Reviews/Commentaries/Position Statements TECHNICAL REVIEW

Management of Diabetes and Hyperglycemia in Hospitals

1 5 STEPHEN CLEMENT MD, CDE REBECCA G. SCHAFER, MS, RD, CDE ● Unrecognized diabetes: hyperglycemia 2 6 SUSAN S. BRAITHWAITE, MD IRL B. HIRSCH, MD (fasting blood glucose Ն126 mg/dl or 3 MICHELLE F. MAGEE, MD, CDE ON BEHALF OF THE DIABETES IN HOSPITALS Ն 4 random blood glucose 200 mg/dl) ANDREW AHMANN, MD WRITING COMMITTEE 1 occurring during hospitalization and ELIZABETH P. SMITH, RN, MS, CANP, CDE confirmed as diabetes after hospitaliza- tion by standard diagnostic criteria, but unrecognized as diabetes by the treat- ing physician during hospitalization. iabetes increases the risk for disor- cemia in hospitals, with particular focus ● Hospital-related hyperglycemia: hyper- ders that predispose individuals to on the issue of glycemic control and its glycemia (fasting blood glucose Ն126 D hospitalization, including coronary possible impact on hospital outcomes. mg/dl or random blood glucose Ն200 artery, cerebrovascular and peripheral The scope of this review encompasses mg/dl) occurring during the hospital- vascular disease, nephropathy, infection, adult nonpregnant patients who do not ization that reverts to normal after hos- and lower-extremity amputations. The have diabetic ketoacidosis or hyperglyce- pital discharge. management of diabetes in the hospital is mic crises. generally considered secondary in impor- For the purposes of this review, the What is the prevalence of diabetes in tance compared with the condition that following terms are defined (adapted hospitals? prompted admission. Recent studies (1,2) from the American Diabetes Association The prevalence of diabetes in hospitalized have focused attention to the possibility [ADA] Expert Committee on the Diagno- adult patients is not known. In the year that hyperglycemia in the hospital is not sis and Classification of Diabetes Mellitus) 2000, 12.4% of hospital discharges in the necessarily a benign condition and that (3): U.S. listed diabetes as a diagnosis. The aggressive treatment of diabetes and hy- average length of stay was 5.4 days (4). perglycemia results in reduced mortality ● Medical history of diabetes: diabetes Diabetes was the principal diagnosis in and morbidity. The purpose of this tech- has been previously diagnosed and ac- only 8% of these hospitalizations. The ac- nical review is to evaluate the evidence knowledged by the patient’s treating curacy of using hospital discharge diag- relating to the management of hypergly- physician. nosis codes for identifying patients with ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● previously diagnosed diabetes has been From the 1Georgetown University Hospital, Washington, DC; the 2University of North Carolina, Chapel Hill, questioned. Discharge diagnosis codes North Carolina; 3Medstar Research Institute at Washington Hospital Center, Washington, DC; the 4Oregon may underestimate the true prevalence of 5 Health and Science University, Portland, Oregon; the VA Medical Center, Bay Pines, Florida; and the diabetes in hospitalized patients by as 6University of Washington, Seattle, Washington. Address correspondence and reprint requests to Dr. Stephen Clement, MD, Georgetown University much as 40% (5,6). In addition to having Hospital, Department of Endocrinology, Bldg. D, Rm. 232, 4000 Reservoir Rd., NW, Washington, DC a medical history of diabetes, patients pre- 20007. E-mail: [email protected].. senting to hospitals may have unrecog- Received and accepted for publication 1 August 2003. nized diabetes or hospital-related S.C. has received honoraria from Aventis and Pfizer. S.S.B. has received honoraria from Aventis and research support from BMS. M.F.M. has been on advisory panels for Aventis; has received honoraria from hyperglycemia. Umpierrez et al. (1) re- Aventis, Pfizer, Bristol Myers Squibb, Takeda, and Lilly; and has received grant support from Aventis, Pfizer, ported a 26% prevalence of known diabe- Lilly, Takeda, Novo Nordisk, Bayer, GlaxoSmithKline, and Hewlett Packard. A.A. has received honoraria tes in hospitalized patients in a from Aventis, Bayer, BMS, GlaxoSmithKline, Johnson & Johnson, Lilly, Novo Nordisk, Pfizer, and Takeda community teaching hospital. An addi- and research support from Aventis, BMS, GlaxoSmithKline, Johnson & Johnson, Lilly, Novo Nordisk, Pfizer, tional 12% of patients had unrecognized Roche, and Takeda. E.P.S. holds stock in Aventis. I.B.H. has received consulting fees from Eli Lilly, Aventis, Novo Nordisk, and Becton Dickinson and grant support from Novo Nordisk. diabetes or hospital-related hyperglyce- Additional information for this article can be found in two online appendixes at http:// mia as defined above. Levetan et al. (6) care.diabetesjournals.org. reported a 13% prevalence of laboratory- Abbreviations: ADA, American Diabetes Association; AMI, acute myocardial infarction; CDE, certified documented hyperglycemia (blood glu- diabetes educator; CHF, congestive heart failure; CK, creatinine kinase; CQI, continuous quality improve- Ͼ ment; CRP, C-reactive protein; CSII, continuous subcutaneous insulin infusion; CVD, cardiovascular dis- cose 200 mg/dl (11.1 mmol) in 1,034 ease; DIGAMI, Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction; DSME, diabetes consecutively hospitalized adult patients. self-management education; DSWI, deep sternal wound infection; FFA, free fatty acid; GIK, glucose-insulin- Based on hospital chart review, 64% of potassium; ICAM, intercellular adhesion molecule; ICU, intensive care unit; IL, interleukin; IIT, intensive patients with hyperglycemia had preex- insulin therapy; JCAHO, Joint Commission of Accredited Hospital Organization; LIMP, lysosomal integral isting diabetes or were recognized as hav- membrane protein; MCP, monocyte chemoattractant protein; MI, myocardial infarction; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NF, nuclear factor; NPO, nothing by mouth; ing new-onset diabetes during PAI, plasminogen activator inhibitor; PCU, patient care unit; PKC, protein kinase C; PBMC, peripheral blood hospitalization. Thirty-six percent of the mononuclear cell; PMN, polymorphonuclear leukocyte; ROS, reactive oxygen species; TNF, tumor necrosis hyperglycemic patients remained unrec- factor; TPN, total parenteral nutrition; UKPDS, U.K. Prospective Diabetes Study. ognized as having diabetes in the dis- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. charge summary, although diabetes or © 2004 by the American Diabetes Association. “hyperglycemia” was documented in

