–186). In catabolic states such as severe burns, hyperglycemia promotes muscle catabolism, while exogenous insulin produces an anabolic effect (187). Insulin therapy has also been associated with an improved fibrinolytic profile in patients at the time of acute coronary events, reducing fibrinogen and PAI-1 levels (132). Finally, insulin infusion reduces collagen-induced platelet aggregation and several other parameters of platelet activity in humans. This effect was attenuated in obese individuals (188).

In summary, the overwhelming balance of evidence supports a beneficial effect of insulin in the acute setting. Whether these benefits are the result of a direct pharmacologic effect of insulin or represent an indirect effect by improved glucose control, enhanced glycolysis, or suppressed lipolysis is more difficult to determine. Studies in cell cultures control for glucose but have other physiologic limitations. Nevertheless, the data are provocative and certainly leave the impression that insulin therapy in the hospital has significant potential for benefit. Considering the numerous contraindications to the use of oral agents in the hospital, insulin is the clear choice for glucose manipulation in the hospitalized patient.

Potential relationships between metabolic stress, hyperglycemia, hypoinsulinemia, and poor hospital outcomes
To explain the dual role of glucose and insulin on hospital outcomes, Levetan and Magee (189) proposed the following relationships. Elevations in counterregularory hormones accelerate catabolism, hepatic gluconeogenesis, and lipolysis. These events elevate blood glucose, FFAs, ketones, and lactate. The rise in glucose blunts insulin secretion via the mechanism of glucose toxicity (190), resulting in further hyperglycemia. The vicious cycle of stress-induced hyperglycemia and hypoinsulinemia subsequently causes maladaptive responses in immune function, fuel production, and synthesis of mediators that cause further tissue and organ dysfunction (Fig. 1). Thus, the combination of hyperglycemia and relative hypoinsulinemia is mechanistically positioned to provide a plausible explanation for the poor hospital outcomes seen in observational studies.

View larger version (25K): [in this window] [in a new window]   Figure 1— Link between hyperglycemia and poor hospital outcomes. Hyperglycemia and relative insulin deficiency caused by metabolic stress triggers immune dysfunction, release of fuel substrates, and other mediators such as ROS. Tissue and organ injury occur via the combined insults of infection, direct fuel-mediated injury, and oxidative stress and other downstream mediators. See text for details.

	WHAT ARE THE TARGET BLOOD GLUCOSE LEVELS FOR THE HOSPITALIZED PATIENT?

TOP INTRODUCTION What is the prevalence... WHAT IS THE LINK... WHAT ARE THE TARGET... HOW ARE TARGET BLOOD... HOW CAN SYSTEM DESIGN... WHAT IS THE ROLE... WHAT IS THE ROLE... WHAT IS THE ROLE... IS IMPROVED DIABETES CARE... SUGGESTIONS FOR FUTURE RESEARCH CONCLUSIONS References

To make the case for defining targets for glucose control in hospital settings, it is necessary to examine the literature on both short- and long-term mortality. Data regarding diabetes and hyperglycemia-associated morbidity have emerged from specific clinical settings. These data include infection rates, need for intensive care unit admission, functional recovery, and health economic outcomes such as length of stay and hospital charges. For their practical implications and for the purpose of this review, literature on the association of blood glucose level with outcomes will be grouped into the medical and surgical areas in which studies have been reported as follows: general medicine and surgery, cardiovascular disease (CVD) and critical care, and neurologic disorders (Table 1).

Umpierrez et al. (1) reviewed 1,886 admissions for the presence of hyperglycemia (fasting blood glucose 126 mg/dl or random blood glucose 200 mg/dl on two or more occasions). Care was provided on general medicine and surgery units. Among these subjects, there were 223 patients (12%) with new hyperglycemia and 495 (26%) with known diabetes. Admission blood glucose for the normoglycemic group was 108 ± 10.8 mg/dl (6 ± 0.6 mmol/l); for the new hyperglycemia group, it was 189 ± 18 mg/dl (10.5 ± 1 mmol/l); and for known diabetes, it was 230.4 ± 18 mg/dl (12.8 ± 1 mmol/l). After adjusting for confounding factors, patients with new hyperglycemia had an 18-fold increased inhospital mortality and patients with known diabetes had a 2.7-fold increased inhospital mortality compared with normoglycemic patients. Length of stay was higher for the new hyperglycemia group compared with normoglycemic and known diabetic patients (9 ± 0.7, 4.5 ± 0.1, and 5.5 ± 0.2 days, respectively, P < 0.001). Both the new hyperglycemia and known diabetic patients were more likely to require intensive care unit (ICU) care when compared with normoglycemic subjects (29 vs. 14 vs. 9%, respectively, P < 0.01) and were more likely to require transitional or nursing home care. There was a trend toward a higher rate of infections and neurologic events in the two groups with hyperglycemia (1). It is likely that the "new" hyperglycemic patients in this report were a heterogeneous population made up of patients with unrecognized diabetes, prediabetes, and/or stress hyperglycemia secondary to severe illness.