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 553 Management of diabetes and hyperglycemia in hospitals the progress notes for one-third of these (10,11). From a mechanistic point of superoxide production in isolated human patients. view, the primary problem has been iden- neutrophils (31). Sato and colleagues Norhammar et al. (7) studied 181 tified as phagocyte dysfunction. Studies (32–34) used chemiluminescence to eval- consecutive patients admitted to the cor- have reported diverse defects in neutro- uate neutrophil bactericidal function. The onary care units of two hospitals in Swe- phil and monocyte function, including authors confirmed a relationship between den with acute myocardial infarction adherence, chemotaxis, phagocytosis, hyperglycemia and reduced superoxide (AMI), no diagnosis of diabetes, and a bacterial killing, and respiratory burst formation in neutrophils. This defect was blood glucose Ͻ200 mg/dl (Ͻ11.1 (10–20). Bagdade et al. (14) were among improved after treatment with an aldose mmol/l) on admission. A standard 75-g the first to attach a glucose value to im- reductase inhibitor. This finding suggests glucose tolerance test was done at dis- provement in granulocyte function when that increased activity of the aldose reduc- charge and again 3 months later. The au- they demonstrated significant improve- tase pathway makes a significant contri- thors found a 31% prevalence of diabetes ment in granulocyte adherence as the bution to the incidence of diabetes- at the time of hospital discharge and a mean fasting blood glucose was reduced related bacterial infections. 25% prevalence of diabetes 3 months af- from 293 Ϯ 20 to 198 Ϯ 29 mg/dl Laboratory evidence of the effect of ter discharge in this group with no previ- (16.3–11 mmol/l) in 10 poorly controlled hyperglycemia on the immune system ous diagnosis of diabetes. patients with diabetes. Other investiga- goes beyond the granulocyte. Nonenzy- Using the A1C test may be a valuable tors have demonstrated similar improve- matic glycation of immunoglobulins has case-finding tool for identifying diabetes ments in leukocyte function with been reported (35). Normal individuals in hospitalized patients. Greci et al. (8) treatment of hyperglycemia (17,21–23). exposed to transient glucose elevation reported that an A1C Ͼ6% was 100% In vitro trials attempting to define hyper- show rapid reduction in lymphocytes, in- specific and 57% sensitive for identifying glycemic thresholds found only rough es- cluding all lymphocyte subsets (36). In persons with diabetes in a small cohort of timates that a mean glucose Ͼ200 mg/dl patients with diabetes, hyperglycemia is patients admitted through the emergency (11.1 mmol/l) causes leukocyte dysfunc- similarly associated with reduced T-cell department of one hospital with a random tion (13,14,16,24–26). populations for both CD-4 and CD-8 sub- blood glucose Ն126 mg/dl (7 mmol/l) Alexiewicz et al. (17) demonstrated sets. These abnormalities are reversed and no prior history of diabetes. elevated basal levels of cytosolic calcium when glucose is lowered (37). From the patient’s perspective, 24% in the polymorphonuclear leukocytes In summary, studies evaluating the of adult patients with known diabetes sur- (PMNs) of patients with type 2 diabetes effect of hyperglycemia on the immune veyed in 1989 reported being hospital- relative to control subjects. Elevated cyto- system comprise small groups of normal ized at least once in the previous year (9). solic calcium was associated with reduced individuals, patients with diabetes of var- The risk for hospitalization increased ATP content and impaired phagocytosis. ious duration and types, and animal stud- with age, duration of diabetes, and num- There was a direct correlation between ies. These studies consistently show that ber of diabetes complications. Persons PMN cytosolic calcium and fasting serum hyperglycemia causes immunosuppres- with diabetes reported being hospitalized glucose. These were both inversely pro- sion. Reduction of glucose by a variety of in the previous year three times more fre- portional to phagocytic activity. Glucose means reverses the immune function quently compared with persons without reduction with glyburide resulted in re- defects. diabetes. In summary, the prevalence of duced cytosolic calcium, increased ATP diabetes in hospitalized adults is conser- content, and improved phagocytosis. Hyperglycemia and the vatively estimated at 12.4–25%, depend- Classic microvascular complications cardiovascular system ing on the thoroughness used in of diabetes are caused by alterations in the Acute hyperglycemia has numerous identifying patients. aldose reductase pathway, AGE pathway, effects on the cardiovascular system. Hy- reactive oxygen species pathway, and the perglycemia impairs ischemic precondi- WHAT IS THE LINK protein kinase C (PKC) pathway (rev. in tioning, a protective mechanism for BETWEEN HIGH BLOOD 27). Several of these pathways may con- ischemic insult (38). Concomitantly, in- GLUCOSE AND POOR tribute to immune dysfunction. PKC may farct size increases in the setting of hyper- OUTCOMES? POSSIBLE mediate the effect of hyperglycemia on glycemia. The same investigators MECHANISMS — The mechanism neutrophil dysfunction (28). Liu et al. demonstrated reduced coronary collat- of harm from hyperglycemia on various (29) found that decreased phagocytic ac- eral blood flow in the setting of moder- cells and organ systems has been studied tivity in diabetic mice correlated inversely ately severe hyperglycemia (39). Acute in in vitro systems and animal models. with the formation of AGEs, although a hyperglycemia may induce cardiac myo- This research has centered on the im- direct cause-and-effect relationship was cyte death through apoptosis (40) or by mune system, mediators of inflammation, not proven. Ortmeyer and Mohsenin (30) exaggerating ischemia-reperfusion cellu- vascular responses, and brain cell re- found that hyperglycemia caused im- lar injury (41). sponses. paired superoxide formation along with Other vascular consequences of acute suppressed activation of phospholipase hyperglycemia relevant to inpatient out- Hyperglycemia and immune function D. Reduced superoxide formation has comes include blood pressure changes, The association of hyperglycemia and in- been linked to leukocyte dysfunction. An- catecholamine elevations, platelet abnor- fection has long been recognized, al- other recent study found a link among malities, and electrophysiologic changes. though the overall magnitude of the hyperglycemia, inhibition of glucose-6- Streptozotocin-induced diabetes in rats problem is still somewhat unclear phosphate dehydrogenase, and reduced results in significant hemodynamic

554 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Clement and Associates

ϭ changes as well as QT prolongation (42). If hyperglycemia-induced platelet hy- positively correlated to HbA1c level (r These changes were reversed with correc- perreactivity is particularly evident with 0.67, P Ͻ 0.005) (72). A recent study by tion of hyperglycemia. In humans, high–shear stress conditions, as sug- Schiefkofer et al. (73) demonstrated in Marfella et al. (43) reported increased sys- gested in the above studies, this finding vivo exposure to hyperglycemia (180 mg/ tolic and diastolic blood pressure and in- may explain the increased thrombotic dl, 10 mmol/l) for 2 h caused NF-␬B ac- creased endothelin levels with acute events commonly seen in hospitalized pa- tivation. hyperglycemia in patients with type 2 di- tients with diabetes. abetes. The same researchers also induced Hyperglycemia and endothelial cell acute hyperglycemia (270 mg/dl or 15 Hyperglycemia and inflammation dysfunction mmol/l) over2hinhealthy men. This The connection between acute hypergly- One proposed link between hyperglyce- produced elevated systolic and diastolic cemia and vascular changes likely in- mia and poor cardiovascular outcomes is blood pressure, increased pulse, elevation volves inflammatory changes. Cultured the effect of acute hyperglycemia on the of catecholamine levels, and QTc prolon- human peripheral blood mononuclear vascular endothelium. In addition to serv- gation (44). Other investigators have cells (PBMCs), when incubated in high ing as a barrier between blood and tissues, demonstrated an association between glucose medium (594 mg/dl, 33 mmol/l) vascular endothelial cells play a critical acute hyperglycemia and increased vis- for 6 h produce increased levels of IL-6 role in overall homeostasis. In the healthy cosity, blood pressure (45), and natiuretic and tumor necrosis factor (TNF)-␣ (53). state, the vascular endothelium maintains peptide levels (46). TNF-␣ is apparently involved in IL-6 pro- the vasculature in a quiescent, relaxant, duction. Blocking TNF-␣ activity with antithrombotic, antioxidant, and antiad- Hyperglycemia and thrombosis anti-TNF monoclonal antibody blocks hesive state (rev. in 74,75). During illness Multiple studies have identified a variety the stimulatory effect of glucose on IL-6 the vascular endothelium is subject to of hyperglycemia-related abnormalities in production by these cells. Other in vitro dysregulation, dysfunction, insufficiency, hemostasis, favoring thrombosis (47–51). studies suggest that glucose-induced ele- and failure (76). Endothelial cell dysfunc- For example, hyperglycemic changes in vations in IL-6, TNF-␣, and other factors tion is linked to increased cellular adhe- rats rapidly reduce plasma fibrinolytic ac- may cause acute inflammation. This in- sion, perturbed angiogenesis, increased tivity and tissue plasminogen activator ac- flammatory response to glucose has been cell permeability, inflammation, and tivity while increasing plasminogen seen in adipose tissue, 3T3-L1 adipocyte thrombosis. Commonly, endothelial activator inhibitor (PAI)-1 activity (52). cell lines, vascular smooth muscle cells, function is evaluated by measuring endo- Human studies in patients with type 2 di- PBMCs, and other tissues or cell types thelial-dependent vasodilatation, looking abetes have shown platelet hyperactivity (55–61). most often at the brachial artery. Human indicated by increased thromboxane bio- In humans, moderate elevation of in vivo studies utilizing this parameter synthesis (47). Thromboxane biosynthe- glucose to 270 mg/dl (15 mmol/l) for 5 h confirm that acute hyperglycemia to the sis decreases with reduction in blood has been associated with increased IL-6, levels commonly seen in the hospital set- glucose. Hyperglycemia-induced eleva- IL-18, and TNF-␣ (62). Elevations of ting (142–300 mg/dl or 7.9–16.7 tions of interleukin (IL)-6 levels have these various inflammatory factors have mmol/l) causes endothelial dysfunction been linked to elevated plasma fibrinogen been linked to detrimental vascular ef- (77–82). Only one study failed to show concentrations and fibrinogen mRNA fects. For example, TNF-␣ extends the evidence of endothelial cell dysfunction (53,54). area of necrosis following left anterior de- induced by short-term hyperglycemia Increased platelet activation as shown scending coronary artery ligation in rab- (83). The degree of endothelial cell dys- by shear-induced platelet adhesion and bits (63). In humans, TNF-␣ levels are function after an oral glucose challenge aggregation on extracellular matrix has elevated in the setting of AMI and corre- was positively associated with the peak been demonstrated in patients with dia- late with severity of cardiac dysfunction glucose level, ranging from 100 to 300 betes (48). As little as 4 h of acute hyper- (63,64). TNF-␣ may also play a role in mg/dl (5.5–16.7 mmol/l) (78,79). Hyper- glycemia enhances platelet activation in some cases of ischemic renal injury and in glycemia may directly alter endothelial patients with type 2 diabetes (51). In this congestive heart failure (CHF) (57,65). cell function by promoting chemical inac- crossover, double-blind study, 12 pa- Ischemic preconditioning is associated tivation of nitric oxide (84). Other mech- tients were subjected to hyperglycemic with decreased postischemic myocardial anisms include triggering production of (250 mg/dl, 13.9 mmol/l) and euglycemic TNF-␣ production (66). IL-18 has been reactive oxygen species (ROS) or activat- (100 mg/dl, 5.55 mmol/l) clamps. Hyper- proposed to destabilize atherosclerotic ing other pathways (rev. in 27). Despite glycemia precipitated stress-induced plaques, leading to acute ischemic syn- compelling experimental data, studies ex- platelet activation as well as platelet P- dromes (67). amining a possible association among hy- selectin and lysosomal integral membrane One of the most commonly demon- perglycemia, endothelial function, and protein (LIMP) expression. Hyperglyce- strated relationships between hyperglyce- outcomes have not to date been done in mia also caused increased plasma von mia and inflammatory markers is the in hospitalized patients. Willebrand factor antigen, von Wille- vitro induction of the proinflammatory brand factor activity, and urinary 11- transcriptional factor, nuclear factor Hyperglycemia and the brain ␬ dehydro-thromboxane B2 (a measure of (NF)- B by exposure of various cell types Acute hyperglycemia is associated with thromboxane A2 production). These to 1–8 days of hyperglycemia (58,59,68– enhanced neuronal damage following in- changes were not seen in the euglycemic 71). In patients with type 1 diabetes, ac- duced brain ischemia (85–98). Explora- state. tivation of NF-␬B in PBMCs was tion of general mechanisms of