The observational data from these two studies suggest that hyperglycemia from any etiology in the hospital on general medicine and surgery services is a significant predictor of poor outcomes, relative to outcomes for normoglycemic subjects. Patients with hyperglycemia, with or without diabetes, had increased risk of inhospital mortality, postoperative infections, neurologic events, intensive care unit admission and increased length of stay. The Pomposelli article (191) found that a blood glucose level of 220 mg/dl (12.2mmol/l) separated patients for risk of infection. Data from the Umpierrez study (1) and most of the literature from other disciplines, as outlined elsewhere in this review, would suggest a lower threshold for optimal hospital outcomes.

Evidence for a blood glucose threshold.
The Umpierrez study demonstrated better outcomes for patients with fasting and admission blood glucose <126 mg/dl (7 mmol/l) and all random blood glucose levels <200 mg/dl (11.1 mmol/l). Because the Pomposelli and Umpierrez studies are observational, a causal link between hyperglycemia and poor outcomes cannot be established.

CVD and critical care
Numerous articles contain data linking blood glucose level to outcomes in AMI and cardiac surgery, for which patients receive care predominantly in the ICU setting. The majority of these trials are observational, but the literature also includes several large, landmark interventional studies that have markedly increased awareness of the need for targeted glycemic control in these settings.

AMI.
In 2000, Capes et al. (192) reviewed blood glucose levels and mortality in the setting of AMI from 15 previously published studies and performed a metaanalysis of the results to compare the RR of in-hospital mortality and CHF in both hyper- and normoglycemic patients with and without diabetes. In subjects without known diabetes whose admission blood glucose was 109.8 mg/dl (6.1 mmol/l), the RR for in-hospital mortality was increased significantly (RR 3.9, 95% CI 2.9–5.4). When diabetes was present and admission glucose was 180 mg/dl (10 mmol/l), risk of death was moderately increased (1.7, 1.2–2.4) compared with patients who had diabetes but no hyperglycemia on admission.

Bolk et al. (193) analyzed admission blood glucose values in 336 prospective, consecutive patients with AMI with average follow-up to 14.2 months. Twelve percent of this cohort had previously diagnosed diabetes. Multivariate analysis revealed an independent association of admission blood glucose and mortality. The 1-year mortality rate was 19.3% in subjects with admission plasma glucose <100.8 mg/dl (5.6 mmol/l) and rose to 44% with plasma glucose 199.8 mg/dl (11 mmol/l). Mortality was higher in patients with known diabetes than in those without diabetes (40 vs. 16%, P < 0.05.).

From the frequently cited Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study, Malmberg and colleagues (128,194) have published the results of a prospective interventional trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with AMI, reporting mortality at 1 year. Of 620 persons with diabetes and AMI, 306 were randomized to intensive treatment with insulin infusion therapy, followed by a multishot insulin regimen for 3 or more months. Patients randomized to conventional therapy received standard diabetes therapy and did not receive insulin unless clinically indicated. Baseline blood glucose values were similar in the intensive treatment group, 277.2 ± 73.8 mg/dl (15.4 ± 4.1 mmol/l), and the conventional treatment group, 282.6 ± 75.6 mg/dl (15.7 ± 4.2 mmol/l). Blood glucose levels decreased in the first 24 h in the intervention group to 172.8 ± 59.4 mg/dl (9.6 ± 3.3 mmol/l; P < 0.001 vs. conventional treatment), whereas blood glucose declined to 210.6 ± 73.8 mg/dl (11.7 ± 4.1mmol/l). The blood glucose range for each group was wide: 116.4–232.2 mg/dl (6.5–12.9 mmol/l) in the intensive treatment group and 136.8–284.4 mg/dl (7.6–15.8 mmol/l) in the conventional treatment group. Mortality at 1 year in the intensive treatment group was 18.6%, and for the conventional treatment group it was 26.1%, a 29% reduction in mortality for the intervention arm (P = 0.027). At 3.4 (1.6–5.6) years follow-up, mortality was 33% in the intensive treatment group and 44% in the conventional treatment group (RR 0.72, 95% CI 0.55–0.92; P = 0.011), consistent with persistent reduction in mortality. The benefit of intensive control was most pronounced in 272 patients who had not had prior insulin therapy and had a less risk for CVD (0.49, 0.30–0.80; P = 0.004).