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 555 Management of diabetes and hyperglycemia in hospitals hyperglycemic damage has used various cular event outcomes, likely contribute to these infusions and the benefits have been models of ischemia and various measures acute cerebrovascular outcomes. Specifi- displayed in normal humans and animals. of outcomes. Models differ according to cally, in brain ischemia models exposed Although the direct effect of insulin may transient versus permanent ischemia as to hyperglycemia, hydroxyl free radicals play a significant role in benefits of GIK well as global versus localized ischemia. are elevated and positively correlate with therapy, other metabolic factors are likely There is some indication from animal tissue damage (116). Likewise, antioxi- to be major contributors to the mecha- studies that irreversible ischemia or end dants have a neuroprotective effect (117). nism of this therapy. The theory promot- arterial ischemia is not affected by hyper- Elevated glucose levels have also been ing this form of therapy centers on the glycemia (87,99,100). The major portion linked to inhibition of nitric oxide gener- imbalance between low glycolytic sub- of the brain that is sensitive to injury from ation, increased IL-6 mRNA, decreased strate in the hypoperfused tissue and ele- hyperglycemia is the ischemic penumbra. cerebral blood flow, and evidence of vas- vated free fatty acids (FFAs) mobilized This area surrounds the ischemic core. cular endothelial injury (90,92,118,119). through catecholamine-induced lipolysis During evolution of the stroke, the isch- Again, the composite of evidence sup- (41,155–159). In ischemic cardiac tissue, emic penumbra may evolve into infarcted ports scientifically viable mechanisms of there is decreased ATP and increased in- tissue or may recover as viable tissue central nervous system injury from hy- organic phosphate production (87,99,101,102). One of the primary perglycemia in the acute setting. (148,156,159). Adequate glycolytic ATP mechanistic links between hyperglycemia is important for maintaining cellular and enhanced cerebral ischemic damage Hyperglycemia and oxidative stress membranes, myocardial contractility, and appears to be increased tissue acidosis Oxidative stress occurs when the forma- avoidance of the negative effect of fatty and lactate levels associated with elevated tion of ROS exceeds the body’s ability to acids as substrate for ischemic myocar- glucose concentrations. This has been metabolize them. Attempts to identify a dium (155,158–161). FFAs are associ- shown in various animal models with rare unifying basic mechanism for many of the ated with cardiac sympathetic overactivity, exception (94,102–108). Lactate has diverse effects of acute hyperglycemia worsened ischemic damage, and possibly been associated with damage to neurons, point to the ability of hyperglycemia to arrhythmias. Accordingly, using a model astrocytes, and endothelial cells (104). In produce oxidative stress (58,69,120). of 60-min low-flow ischemia followed by humans, Parsons et al. (109) demon- Acute experimental hyperglycemia to 30 min of reperfusion in rat hearts, inves- strated that the lactate-to-choline ratio levels commonly seen in hospitalized pa- tigators have demonstrated the ability of determined by proton magnetic reso- tients induces ROS generation. Endothe- GIK infusion to increase glycolysis, de- nance spectroscopy (MRS) had value in lial cells exposed to hyperglycemia in crease ATP depletion, and maintain lower predicting clinical outcomes and final in- vitro switch from producing nitric oxide inorganic phosphate levels in the affected farct size in acute stroke. More recently, to superoxide anion (84). Increased ROS tissue (148). These effects extrapolated to the same investigators used this method generation causes activation of transcrip- improved systolic and diastolic function to demonstrate a positive correlation be- tional factors, growth factors, and second- in this model. In other animal models, tween glucose elevations and lactate pro- ary mediators. Through direct tissue GIK infusion in improved left ventricular duction (110). Through this mechanism, injury or via activation of these secondary contractility, decreased tissue acidosis, hyperglycemia appears to cause hypoper- mediators, hyperglycemia-induced oxi- and decreased infarct size (144,152,162). fused at-risk tissue to progress to infarction. dative stress causes cell and tissue injury In small studies of individuals with or Animal studies have shown addi- (58,59,62,70,72,74,80,121–127). In all without diabetes undergoing coronary ar- tional association of hyperglycemia with cases studied, abnormalities were re- tery bypass surgery, GIK therapy is asso- various acute consequences that likely versed by antioxidants or by restoring eu- ciated with shorter length of intubation serve as intermediaries of adverse out- glycemia (58,59,70,72,80,122,127). and shorter length of stay (142,143,163). comes. For example, hyperglycemia As therapy for patients with an AMI, GIK causes accumulation of extracellular glu- Is insulin per se therapeutic? therapy is associated with the expected tamate in the neocortex. Increased gluta- Two large, well-done prospective studies decrease in FFAs, decreased heart failure, mate levels predict ensuing neuronal support the relationship between insulin and a suggestion of improved short-term damage (95). A unique hippocampal cell therapy and improved inpatient out- survival (133–135,139,164). In fol- culture model of “in vitro ischemia” dem- comes (2,128). The prevalent assumption low-up of a first myocardial infarction onstrated a similar relationship between has been that insulin attained this benefit (MI), individuals who received GIK ther- hyperglycemia, glutamate activity, and indirectly by controlling blood glucose. apy reported better stress tolerance, an el- increased intracellular calcium with en- However, a growing body of literature evated ischemic threshold, and improved hanced cell death (98). Hyperglycemia raises the question of whether insulin may myocardial perfusion by 99 m-Tc- has also been associated with DNA frag- have direct beneficial effects independent tetrofosmin–gated single photon emis- mentation, disruption of the blood-brain of its effect on blood glucose (121,129– sion computed tomography (SPECT) barrier, more rapid repolarization in se- 132). compared with those receiving saline in- verely hypoperfused penumbral tissue, Multiple studies suggest cardiac and fusion (149). These studies of classic GIK ␤-amyloid precursor protein elevation, as neurological benefits of glucose-insulin- therapy with emphasis on glucose deliv- well as elevated superoxide levels in neu- potassium (GIK) infusions (133–154). ery have been small and more suggestive ronal tissue (111–115). One may propose that such therapy sup- than conclusive. No large, randomized, Many of the same factors noted ear- ports a direct effect of the insulin since placebo-controlled studies have been re- lier, linking hyperglycemia to cardiovas- blood glucose control is not the goal of ported. Even less information is available

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Figure 1—Link between hyperglyce- mia and poor hospital outcomes. Hy- perglycemia 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 in- fection, direct fuel-mediated injury, and oxidative stress and other down- stream mediators. See text for details.