In the DIGAMI study, insulin infusion in AMI followed by intensive subcutaneous insulin therapy for 3 or more months improved long-term survival, with a benefit that extends to at least 3.4 years (128). An absolute reduction in mortality of 11% was observed, meaning that one life was saved for every nine treated patients. The observation that higher mean glucose levels were associated with increased mortality between groups of patients with diabetes would suggest that stress hyperglycemia plays an independent role in the determination of outcomes. In addition, it is of interest that in spite of the observation that blood glucose levels between the intensive and conventional treatment groups were similar, a significant difference in mortality between these groups was found. A relatively modest reduction in blood glucose in the intensive treatment group compared with the conventional treatment group produced a statistically significant improvement in mortality. This suggests the possibility that the beneficial effect of improved control may be mediated through mechanisms other than a direct effect of hyperglycemia, such as a direct effect of insulin.

Evidence for a blood glucose threshold for increased mortality in AMI.

• The metaanalysis of Capes et al. (192) reported a blood glucose threshold of >109.8 mg/dl (6.1 mmol/l) for patients without diabetes and >180 mg/dl (10 mmol/l) for known diabetes.
  
• The observational study of Bolk et al. (193) identified threshold blood glucoses, divided by World Health Organization (WHO) classification criteria, with mortality risk of 19.3% for normoglycemia (blood glucose <100.8 mg/dl [5.6 mmol/l]), which rose progressively to 44% for blood glucose >199.8 mg/dl (11 mmol/l).
  
• In the DIGAMI study, mean blood glucose in the intensive insulin intervention arm was 172.8 mg/dl (9.6 mmol/l), where lower mortality risk was observed. In the conventional treatment arm, mean blood glucose was 210.6 mg/dl (11.7 mmol/l). The broad range of blood glucose levels within each arm limits the ability to define specific blood glucose target thresholds.
  

Cardiac surgery.
Attainment of targeted glucose control in the setting of cardiac surgery is associated with reduced mortality and risk of deep sternal wound infections. Furnary and colleagues (196,197) treated cardiac surgery patients with diabetes with either subcutaneous insulin (years 1987–1991) or with intravenous insulin (years 1992–2003) in the perioperative period. From 1991–1998, the target glucose range was 150 -200 mg/dl (8.3–11.1 mmol/l); in 1999 it was dropped to 125–175 mg/dl (6.9–9.7 mmol/l), and in 2001 it was again lowered to 100–150 mg/dl (5.5–8.3 mmol/l). Following implementation of the protocol in 1991, the authors reported a decrease in blood glucose level for the first 2 days after surgery and a concomitant decrease in the proportion of patients with deep wound infections, from 2.4% (24 of 990) to 1.5% (5 of 595) (P < 0.02) (198). A recent analysis or the cohort found a positive correlation between the average postoperative glucose level and mortality, with the lowest mortality in patients with average postoperative blood glucose <150 mg/dl (8.3 mmol/l) (197).

Golden et al. (199) performed a nonconcurrent prospective cohort chart review study in cardiac surgery patients with diabetes (n = 411). Perioperative glucose control was assessed by the mean of six capillary blood glucose measures performed during the first 36 h following surgery. The overall infectious complication rate was 24.3%. After adjustment for variables, patients with higher mean capillary glucose readings were at increased risk of developing infections. Compared with subjects in the lowest quartile for blood glucose, those in quartiles 2–4 were at progressively increased risk for infection (RR 1.17, 1.86, and 1.78 for quartiles 2, 3, and 4, respectively, P = 0.05 for trend). These data support the concept that perioperative hyperglycemia is an independent predictor of infection in patients with diabetes.

Critical care.
Van den Berghe et al. (200) performed a prospective, randomized controlled study of 1,548 adults who were admitted to a surgical intensive care unit and were receiving mechanical ventilation. Reasons for ICU admission were cardiac surgery (60%) and noncardiac indications, including neurologic disease (cerebral trauma or brain surgery), other thoracic surgery, abdominal surgery or peritonitis, vascular surgery, multiple trauma, or burns and transplant (4–9% each group). Patients were randomized to receive intensive insulin therapy (IIT) to maintain target blood glucose in the 80–110 mg/dl (4.4–6.1) range or conventional therapy to maintain target blood glucose between 180 and 200 mg/dl (10–11.1 mmol/l). Insulin infusion was initiated in the conventional treatment group only if blood glucose exceeded 215 mg/dl (11.9 mmol/l), and the infusion was adjusted to maintain the blood glucose level between 180 and 200 mg/dl (10.0 and 11.1 mmol/l). After the patients left the ICU they received standard care in the hospital with a target blood glucose of 180 and 200 mg/dl (10.0 and 11.1 mmol/l).

Ninety-nine percent of patients in the IIT group received insulin infusion, as compared with 39% of the patients in the conventional treatment group. In the IIT arm, blood glucose levels were 103 ± 19 mg/dl (5.7 ± 1.1 mmol/l) and in conventional treatment 153 ± 33 mg/dl (8.5 ± 1.8 mmol/l). IIT reduced mortality during ICU care from 8.0% with conventional treatment to 4.6% (P < 0.04). The benefit of IIT was attributable to its effect on mortality among patients who remained in the unit for more than 5 days (20.2% with conventional treatment vs. 10.6% with IIT, P = 0.005). IIT also reduced overall inhospital mortality by 34% (2). In a subsequent analysis, Van den Berghe (200) demonstrated that for each 20 mg/dl (1.1 mmol/l), glucose was elevated >100 mg/dl (5.5 mmol/l) and the risk of ICU death increased by 30% (P < 0.0001). Daily insulin dose (per 10 units added) was found as a positive rather than negative risk factor, suggesting that it was not the amount of insulin that produced the observed reduction in mortality. Hospital and ICU survival were linearly associated with ICU glucose levels, with the highest survival rates occurring in patients achieving an average blood glucose <110 mg/dl (6.1 mmol). An improvement in outcomes was found in patients who had prior diabetes as well as in those who had no history of diabetes.

Evidence for a blood glucose threshold in cardiac surgery and critical care.

• Furnary et al. (196) and Zerr et al. (198) identified a reduction in mortality throughout the blood glucose spectrum with the lowest mortality in patients with blood glucose <150 mg/dl (8.3 mmol/l).
  
• Van den Berghe et al. (2), using intensive intravenous insulin therapy, reported a 45% reduction in ICU mortality with a mean blood glucose of 103 mg/dl (5.7 mmol/l), as compared with the conventional treatment arm, where mean blood glucose was 153 mg/dl (8.5 mmol/l) in a mixed group of patients with and without diabetes.
  

Acute neurologic illness and stroke.
In the setting of acute neurologic illness, stroke, and head injury, data support a weak association between hyperglycemia and increased mortality and are scanty for patients with known diabetes. In these clinical settings, available data, with one exception, are observational. Capes et al. (96) reported on mortality after stroke in relation to admission glucose level from 26 studies, published between 1996 and 2000, where RRs for prespecified outcomes were reported or could be calculated. After ischemic stroke, admission glucose level >110–126 mg/dl (>6.1–7 mmol/l) was associated with increased risk of inhospital or 30-day mortality in patients without diabetes only (RR 3.8, 95% CI 2.32–4.64). Stroke survivors without diabetes and blood glucose >121–144 mg/dl (6.7–8 mmol/l) had an RR of 1.41 (1.16–1.73) for poor functional recovery. After hemorrhagic stroke, admission hyperglycemia was not associated with higher mortality in either the diabetes or nondiabetes groups.

Several of the studies that were included in the analysis of Capes et al. (96) contain additional data that support an association between blood glucose and outcomes in stroke. In the Acute Stroke Treatment Trial (TOAST), a controlled, randomized study of the efficacy of a low–molecular weight heparinoid in acute ischemic stroke (n = 1,259), neurologic improvement at 3 months (a decrease by four or more points on the National Institutes of Health [NIH] Stroke Scale or a final score of 0) was seen in 63% of subjects. Those with improvement had a mean admission glucose of 144 ± 68 mg/dl, and those without improvement had blood glucose of 160 ± 84 mg/dl. In multivariate analysis, as admission blood glucose increased, the odds for neurologic improvement decreased with an OR of 0.76 per 100 mg/dl increase in admission glucose (95% CI 0.61–0.95, P = 0.01) (201). Subgroup analysis for patients with or without a history of diabetes was not done. Pulsinelli et al. (202) reported worse outcomes for both patients with diabetes and hyperglycemic patients without an established diagnosis of diabetes compared with those who were normoglycemic. Stroke-related deficits were more severe when admission glucose values were >120 mg/dl (6.7 mmol/l). Only 43% of the patients with an admission glucose value of >120 mg/dl were able to return to work, whereas 76% of patients with lower glucose values regained employment.