regarding the use of GIK therapy in the upregulation of the endothelial adhe- These effects suggest a general anti- strokes or cerebral ischemia. Limited sion molecule P-selectin expression seen inflammatory action of insulin. studies have demonstrated safety of GIK as a consequence of elevated glucose lev- In an animal model of myocardial therapy in the acute stroke patient, with a els (121). ischemia, insulin given early in the acute trend to reduced mortality, and a decrease Insulin infusion has anti-inflamma- insult reduced infarct size by Ͼ45% in blood pressure (147,150). However, tory effects (129,174,175). In a large (182). This effect was mediated through the data are clearly inadequate to make study of intensive insulin infusion ther- the Akt and p70s6 kinase–dependent sig- any conclusions of benefit. apy in the intensive care unit, investiga- naling pathway and was independent of Beyond GIK therapy, one finds in- tors found decreased C-reactive protein glucose. There is preliminary evidence of creasing support for a direct effect of in- (CRP) levels in insulin-treated patients insulin’s ability to improve pulmonary sulin on many of the abnormalities that (176). Cell culture studies have shown diffusion and CHF in humans (183). underlie inpatient complications. Insulin the ability of insulin incubation to reduce Studies have also suggested that insulin treatment, ranging in duration from brief protects from ischemic damage in the oxidative stress and its associated apopto- euglycemic-hyperinsulinemic clamps to brain, kidney, and lung (184–186). In sis in cardiomyocytes (177). In addition 2 months of ongoing therapy, improves catabolic states such as severe burns, hy- endothelial cell function (165–171). to the induction of endothelial-derived perglycemia promotes muscle catabo- There are rare exceptions to this finding nitric oxide, human aorta cell and human lism, while exogenous insulin produces (172). Insulin also has vasodilatory prop- mononuclear cell culture studies have an anabolic effect (187). Insulin therapy erties in the internal carotid and femoral shown dose-dependent reductions in has also been associated with an im- arteries (165,167). The vasodilatory ROS, the proinflammatory transcription proved fibrinolytic profile in patients at ␬ properties of insulin appear to be medi- factor NF- B, intercellular adhesion mol- the time of acute coronary events, reduc- ated at least in part by stimulating nitric ecule (ICAM)-1, and the chemokine ing fibrinogen and PAI-1 levels (132). Fi- oxide release (165,166). Aortic endothe- monocyte chemoattractant protein nally, insulin infusion reduces collagen- lial cell cultures have also demonstrated (MCP)-1 (173,178–180). Insulin also in- induced platelet aggregation and several insulin-induced nitric oxide synthase ac- hibits the production TNF-␣ and the other parameters of platelet activity in hu- tivity and increased nitric oxide levels proinflammatory transcription factor mans. This effect was attenuated in obese (172,173). In a rat model, insulin inhibits early growth response gene (Egr)-1 (181). individuals (188).

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 557 Management of diabetes and hyperglycemia in hospitals

In summary, the overwhelming bal- and/or may be iatrogenic due to adminis- When minor infections of the urinary ance of evidence supports a beneficial ef- tration of pharmacologic agents, includ- tract were excluded, the relative risk (RR) fect of insulin in the acute setting. ing glucocorticoids, vasopressors, etc. for serious postoperative infection, in- Whether these benefits are the result of a Distinction between decompensated dia- cluding sepsis, pneumonia, and wound direct pharmacologic effect of insulin or betes and stress hyperglycemia is often infections, was 5.7. represent an indirect effect by improved not made or alternatively is not clear at the Umpierrez et al. (1) reviewed 1,886 glucose control, enhanced glycolysis, or time of presentation with an acute illness. admissions for the presence of hypergly- suppressed lipolysis is more difficult to When hyperglycemia is treated along cemia (fasting blood glucose Ն126 mg/dl determine. Studies in cell cultures control with other acute problems, outcomes are or random blood glucose Ն200 mg/dl on for glucose but have other physiologic generally improved. This section will re- two or more occasions). Care was pro- limitations. Nevertheless, the data are view the evidence for outcomes from ob- vided on general medicine and surgery provocative and certainly leave the im- servational and interventional studies in units. Among these subjects, there were pression that insulin therapy in the hos- hospitalized patients with hyperglycemia. 223 patients (12%) with new hyperglyce- pital has significant potential for benefit. While observational reports abound, in- mia and 495 (26%) with known diabetes. Considering the numerous contraindica- terventional studies that report improved Admission blood glucose for the normo- tions to the use of oral agents in the hos- outcomes with targeted glucose control— glycemic group was 108 Ϯ 10.8 mg/dl pital, insulin is the clear choice for glucose though few in number—are now begin- (6 Ϯ 0.6 mmol/l); for the new hypergly- manipulation in the hospitalized patient. ning to provide a source of evidence in the cemia group, it was 189 Ϯ 18 mg/dl literature. (10.5 Ϯ 1 mmol/l); and for known diabe- Potential relationships between To make the case for defining targets tes, it was 230.4 Ϯ 18 mg/dl (12.8 Ϯ 1 metabolic stress, hyperglycemia, for glucose control in hospital settings, it mmol/l). After adjusting for confounding hypoinsulinemia, and poor hospital is necessary to examine the literature on factors, patients with new hyperglycemia outcomes both short- and long-term mortality. Data had an 18-fold increased inhospital mor- To explain the dual role of glucose and regarding diabetes and hyperglycemia- tality and patients with known diabetes insulin on hospital outcomes, Levetan associated morbidity have emerged from had a 2.7-fold increased inhospital mor- and Magee (189) proposed the following specific clinical settings. These data in- tality compared with normoglycemic pa- relationships. Elevations in counterregu- clude infection rates, need for intensive tients. Length of stay was higher for the larory hormones accelerate catabolism, care unit admission, functional recovery, new hyperglycemia group compared with hepatic gluconeogenesis, and lipolysis. and health economic outcomes such as normoglycemic and known diabetic pa- These events elevate blood glucose, FFAs, length of stay and hospital charges. For tients (9 Ϯ 0.7, 4.5 Ϯ 0.1, and 5.5 Ϯ 0.2 ketones, and lactate. The rise in glucose their practical implications and for the days, respectively, P Ͻ 0.001). Both the blunts insulin secretion via the mecha- purpose of this review, literature on the new hyperglycemia and known diabetic nism of glucose toxicity (190), resulting association of blood glucose level with patients were more likely to require inten- in further hyperglycemia. The vicious cy- outcomes will be grouped into the medi- sive care unit (ICU) care when compared cle of stress-induced hyperglycemia and cal and surgical areas in which studies with normoglycemic subjects (29 vs. 14 hypoinsulinemia subsequently causes have been reported as follows: general vs. 9%, respectively, P Ͻ 0.01) and were maladaptive responses in immune func- medicine and surgery, cardiovascular dis- more likely to require transitional or nurs- tion, fuel production, and synthesis of ease (CVD) and critical care, and neuro- ing home care. There was a trend toward mediators that cause further tissue and or- logic disorders (Table 1). a higher rate of infections and neurologic gan dysfunction (Fig. 1). Thus, the com- events in the two groups with hypergly- bination of hyperglycemia and relative General medicine and surgery cemia (1). It is likely that the “new” hy- hypoinsulinemia is mechanistically posi- Observational studies suggest an associa- perglycemic patients in this report were a tioned to provide a plausible explanation tion between hyperglycemia and in- heterogeneous population made up of pa- for the poor hospital outcomes seen in creased mortality. Recently, investigators tients with unrecognized diabetes, predi- observational studies. have reported on outcomes correlated abetes, and/or stress hyperglycemia with blood glucose levels in the general secondary to severe illness. WHAT ARE THE TARGET medicine and surgery setting. Pomposelli The observational data from these two BLOOD GLUCOSE LEVELS et al. (191) studied 97 patients with dia- studies suggest that hyperglycemia from FOR THE HOSPITALIZED betes undergoing general surgery proce- any etiology in the hospital on general med- PATIENT? dures. Blood glucose testing occurred icine and surgery services is a significant A rapidly growing body of literature sup- every 6 h. The authors found that a single predictor of poor outcomes, relative to out- ports targeted glucose control in the hos- blood glucose level Ͼ220 mg/dl (12.2 comes for normoglycemic subjects. Patients pital setting with potential for improved mmol/l) on the first postoperative day was with hyperglycemia, with or without diabe- mortality, morbidity, and health care eco- a sensitive (85%), but relatively nonspe- tes, had increased risk of inhospital mortal- nomic outcomes. The relationship of hos- cific (35%), predictor of nosocomial in- ity, postoperative infections, neurologic pital outcomes to hyperglycemia has been fections. Patients with a blood glucose events, intensive care unit admission and extensively examined. Hyperglycemia in value(s) Ͼ220 mg/dl (12.2 mmol/l) had increased length of stay. The Pomposelli ar- the hospital may result from stress, de- infection rates that were 2.7 times higher ticle (191) found that a blood glucose level compensation of type 1 diabetes, type 2 than the rate for patients with blood glu- of 220 mg/dl (12.2mmol/l) separated pa- diabetes, or other forms of diabetes cose values Ͻ220 mg/dl (12.2 mmol/l). tients for risk of infection. Data from the

558 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 D IABETES Table 1—Evidence for association of blood glucose level with clinical outcomes

C Clinical setting Threshold BG levels [mg/dl, (mmol/l)] Outcomes and comments ARE General medicine and surgery Mortality, ICU admits, length of stay, and nursing home or transitional care admits Review of BG levels of patients on general medicine and surgery wards. Hyperglycemia defined as two or more , Ն Ն

VOLUME correlated with BG and glucose tolerance status: measurements with fasting BG 126 (7) and/or random 200 (11.1). Hospital mortality for normoglycemic Normoglycemia ϭ 108 Ϯ 10.8 (6 Ϯ 0.6); patients was 1.7%. With known diabetes mortality was 3% and with “new” hyperglycemia it was 16%. After New hyperglycemia ϭ 189 Ϯ 18 (10.5 Ϯ 1); adjustment for variables, the “new” hyperglycemia group had an 18.3-fold increased mortality rate compared Known diabetes ϭ 230.4 Ϯ 18 (12.8 Ϯ 1). with a 2.7-fold increase with known diabetes. Patients with new hyperglycemia also had an increased length of

27, stay, were more likely to require ICU care, and were more likely to require transitional or nursing home care (Obs, n ϭ 1,886) (1).