Demchuk et al. (203) studied the effect of admission glucose level and risk for intracerebral hemorrhage into an infarct when treatment with recombinant tissue plasminogen activator was given to 138 patients presenting with stroke. Twenty-three percent of the cohort had known diabetes. The authors reported admission blood glucose and/or history of diabetes as the only independent predictors of hemorrhage. Kiers et al. (204) prospectively studied 176 sequential acute stroke patients and grouped them by admission blood glucose level, HbA_1c level, and history of diabetes. Threshold blood glucose for euglycemia was defined as fasting blood glucose <140 mg/dl (7.8 mmol/l). The authors divided patients into one of four groups: euglycemia with no history of diabetes, patients with "stress hyperglycemia" (blood glucose >140 mg/dl, 7.8 mmol/l, and HbA_1c <8%), newly diagnosed diabetes (blood glucose >140 mg/dl, 7.8 mmol/l, and HbA_1c >8%), and known diabetes. No difference was found in the type or site of stroke among the four groups. Compared with the euglycemic, nondiabetic patients, mortality was increased in all three groups of hyperglycemic patients.

Williams et al. (205) reported on the association of hyperglycemia and outcomes in a group of 656 acute stroke patients. Fifty-two percent of the cohort had a known history of diabetes. Hyperglycemia, defined as a random blood glucose 130 mg/dl (7.22 mmol/l), was present in 40% of patients at the time of admission. Hyperglycemia was an independent predictor of death at 30 days (RR 1.87) and at 1 year (RR 1.75) (both P 0.01). Other outcomes that were significantly correlated with hyperglycemia, when compared with normal blood glucose, were length of stay (7 vs. 6 days, P = 0.015) and charges ($6,611 vs. $5,262, P < 0.001).

Recently, Parsons et al. (110) reported a study of magnetic resonance imaging (MRI) and MRS in acute stroke. Sixty-three acute stroke patients were prospectively evaluated with serial diffusion-weighted and perfusion-weighted MRI and acute blood glucose measurements. Median acute blood glucose was 133.2 mg/dl (7.4 mmol/l), range 104.4–172.8 mg/dl (5.8–9.6 mmol/l). A doubling of blood glucose from 90 to 180 mg/dl (5-10 mmol/l) led to a 60% reduction in penumbral salvage and a 56 cm³ increase in final infarct size. For patients with acute perfusion-diffusion mismatch, acute hyperglycemia was correlated with reduced salvage of mismatch tissue from infarction, greater final infarct size, and worse functional outcome, independent of baseline stroke severity, lesion size, and diabetes status. Furthermore, higher acute blood glucose in patients with perfusion-diffusion mismatch was associated with greater acute-subacute lactate production, which, in turn, was independently associated with reduced salvage of mismatch tissue. Acute hyperglycemia increases brain lactate production and facilitates conversion of hypoperfused at-risk tissue into infarction, which may adversely affect stroke outcome.

These numerous observational studies further support the need for randomized controlled trials that aggressively target glucose control in acute stroke. To date, there is just one report of a treat-to-target intervention in stroke patients. The Glucose Insulin in Stroke Trial (GIST) examined the safety of GIK infusion in treating to a target glucose of 72–126 mg/dl (4–7 mmol/l). Lowering plasma glucose levels was found to be without significant risk of hypoglycemia or excess mortality in patients with acute stroke and mild-to-moderate hyperglycemia (206). No data on functional recovery were reported. While it is promising that these investigators were able to lower plasma glucose without increasing risk of hypoglycemia or mortality for stroke patients, until further studies test the effectiveness of this approach and possible impact on outcomes, it cannot be considered standard practice.

Hyperglycemia is associated with worsened outcomes in patients with acute stroke and head injury, as evidenced by the large number of observational studies in the literature. It seems likely that the hyperglycemia associated with these acute neurologic conditions results from the effects of stress and release of insulin counterregulatory hormones. The elevated blood glucose may well be a marker of the level of stress the patient is experiencing. The hyperglycemia can be marked in these patients. Studies are needed to assess the role of antihyperglycemic pharmacotherapy in these settings for possible impact on outcomes. Clinical trials to investigate the impact of targeted glycemic control on outcomes in patients with stress hyperglycemia and/or known diabetes and acute neurologic illness are needed.