NUMBER Infection rates correlated with BG above 220. 5.9-fold increase in serious infections, including sepsis, pneumonia, and wound infections for BG over 220 (12.2), which was a sensitive (85%) predictor of nosocomial infection (Obs, n ϭ 97) (191). CVD and critical care

,F 2, Acute MI Mortality, CHF, and cardiogenic shock risk correlated with BG Literature review. Relative risk (RR) for inhospital mortality increased 3.9-fold in subjects without diabetes with BG at or Above 109.8 (6), above range of 109.8–144 (6.1–8), 95% CI 2.9–5.4; risk of CHF and cardiogenic shock was also increased. RR

EBRUARY in patients without known diabetes; for moderate increase in mortality with known diabetes with was 1.7 (14 article review with meta-analysis) (192). At or above 124 (6.9), with diabetes diagnosis. Admit BG, stratified according to WHO criteria and correlated with mortality: One-year mortality was 19.3% for BG Ͻ100.8 (5.6) at time of admission, compared with 44% when BG Ն199.8 (11). Ͻ ϭ 2004 I. BG less than 100.8 (5.6) to Mortality was higher in patients with diabetes than in those without (40 vs. 16%, P 0.05) (Obs, n 336) IV. BG greater than or equal to 199.8 (11) (193). Mortality correlated with BG in intensive insulin therapy group where mean BG ϭ Intensive insulin therapy in patients with acute MI, followed by multishot regimen for 3 or more months, with 29% 172.8 Ϯ 59.4 (9.6 Ϯ 3.3) compared with conventional therapy group reduction in mortality at 1 year. Benefit extends to at least 3.4 years. One life saved for nine patients treated (Int, where mean BG ϭ 210.6 Ϯ 73.8 (11.7 Ϯ 4.1). n ϭ 620) (128). Cardiac surgery Mortality positively correlated with BG in a dose-dependent manner, with the Observational studies using historical controls. Both mortality and incidence of DSWIs were reduced to the nondiabetic lowest mortality in the group where mean postoperative BG Ͻ150 (8.3). range after implementing insulin infusion protocols with progressively lower BG targets over time (196,197). Critical care Mortality and sepsis risk correlated with BG. Intensive insulin therapy arm with Prospective randomized controlled study of adults admitted to surgical ICU and on mechanical ventilation. Sixty mean BG 103 Ϯ 19 (5.7 Ϯ 1.06); conventional treatment arm with mean percent had had cardiac surgery, majority of others also surgical patients. IIT to maintain BG in 80–110 (4.4–6.1) BG 153 Ϯ 33 (8.5 Ϯ 1.8). range compared with conventional therapy (CT) to target BG to 180–200 (10–11.1). IIT reduced ICU mortality by 40% from 8.0 to 4.6%, P Ͻ 0.04. For each 20 mg/dl increase in BG, risk of death was increased by 30%. IIT also reduced incidence of sepsis by 46% and overall hospital mortality by 34%. A gradual decline in risk for ICU and hospital death with decline in BG level was observed, with no identifiable threshold below which there was no further risk reduction. Prolonged inflammation, defined as elevation in CRP above 150 mg/dl for over 3 days, was associated with mean BG level (per 20 mg/dl added) with or of 1.16 (95% CI 1.06–1.24), P ϭ 0.0006. Threshold may be higher than 110 (6.1) (Int, n ϭ 1,548) (2,200). Neurologic disorders Acute stroke Mortality and functional recovery after acute ischemic stroke correlated with BG. Literature review (1966–2000). After ischemic stroke, admission glucose level Ͼ110–126 (Ͼ6.1–7) associated with Admission BG over 110 (6.1) for mortality; increased risk of in hospital or 30-day mortality in patients without diabetes only (RR 3.8; 95% CI 2.32–4.64). over 121 for functional recovery. Stroke survivors without diabetes and BG over 121–144 (6.7–8) had RR of 1.41 (1.16–1.73) for poor functional recovery (metaanalysis, 26 studies) (96). Neurologic function after acute stroke correlated with admission BG. Controlled, randomized trial of molecular heparin in acute stroke. Mean admission BG 144 Ϯ 68 (8 Ϯ 3.8) associated Odds for neurologic improvement decreased with neurologic improvement at 3 months. In those without improvement, BG was 160 Ϯ 84 (8.9 Ϯ 4.7). As BG with OR of 0.76 for each 100 mg/dl BG increased, odds for neurologic improvement decreased, with OR ϭ 0.76 per 100-mg/dl increase in admission BG increase. (95% CI 0.61–0.95, P ϭ 0.01) (Obs, n ϭ 1,259) (201). Functional outcomes and return to work after stroke correlated with admission Prospective data. Stroke-related deficits were more severe when admission glucose values were Ͼ120 (6.7). Only 43% BG. of patients with an admission glucose value of Ͼ120 mg/dl able to return to work, whereas 76% of patients with Admission BG under 120 (6.7) with positive lower glucose values regained employment (202). relationship. RtPA-induced hemorrhage into an infarct correlated with BG over 300 (16.7). Central collection of retrospective and prospective data on acute ischemic stroke treated in clinical practices with alteplase. BG Ͼ300 mg/dl an independent risk factor for hemorrhage into an infarct when treatment with recombinant RtPA is given (Obs, n ϭ 1,205) (203). Mortality, length of stay, and charges increased with admission BG Ն130 (7.2). Hospitalization for acute ischemic stroke. Hyperglycemia (random BG at or above 130) present in 40% at admission. Most remained hyperglycemic with mean BG values of 206 (11.4). Random admission serum glucose Ն130 (7.2) independently associated with increased risk of death at 30 days (HR 1.87) and 1 year (HR 1.75), both P Յ 0.01. Other significant correlates with hyperglycemia, when compared with normal BG, were length of stay (7 vs. 6 days, P ϭ 0.015) and charges ($5,262 vs. $6,611, P Ͻ 0.001) (Obs, n ϭ 656) (205). Associates and Clement Hypoglycemia risk and 4 week mortality with BG targeted to 72–126 (4–7). Glucose-insulin infusion in acute stroke with mild-to-moderate hyperglycemia. Examined the safety of treating to a target glucose of 72–126 (4–7). Lowering BG was found to be without significant risk of hypoglycemia or 4-week excess mortality in patients with acute stroke and mild-to-moderate hyperglycemia (147). Penumbral salvage, final infarct size, and functional outcome in patients with Study of MRI and MRS in acute stroke. Prospective evaluation with serial diffusion-weighted and perfusion-weighted median acute BG ranging from 104.4 to 172.8 (5.8–9.6). MRI and acute BG measurements. Median acute BG 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 BG from 5 to 10 mmol/l led to a 60% reduction in penumbral salvage and a 56- cm3 increase in final infarct size. In patients with acute perfusion-diffusion mismatch, acute hyperglycemia was also 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 diabetic status (Obs, n ϭ 63) (110). BG, blood glucose; CT, conventional therapy; DM, diabetes mellitus; HR, hazard ratio; Int, interventional study; Obs, observational study; RtPA, recombinant tissue plasminogen activator; Rx, therapy. 559 Management of diabetes and hyperglycemia in hospitals