Evidence for a blood glucose threshold in acute neurologic disorders.
Observational studies suggest a correlation between blood glucose level, mortality, morbidity, and health outcomes in patients with stroke.

• Capes et al.’s (96) metaanalysis identified an admission blood glucose >110 mg/dl (6.1 mmol/l) for increased mortality for acute stroke.
  
• Studies by Pulsinelli, Jorgenson, and Weir et al. (202) identified an admission blood glucose >120 mg/dl (6.67 mmol/l), 108 mg/dl (6 mmol/l), and 144 mg/dl (8 mmol/l), respectively, for increased severity ad mortality for acute stroke.
  
• Williams et al. (205) reported a threshold admission blood glucose 130 mg/dl (7.2 mmol/l) for increased mortality, length of stay, and charges in acute stroke.
  
• Scott et al. (206) demonstrated acceptable hypoglycemia risk and no excess 4-week mortality with glucose-insulin infusion treatment targeted to blood glucose range of 72–126 mg/dl (4–7 mmol/l) in acute stroke.
  
• Parsons et al. (110) reported that a doubling of blood glucose from 90 to 180 mg/dl (5–10 mmol/l) was associated with 60% worsening of penumbral salvage and a 56-cm³ increase in infarct size.
  

	HOW ARE TARGET BLOOD GLUCOSE LEVELS BEST ACHIEVED IN THE HOSPITAL?

TOP INTRODUCTION What is the prevalence... WHAT IS THE LINK... WHAT ARE THE TARGET... HOW ARE TARGET BLOOD... HOW CAN SYSTEM DESIGN... WHAT IS THE ROLE... WHAT IS THE ROLE... WHAT IS THE ROLE... IS IMPROVED DIABETES CARE... SUGGESTIONS FOR FUTURE RESEARCH CONCLUSIONS References

 
Role of oral diabetes agents
No large studies have investigated the potential roles of various oral agents on outcomes in hospitalized patients with diabetes. A number of observational studies have commented on the outcomes of patients treated as outpatients with diet alone, oral agents, or insulin. However, the results are variable and the methods cannot account for patient characteristics that would influence clinician selection of the various therapies in the hospital setting. Of the three primary categories of oral agents, secretagogues (sulfonylureas and meglitinides), biguanides, and thiazolidinediones, none have been systematically studied for inpatient use. However, all three groups have characteristics that could impact acute care.

Sulfonylureas
Concern about inpatient use of sulfonylureas centers on vascular effects (207,208). Over 30 years ago the report of the University Group Diabetes Program proposed increased cardiovascular events in patients treated with sulfonylureas (209). This report resulted in an ongoing labeling caution for sulfonylureas and heart disease, although the findings have been questioned and have had very limited influence on prescribing habits. Residual fears seemingly were allayed with the findings of the U.K. Prospective Diabetes Study (UKPDS) (210). This large prospective trial did not find any evidence of increased frequency of MI among individuals treated with sulfonylureas. Rather, the trend was in the direction of reduced events. However, questions remain. For instance, it is possible that control of hyperglycemia by any means reduces the frequency of vascular events to a greater extent than any effect sulfonylureas may have to increase vascular events. A variety of studies have served to fuel continued controversy.

Ischemic preconditioning appears to be an adaptive, protective mechanism serving to reduce ischemic injury in humans (211,212). Sulfonylureas inhibit ATP-sensitive potassium channels, resulting in cell membrane depolarization, elevation of intracellular calcium, and cellular response (213,214). This mechanism may inhibit ischemic preconditioning (215–217). Various methods evaluating cardiac ischemic preconditioning have been used to compare certain of the available sulfonylureas. For example, using isolated rabbit hearts, researchers found that glyburide but not glimepiride reversed the beneficial effects of ischemic preconditioning and diazoxide in reducing infarct size (218). Other studies using similar animal heart models or cell cultures have found differences among the sulfonylureas, usually showing glyburide to be potentially more harmful than other agents studied (219–222). A unique, double-blind, placebo-controlled study using acute balloon occlusion of high-grade coronary stenoses in humans looked at the relative effects of intravenously administered placebo, glimepiride, or glyburide (223). The researchers measured mean ST segment shifts and time to angina. The results again demonstrated suppression of the myocardial preconditioning by glyburide but not by glimepiride. In perfused animal heart models, both glimepiride and glyburide also appear to reduce baseline coronary blood flow at high doses (220,224).