Umpierrez study (1) and most of the litera- and Insulin-Glucose Infusion in Acute outcomes. In addition, it is of interest that ture from other disciplines, as outlined else- Myocardial Infarction (DIGAMI) study, in spite of the observation that blood glu- where in this review, would suggest a lower Malmberg and colleagues (128,194) have cose levels between the intensive and con- threshold for optimal hospital outcomes. published the results of a prospective in- ventional treatment groups were similar, Evidence for a blood glucose threshold. terventional trial of insulin-glucose infu- a significant difference in mortality be- The Umpierrez study demonstrated bet- sion followed by subcutaneous insulin tween these groups was found. A rela- ter outcomes for patients with fasting and treatment in diabetic patients with AMI, tively modest reduction in blood glucose admission blood glucose Ͻ126 mg/dl (7 reporting mortality at 1 year. Of 620 per- in the intensive treatment group com- mmol/l) and all random blood glucose sons with diabetes and AMI, 306 were pared with the conventional treatment levels Ͻ200 mg/dl (11.1 mmol/l). Be- randomized to intensive treatment with group produced a statistically significant cause the Pomposelli and Umpierrez insulin infusion therapy, followed by a improvement in mortality. This suggests studies are observational, a causal link be- multishot insulin regimen for 3 or more the possibility that the beneficial effect of tween hyperglycemia and poor outcomes months. Patients randomized to conven- improved control may be mediated cannot be established. tional therapy received standard diabetes through mechanisms other than a direct therapy and did not receive insulin unless effect of hyperglycemia, such as a direct CVD and critical care clinically indicated. Baseline blood glu- effect of insulin. Numerous articles contain data linking cose values were similar in the intensive Evidence for a blood glucose threshold blood glucose level to outcomes in AMI treatment group, 277.2 Ϯ 73.8 mg/dl for increased mortality in AMI. and cardiac surgery, for which patients (15.4 Ϯ 4.1 mmol/l), and the conven- ● The metaanalysis of Capes et al. (192) receive care predominantly in the ICU tional treatment group, 282.6 Ϯ 75.6 reported a blood glucose threshold of setting. The majority of these trials are ob- mg/dl (15.7 Ϯ 4.2 mmol/l). Blood glucose Ͼ109.8 mg/dl (6.1 mmol/l) for patients servational, but the literature also in- levels decreased in the first 24 h in the without diabetes and Ͼ180 mg/dl (10 cludes several large, landmark intervention group to 172.8 Ϯ 59.4 mg/dl mmol/l) for known diabetes. interventional studies that have markedly (9.6 Ϯ 3.3 mmol/l; P Ͻ 0.001 vs. conven- ● The observational study of Bolk et al. increased awareness of the need for tar- tional treatment), whereas blood glucose (193) identified threshold blood glu- geted glycemic control in these settings. declined to 210.6 Ϯ 73.8 mg/dl (11.7 Ϯ coses, divided by World Health Orga- AMI. In 2000, Capes et al. (192) re- 4.1mmol/l). The blood glucose range for nization (WHO) classification criteria, viewed blood glucose levels and mortality each group was wide: 116.4–232.2 mg/dl with mortality risk of 19.3% for normo- in the setting of AMI from 15 previously (6.5–12.9 mmol/l) in the intensive treat- glycemia (blood glucose Ͻ100.8 mg/dl published studies and performed a meta- ment group and 136.8–284.4 mg/dl [5.6 mmol/l]), which rose progressively analysis of the results to compare the RR (7.6–15.8 mmol/l) in the conventional to 44% for blood glucose Ͼ199.8 of in-hospital mortality and CHF in both treatment group. Mortality at 1 year in the mg/dl (11 mmol/l). hyper- and normoglycemic patients with intensive treatment group was 18.6%, ● In the DIGAMI study, mean blood glu- and without diabetes. In subjects without and for the conventional treatment group cose in the intensive insulin interven- known diabetes whose admission blood it was 26.1%, a 29% reduction in mortal- tion arm was 172.8 mg/dl (9.6 mmol/l), glucose was Ն109.8 mg/dl (6.1 mmol/l), ity for the intervention arm (P ϭ 0.027). where lower mortality risk was ob- the RR for in-hospital mortality was in- At 3.4 (1.6–5.6) years follow-up, mortal- served. In the conventional treatment creased significantly (RR 3.9, 95% CI ity was 33% in the intensive treatment arm, mean blood glucose was 210.6 2.9–5.4). When diabetes was present and group and 44% in the conventional treat- mg/dl (11.7 mmol/l). The broad range admission glucose was Ն180 mg/dl (10 ment group (RR 0.72, 95% CI 0.55–0.92; of blood glucose levels within each arm mmol/l), risk of death was moderately in- P ϭ 0.011), consistent with persistent re- limits the ability to define specific blood creased (1.7, 1.2–2.4) compared with pa- duction in mortality. The benefit of inten- glucose target thresholds. tients who had diabetes but no sive control was most pronounced in 272 hyperglycemia on admission. patients who had not had prior insulin Cardiac surgery. Attainment of targeted Bolk et al. (193) analyzed admission therapy and had a less risk for CVD (0.49, glucose control in the setting of cardiac blood glucose values in 336 prospective, 0.30–0.80; P ϭ 0.004). surgery is associated with reduced mor- consecutive patients with AMI with aver- In the DIGAMI study, insulin infu- tality and risk of deep sternal wound in- age follow-up to 14.2 months. Twelve sion in AMI followed by intensive subcu- fections. Furnary and colleagues percent of this cohort had previously di- taneous insulin therapy for 3 or more (196,197) treated cardiac surgery pa- agnosed diabetes. Multivariate analysis months improved long-term survival, tients with diabetes with either subcuta- revealed an independent association of with a benefit that extends to at least 3.4 neous insulin (years 1987–1991) or with admission blood glucose and mortality. years (128). An absolute reduction in intravenous insulin (years 1992–2003) in The 1-year mortality rate was 19.3% in mortality of 11% was observed, meaning the perioperative period. From 1991– subjects with admission plasma glucose that one life was saved for every nine 1998, the target glucose range was 150 Ͻ100.8 mg/dl (5.6 mmol/l) and rose to treated patients. The observation that Ϫ200 mg/dl (8.3–11.1 mmol/l); in 1999 44% with plasma glucose Ն199.8 mg/dl higher mean glucose levels were associ- it was dropped to 125–175 mg/dl (6.9– (11 mmol/l). Mortality was higher in pa- ated with increased mortality between 9.7 mmol/l), and in 2001 it was again tients with known diabetes than in those groups of patients with diabetes would lowered to 100–150 mg/dl (5.5– 8.3 without diabetes (40 vs. 16%, P Ͻ 0.05.). suggest that stress hyperglycemia plays an mmol/l). Following implementation of From the frequently cited Diabetes independent role in the determination of the protocol in 1991, the authors re-

560 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Clement and Associates ported a decrease in blood glucose level 180 and 200 mg/dl (10.0 and 11.1 mmol/ clinical settings, available data, with one for the first 2 days after surgery and a con- l). exception, are observational. Capes et al. comitant decrease in the proportion of pa- Ninety-nine percent of patients in the (96) reported on mortality after stroke in tients with deep wound infections, from IIT group received insulin infusion, as relation to admission glucose level from 2.4% (24 of 990) to 1.5% (5 of 595) (P Ͻ compared with 39% of the patients in the 26 studies, published between 1996 and 0.02) (198). A recent analysis or the co- conventional treatment group. In the IIT 2000, where RRs for prespecified out- hort found a positive correlation between arm, blood glucose levels were 103 Ϯ 19 comes were reported or could be calcu- the average postoperative glucose level mg/dl (5.7 Ϯ 1.1 mmol/l) and in conven- lated. After ischemic stroke, admission and mortality, with the lowest mortality tional treatment 153 Ϯ 33 mg/dl (8.5 Ϯ glucose level Ͼ110–126 mg/dl (Ͼ6.1–7 in patients with average postoperative 1.8 mmol/l). IIT reduced mortality during mmol/l) was associated with increased blood glucose Ͻ150 mg/dl (8.3 mmol/l) ICU care from 8.0% with conventional risk of inhospital or 30-day mortality in (197). treatment to 4.6% (P Ͻ 0.04). The benefit patients without diabetes only (RR 3.8, Golden et al. (199) performed a non- of IIT was attributable to its effect on mor- 95% CI 2.32– 4.64). Stroke survivors concurrent prospective cohort chart re- tality among patients who remained in the without diabetes and blood glucose view study in cardiac surgery patients unit for more than 5 days (20.2% with Ͼ121–144 mg/dl (6.7–8 mmol/l) had an with diabetes (n ϭ 411). Perioperative conventional treatment vs. 10.6% with RR of 1.41 (1.16–1.73) for poor func- glucose control was assessed by the mean IIT, P ϭ 0.005). IIT also reduced overall tional recovery. After hemorrhagic stroke, of six capillary blood glucose measures inhospital mortality by 34% (2). In a sub- admission hyperglycemia was not associ- performed during the first 36 h following sequent analysis, Van den Berghe (200) ated with higher mortality in either the surgery. The overall infectious complica- demonstrated that for each 20 mg/dl (1.1 diabetes or nondiabetes groups. tion rate was 24.3%. After adjustment for mmol/l), glucose was elevated Ͼ100 Several of the studies that were in- variables, patients with higher mean cap- mg/dl (5.5 mmol/l) and the risk of ICU cluded in the analysis of Capes et al. (96) illary glucose readings were at increased death increased by 30% (P Ͻ 0.0001). contain additional data that support an risk of developing infections. Compared Daily insulin dose (per 10 units added) association between blood glucose and with subjects in the lowest quartile for was found as a positive rather than nega- outcomes in stroke. In the Acute Stroke blood glucose, those in quartiles 2– 4 tive risk factor, suggesting that it was not Treatment Trial (TOAST), a controlled, were at progressively increased risk for the amount of insulin that produced the randomized study of the efficacy of a low– infection (RR 1.17, 1.86, and 1.78 for observed reduction in mortality. Hospital molecular weight heparinoid in acute quartiles 2, 3, and 4, respectively, P ϭ and ICU survival were linearly associated ischemic stroke (n ϭ 1,259), neurologic 0.05 for trend). These data support the with ICU glucose levels, with the highest improvement at 3 months (a decrease by concept that perioperative hyperglycemia survival rates occurring in patients four or more points on the National Insti- is an independent predictor of infection in achieving an average blood glucose Ͻ110 tutes of Health [NIH] Stroke Scale or a patients with diabetes. mg/dl (6.1 mmol). An improvement in final score of 0) was seen in 63% of sub- Critical care. Van den Berghe et al. (200) outcomes was found in patients who had jects. Those with improvement had a performed a prospective, randomized prior diabetes as well as in those who had mean admission glucose of 144 Ϯ 68 mg/ controlled study of 1,548 adults who no history of diabetes. dl, and those without improvement had were admitted to a surgical intensive care Evidence for a blood glucose threshold blood glucose of 160 Ϯ 84 mg/dl. In mul- unit and were receiving mechanical ven- in cardiac surgery and critical care. tivariate analysis, as admission blood glu- tilation. Reasons for ICU admission were ● Furnary et al. (196) and Zerr et al. (198) cose increased, the odds for neurologic cardiac surgery (ϳ60%) and noncardiac identified a reduction in mortality improvement decreased with an OR of indications, including neurologic disease throughout the blood glucose spectrum 0.76 per 100 mg/dl increase in admission (cerebral trauma or brain surgery), other with the lowest mortality in patients glucose (95% CI 0.61–0.95, P ϭ 0.01) thoracic surgery, abdominal surgery or with blood glucose Ͻ150 mg/dl (8.3 (201). Subgroup analysis for patients peritonitis, vascular surgery, multiple mmol/l). with or without a history of diabetes was trauma, or burns and transplant (4–9% ● Van den Berghe et al. (2), using inten- not done. Pulsinelli et al. (202) reported each group). Patients were randomized to sive intravenous insulin therapy, re- worse outcomes for both patients with di- receive intensive insulin therapy (IIT) to ported a 45% reduction in ICU abetes and hyperglycemic patients with- maintain target blood glucose in the 80– mortality with a mean blood glucose of out an established diagnosis of diabetes 110 mg/dl (4.4–6.1) range or conven- 103 mg/dl (5.7 mmol/l), as compared compared with those who were normo- tional therapy to maintain target blood with the conventional treatment arm, glycemic. Stroke-related deficits were glucose between 180 and 200 mg/dl (10– where mean blood glucose was 153 more severe when admission glucose val- 11.1 mmol/l). Insulin infusion was initi- mg/dl (8.5 mmol/l) in a mixed group of ues were Ͼ120 mg/dl (6.7 mmol/l). Only ated in the conventional treatment group patients with and without diabetes. 43% of the patients with an admission only if blood glucose exceeded 215 mg/dl glucose value of Ͼ120 mg/dl were able to (11.9 mmol/l), and the infusion was ad- Acute neurologic illness and stroke. In return to work, whereas 76% of patients justed to maintain the blood glucose level the setting of acute neurologic illness, with lower glucose values regained between 180 and 200 mg/dl (10.0 and stroke, and head injury, data support a employment. 11.1 mmol/l). After the patients left the weak association between hyperglycemia Demchuk et al. (203) studied the ef- ICU they received standard care in the and increased mortality and are scanty for fect of admission glucose level and risk for hospital with a target blood glucose of patients with known diabetes. In these intracerebral hemorrhage into an infarct