Cardiac effects of sulfonylureas have also been compared with other classes of oral diabetes medications. In individuals with type 2 diabetes, investigators found that glyburide increased QT dispersion (225). This effect, proposed to reflect risk for arrhythmias, was measured after 2 months of therapy with glyburide or metformin. Glyburide also increased QTc, while metformin produced no negative effects. This study is in contradiction to the conclusions of a study using isolated rabbit hearts, where glyburide exerted an antiarrhythmic effect despite repeat evidence that it interfered with postischemic hyperemia (226). There have been few other comparisons of sulfonylureas and metformin with regard to direct cardiac effects. In a study of rat ventricular myocytes, hyperglycemia induced abnormalities of myocyte relaxation. These abnormalities were improved when myocytes were incubated with metformin, but glyburide had no beneficial effect (227). Finally, one experiment recently evaluated the relative functional cardiac effects of glyburide versus insulin (228). In this study of patients with type 2 diabetes, left ventricular function was measured by echocardiography after 12-week treatment periods with each agent, attaining similar metabolic control. Neither treatment influenced resting cardiac function. However, after receiving dipyridamole, glyburide-treated patients experienced decreased left ventricular ejection fraction and increased wall motion score index. Insulin treatment did not produce these deleterious effects on contractility.

Although these various findings using different research models raise questions about potential adverse cardiovascular effects of sulfonylureas in general and glyburide in particular, they do not necessarily extrapolate to clinical relevancy. A series of observational studies have attempted to add to our knowledge about whether any of the negative effects of sulfonylureas impact on vascular events, but they have yielded mixed results. For example, outcomes of direct balloon angioplasty after AMI were evaluated comparing 67 patients taking sulfonylureas with 118 patients on other diabetes therapies (229). Logistic regression found sulfonylurea use to be independently associated with increased hospital mortality. Others have reported similar trends in patients receiving angioplasty (230). A third observational study investigated 636 elderly patients with diabetes (mean age 80 years) and previous MI. The researchers looked for subsequent coronary events, including fatal and nonfatal MI or sudden coronary death (231). They found sulfonylurea therapy to be a predictor of new coronary events compared with insulin or to diet therapy (82 vs. 69 and 70%, respectively). Not enough metformin-treated patients were included to comment statistically on a comparison with sulfonylureas.

Conversely, other observational studies have failed to support a relationship between sulfonylurea use and vascular events. Klaman et al. (232) found no differences in mortality or creatinine kinase (CK) elevations after acute MI in 245 patients with type 2 diabetes when comparing those treated with insulin, those treated with oral agents, or those newly diagnosed. Others have reported a similar lack of association with MI outcomes and sulfonylureas (233–236). In one study, ventricular fibrillation was found to be less associated with sulfonylurea therapy than with gliclazide or insulin (234). Finally, in a related vascular consideration, there was no evidence of increased stroke mortality or severity in patients with type 2 diabetes treated with sulfonylureas versus other therapies (237).

None of the studies looking at sulfonylurea effects on vascular inpatient mortality have been prospective. Investigators have not made attempts to separate out duration of therapy or whether sulfonylureas were continued after presentation to the hospital. The one prospective study looking at treatment after admission for AMI indicated a benefit for insulin therapy over conventional therapy with sulfonylureas, but the improved outcomes were proposed to occur as a benefit of improved glucose control (238). No suggestion was made that sulfonylurea therapy had specific negative effects.

Despite a spectrum of data raising concern about potential adverse effects of sulfonylureas in the inpatient setting, where cardiac or cerebral ischemia is a frequent problem in an at-risk population, there are insufficient data to specifically recommend against the use of sulfonylureas in this setting. However, sulfonylureas have other limitations in the inpatient setting. Their long action and predisposition to hypoglycemia in patients not consuming their normal nutrition serve as relative contraindications to routine use in the hospital for many patients (239). Sulfonylureas do not generally allow rapid dose adjustment to meet the changing inpatient needs. Sulfonylureas also vary in duration of action between individuals and likely vary in the frequency with which they induce hypoglycemia (240).

Metformin
Metformin represents a second agent that individuals are likely to be using as an outpatient, with potential for continuation as an inpatient. There is a suggestion from the UKPDS that metformin may have cardioprotective effects, although the study was not powered to allow for a comparison with sulfonylureas (241).

The major limitation to metformin use in the hospital is a number of specific contraindications to its use, many of which occur in the hospital. All of these contraindications relate to a potentially fatal complication of metformin therapy, lactic acidosis. The most common risk factors for lactic acidosis in metformin-treated patients are cardiac disease, including CHF, hypoperfusion, renal insufficiency, old age, and chronic pulmonary disease (242). In an outpatient setting, using slightly variable criteria, 22–54% of patients treated with metformin have absolute or relative contraindications to its use (242–245). One recent report noted that 27% of patients on metformin in the hospital had at least one contraindication to its use (246). In 41% of these cases, metformin was continued despite the contraindication. This study seemingly underestimates the usual frequency of contraindications since it identified no individuals with CHF, a risk factor that has been frequently noted in many of the outpatient studies. Not surprisingly, a recent review of hospital Medicare data found that 11.2% of patients with concomitant diagnoses of diabetes and CHF were discharged with a prescription of metformin (247).

Recent evidence continues to indicate lactic acidosis is a rare complication, despite the relative frequency of risk factors (248). However, in the hospital,where the risk for hypoxia, hypoperfusion, and renal insufficiency is much higher, it still seems prudent to avoid the use of metformin in most patients. In addition to the risk of lactic acidosis, metformin has added side effects of nausea, diarrhea, and decreased appetite, all of which may be problematic during acute illness in the hospital.

Thiazolidinediones
Although thiazolidinediones have very few acute adverse effects (249,250), they do increase intravascular volume, a particular problem in those predisposed to CHF and potentially a problem for patients with hemodynamic changes related to admission diagnoses (e.g., acute coronary ischemia) or interventions common in hospitalized patients. The same study of Medicare patient hospital data cited above (247) found that 16.1% of patients with diabetes and CHF received a prescription for a thiazolidinedione at the time of discharge. Twenty-four percent of patients with these combined diagnoses received either metformin or a thiazolidinedione, both drugs carrying contraindications in this setting.

Most recently it has been demonstrated that when exposed to high concentrations of rosiglitazone, a monolayer of pulmonary artery endothelial cells will exhibit significantly increased permeability to albumin (251). Although this is a preliminary in vitro study, it raises the possibility of thiazolidinediones causing a direct effect on capillary permeability. This process may be of greater significance in the inpatient setting. On the positive side, thiazoladinediones may have benefits in preventing restenosis of coronary arteries after placement of coronary stents in patients with type 2 diabetes (252). For inpatient glucose control, however, thiazolidinediones are not suitable for initiation in the hospital because the onset of effect, which is mediated through nuclear transcription, is quite slow.

In summary, each of the major classes of oral agents has significant limitations for inpatient use. Additionally, they provide little flexibility or opportunity for titration in a setting where acute changes demand these characteristics. Therefore, insulin, when used properly, may have many advantages in the hospital setting.

Use of insulin
As in the outpatient setting, in the hospital a thorough understanding of normal insulin physiology and the pharmacokinetics of exogenous insulin is essential for providing effective insulin therapy. The inpatient insulin regimen must be matched or tailored to the specific clinical circumstance of the individual patient.

Components of the insulin dose requirement defined physiologically.
In the outpatient setting, it is convenient to think of the insulin dose requirement in physiologic terms as consisting of "basal" and "prandial" needs. In the hospital, nutritional intake is not necessarily provided as discrete meals. The insulin dose requirement may be thought of as consisting of "basal" and "nutritional" needs. The term "nutritional insulin requirement" refers to the amount of insulin necessary to cover intravenous dextrose, TPN, enteral feedings, nutritional supplements administered, or discrete meals. When patients eat discrete meals without receiving other nutritional supplementation, the nutritional insulin requirement is the same as the "prandial" requirement. The term "basal insulin requirement" is used to refer to the amount of exogenous insulin per unit of time necessary to prevent unchecked gluconeogenesis and ketogenesis.

An additional variable that determines total insulin needs in the hospital is an increase in insulin requirement that generally accompanies acute illness. Insulin resistance occurs due to counterregulatory hormone responses to stress (e.g., surgery) and/or illness and the use of corticosteroids, pressors, or other diabetogenic drugs. The net effect of these factors is an increase in insulin requirement, compared with a nonsick population. This proportion of insulin requirement specific to illness is referred to as "illness" or "stress-related" insulin and varies between individuals (Fig. 2).

View larger version (34K): [in this window] [in a new window]   Figure 2— Insulin requirements in health and illness. Components of insulin requirement are divided into basal, prandial or nutritional