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 561 Management of diabetes and hyperglycemia in hospitals when treatment with recombinant tissue reduced salvage of mismatch tissue from Evidence for a blood glucose threshold plasminogen activator was given to 138 infarction, greater final infarct size, and in acute neurologic disorders. Obser- patients presenting with stroke. Twenty- worse functional outcome, independent vational studies suggest a correlation be- three percent of the cohort had known of baseline stroke severity, lesion size, and tween blood glucose level, mortality, diabetes. The authors reported admission diabetes status. Furthermore, higher morbidity, and health outcomes in pa- blood glucose and/or history of diabetes acute blood glucose in patients with per- tients with stroke. as the only independent predictors of fusion-diffusion mismatch was associated hemorrhage. Kiers et al. (204) prospec- with greater acute-subacute lactate pro- ● Capes et al.’s (96) metaanalysis identi- tively studied 176 sequential acute stroke duction, which, in turn, was indepen- fied an admission blood glucose Ͼ110 patients and grouped them by admission dently associated with reduced salvage of mg/dl (6.1 mmol/l) for increased mor- blood glucose level, HbA1c level, and his- mismatch tissue. Acute hyperglycemia in- tality for acute stroke. tory of diabetes. Threshold blood glucose creases brain lactate production and facil- ● Studies by Pulsinelli, Jorgenson, and for euglycemia was defined as fasting itates conversion of hypoperfused at-risk Weir et al. (202) identified an admis- Ͻ Ͼ blood glucose 140 mg/dl (7.8 mmol/l). tissue into infarction, which may ad- sion blood glucose 120 mg/dl (6.67 The authors divided patients into one of versely affect stroke outcome. mmol/l), 108 mg/dl (6 mmol/l), and four groups: euglycemia with no history These numerous observational stud- 144 mg/dl (8 mmol/l), respectively, for of diabetes, patients with “stress hyper- ies further support the need for random- increased severity ad mortality for acute Ͼ glycemia” (blood glucose 140 mg/dl, ized controlled trials that aggressively stroke. Ͻ ● 7.8 mmol/l, and HbA1c 8%), newly di- target glucose control in acute stroke. To Williams et al. (205) reported a thresh- agnosed diabetes (blood glucose Ͼ140 old admission blood glucose Ն130 Ͼ date, there is just one report of a treat-to- mg/dl, 7.8 mmol/l, and HbA1c 8%), and target intervention in stroke patients. The mg/dl (7.2 mmol/l) for increased mor- known diabetes. No difference was found Glucose Insulin in Stroke Trial (GIST) ex- tality, length of stay, and charges in in the type or site of stroke among the four acute stroke. amined the safety of GIK infusion in treat- ● groups. Compared with the euglycemic, ing to a target glucose of 72–126 mg/dl Scott et al. (206) demonstrated accept- nondiabetic patients, mortality was in- (4–7 mmol/l). Lowering plasma glucose able hypoglycemia risk and no excess creased in all three groups of hyperglyce- levels was found to be without significant 4-week mortality with glucose-insulin mic patients. infusion treatment targeted to blood risk of hypoglycemia or excess mortality Williams et al. (205) reported on the glucose range of 72–126 mg/dl (4–7 in patients with acute stroke and mild-to- association of hyperglycemia and out- mmol/l) in acute stroke. moderate hyperglycemia (206). No data comes in a group of 656 acute stroke pa- ● Parsons et al. (110) reported that a dou- on functional recovery were reported. tients. Fifty-two percent of the cohort had bling of blood glucose from 90 to 180 While it is promising that these investiga- a known history of diabetes. Hyperglyce- mg/dl (5–10 mmol/l) was associated tors were able to lower plasma glucose mia, defined as a random blood glucose with 60% worsening of penumbral sal- Ն130 mg/dl (7.22 mmol/l), was present without increasing risk of hypoglycemia vage and a 56-cm3 increase in infarct in 40% of patients at the time of admis- or mortality for stroke patients, until fur- size. sion. Hyperglycemia was an independent ther studies test the effectiveness of this predictor of death at 30 days (RR 1.87) approach and possible impact on out- HOW ARE TARGET BLOOD and at 1 year (RR 1.75) (both P Յ 0.01). comes, it cannot be considered standard GLUCOSE LEVELS BEST Other outcomes that were significantly practice. ACHIEVED IN THE correlated with hyperglycemia, when Hyperglycemia is associated with HOSPITAL? compared with normal blood glucose, worsened outcomes in patients with acute were length of stay (7 vs. 6 days, P ϭ stroke and head injury, as evidenced by Role of oral diabetes agents 0.015) and charges ($6,611 vs. $5,262, the large number of observational studies No large studies have investigated the po- P Ͻ 0.001). in the literature. It seems likely that the tential roles of various oral agents on out- Recently, Parsons et al. (110) re- hyperglycemia associated with these comes in hospitalized patients with ported a study of magnetic resonance im- acute neurologic conditions results from diabetes. A number of observational stud- aging (MRI) and MRS in acute stroke. the effects of stress and release of insulin ies have commented on the outcomes of Sixty-three acute stroke patients were counterregulatory hormones. The ele- patients treated as outpatients with diet prospectively evaluated with serial diffu- vated blood glucose may well be a marker alone, oral agents, or insulin. However, sion-weighted and perfusion-weighted of the level of stress the patient is experi- the results are variable and the methods MRI and acute blood glucose measure- encing. The hyperglycemia can be cannot account for patient characteristics ments. Median acute blood glucose was marked in these patients. Studies are that would influence clinician selection of 133.2 mg/dl (7.4 mmol/l), range 104.4– needed to assess the role of antihypergly- the various therapies in the hospital set- 172.8 mg/dl (5.8–9.6 mmol/l). A dou- cemic pharmacotherapy in these settings ting. Of the three primary categories of bling of blood glucose from 90 to 180 for possible impact on outcomes. Clinical oral agents, secretagogues (sulfonylureas mg/dl (5Ϫ10 mmol/l) led to a 60% reduc- trials to investigate the impact of targeted and meglitinides), biguanides, and thia- tion in penumbral salvage and a 56 cm3 glycemic control on outcomes in patients zolidinediones, none have been systemat- increase in final infarct size. For patients with stress hyperglycemia and/or known ically studied for inpatient use. However, with acute perfusion-diffusion mismatch, diabetes and acute neurologic illness are all three groups have characteristics that acute hyperglycemia was correlated with needed. could impact acute care.

562 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Clement and Associates

Sulfonylureas buride but not by glimepiride. In per- sion found sulfonylurea use to be inde- Concern about inpatient use of sulfonyl- fused animal heart models, both pendently associated with increased ureas centers on vascular effects glimepiride and glyburide also appear to hospital mortality. Others have reported (207,208). Over 30 years ago the report of reduce baseline coronary blood flow at similar trends in patients receiving angio- the University Group Diabetes Program high doses (220,224). plasty (230). A third observational study proposed increased cardiovascular events Cardiac effects of sulfonylureas have investigated 636 elderly patients with di- in patients treated with sulfonylureas also been compared with other classes of abetes (mean age 80 years) and previous (209). This report resulted in an ongoing oral diabetes medications. In individuals MI. The researchers looked for subse- labeling caution for sulfonylureas and with type 2 diabetes, investigators found quent coronary events, including fatal heart disease, although the findings have that glyburide increased QT dispersion and nonfatal MI or sudden coronary been questioned and have had very lim- (225). This effect, proposed to reflect risk death (231). They found sulfonylurea ited influence on prescribing habits. Re- for arrhythmias, was measured after 2 therapy to be a predictor of new coronary sidual fears seemingly were allayed with months of therapy with glyburide or met- events compared with insulin or to diet the findings of the U.K. Prospective Dia- formin. Glyburide also increased QTc, therapy (82 vs. 69 and 70%, respectively). betes Study (UKPDS) (210). This large while metformin produced no negative Not enough metformin-treated patients prospective trial did not find any evidence effects. This study is in contradiction to were included to comment statistically on of increased frequency of MI among indi- the conclusions of a study using isolated a comparison with sulfonylureas. viduals treated with sulfonylureas. rabbit hearts, where glyburide exerted an Conversely, other observational stud- Rather, the trend was in the direction of antiarrhythmic effect despite repeat evi- ies have failed to support a relationship reduced events. However, questions re- dence that it interfered with postischemic between sulfonylurea use and vascular main. For instance, it is possible that con- hyperemia (226). There have been few events. Klaman et al. (232) found no dif- trol of hyperglycemia by any means other comparisons of sulfonylureas and ferences in mortality or creatinine kinase reduces the frequency of vascular events metformin with regard to direct cardiac (CK) elevations after acute MI in 245 pa- to a greater extent than any effect sulfo- effects. In a study of rat ventricular myo- tients with type 2 diabetes when compar- nylureas may have to increase vascular cytes, hyperglycemia induced abnormali- ing those treated with insulin, those events. A variety of studies have served to ties of myocyte relaxation. These treated with oral agents, or those newly fuel continued controversy. abnormalities were improved when myo- diagnosed. Others have reported a similar Ischemic preconditioning appears to cytes were incubated with metformin, but lack of association with MI outcomes and be an adaptive, protective mechanism glyburide had no beneficial effect (227). sulfonylureas (233–236). In one study, serving to reduce ischemic injury in hu- Finally, one experiment recently evalu- ventricular fibrillation was found to be mans (211,212). Sulfonylureas inhibit ated the relative functional cardiac effects less associated with sulfonylurea therapy ATP-sensitive potassium channels, result- of glyburide versus insulin (228). In this than with gliclazide or insulin (234). Fi- ing in cell membrane depolarization, ele- study of patients with type 2 diabetes, left nally, in a related vascular consideration, vation of intracellular calcium, and ventricular function was measured by there was no evidence of increased stroke cellular response (213,214). This mecha- echocardiography after 12-week treat- mortality or severity in patients with type nism may inhibit ischemic precondition- ment periods with each agent, attaining 2 diabetes treated with sulfonylureas ver- ing (215–217). Various methods similar metabolic control. Neither treat- sus other therapies (237). evaluating cardiac ischemic precondi- ment influenced resting cardiac function. None of the studies looking at sulfo- tioning have been used to compare cer- However, after receiving dipyridamole, nylurea effects on vascular inpatient mor- tain of the available sulfonylureas. For glyburide-treated patients experienced tality have been prospective. Investigators example, using isolated rabbit hearts, re- decreased left ventricular ejection fraction have not made attempts to separate out searchers found that glyburide but not and increased wall motion score index. duration of therapy or whether sulfonyl- glimepiride reversed the beneficial effects Insulin treatment did not produce these ureas were continued after presentation of ischemic preconditioning and diazox- deleterious effects on contractility. to the hospital. The one prospective study ide in reducing infarct size (218). Other Although these various findings using looking at treatment after admission for studies using similar animal heart models different research models raise questions AMI indicated a benefit for insulin ther- or cell cultures have found differences about potential adverse cardiovascular ef- apy over conventional therapy with sulfo- among the sulfonylureas, usually show- fects of sulfonylureas in general and gly- nylureas, but the improved outcomes ing glyburide to be potentially more buride in particular, they do not were proposed to occur as a benefitof harmful than other agents studied (219– necessarily extrapolate to clinical rele- improved glucose control (238). No sug- 222). A unique, double-blind, placebo- vancy. A series of observational studies gestion was made that sulfonylurea ther- controlled study using acute balloon have attempted to add to our knowledge apy had specific negative effects. occlusion of high-grade coronary steno- about whether any of the negative effects Despite a spectrum of data raising ses in humans looked at the relative ef- of sulfonylureas impact on vascular concern about potential adverse effects of fects of intravenously administered events, but they have yielded mixed re- sulfonylureas in the inpatient setting, placebo, glimepiride, or glyburide (223). sults. For example, outcomes of direct where cardiac or cerebral ischemia is a The researchers measured mean ST seg- balloon angioplasty after AMI were eval- frequent problem in an at-risk popula- ment shifts and time to angina. The re- uated comparing 67 patients taking sulfo- tion, there are insufficient data to specifi- sults again demonstrated suppression of nylureas with 118 patients on other cally recommend against the use of the myocardial preconditioning by gly- diabetes therapies (229). Logistic regres- sulfonylureas in this setting. However,

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 563 Management of diabetes and hyperglycemia in hospitals sulfonylureas have other limitations in the seems prudent to avoid the use of met- insulin physiology and the pharmacoki- inpatient setting. Their long action and formin in most patients. In addition to the netics of exogenous insulin is essential for predisposition to hypoglycemia in pa- risk of lactic acidosis, metformin has providing effective insulin therapy. The tients not consuming their normal nutri- added side effects of nausea, diarrhea, and inpatient insulin regimen must be tion serve as relative contraindications to decreased appetite, all of which may be matched or tailored to the specific clinical routine use in the hospital for many pa- problematic during acute illness in the circumstance of the individual patient. tients (239). Sulfonylureas do not gener- hospital. Components of the insulin dose re- ally allow rapid dose adjustment to meet quirement defined physiologically. In the changing inpatient needs. Sulfonyl- Thiazolidinediones the outpatient setting, it is convenient to ureas also vary in duration of action be- Although thiazolidinediones have very think of the insulin dose requirement in tween individuals and likely vary in the few acute adverse effects (249,250), they physiologic terms as consisting of “basal” frequency with which they induce hypo- do increase intravascular volume, a par- and “prandial” needs. In the hospital, nu- glycemia (240). ticular problem in those predisposed to tritional intake is not necessarily provided CHF and potentially a problem for pa- as discrete meals. The insulin dose re- Metformin tients with hemodynamic changes related quirement may be thought of as consist- Metformin represents a second agent that to admission diagnoses (e.g., acute coro- ing of “basal” and “nutritional” needs. The individuals are likely to be using as an nary ischemia) or interventions common term “nutritional insulin requirement” re- outpatient, with potential for continua- in hospitalized patients. The same study fers to the amount of insulin necessary to tion as an inpatient. There is a suggestion of Medicare patient hospital data cited cover intravenous dextrose, TPN, enteral from the UKPDS that metformin may above (247) found that 16.1% of patients feedings, nutritional supplements admin- have cardioprotective effects, although with diabetes and CHF received a pre- istered, or discrete meals. When patients the study was not powered to allow for a scription for a thiazolidinedione at the eat discrete meals without receiving other comparison with sulfonylureas (241). time of discharge. Twenty-four percent of nutritional supplementation, the nutri- The major limitation to metformin patients with these combined diagnoses tional insulin requirement is the same as use in the hospital is a number of specific received either metformin or a thiazo- the “prandial” requirement. The term contraindications to its use, many of lidinedione, both drugs carrying contra- “basal insulin requirement” is used to re- which occur in the hospital. All of these indications in this setting. fer to the amount of exogenous insulin contraindications relate to a potentially Most recently it has been demon- per unit of time necessary to prevent un- fatal complication of metformin therapy, strated that when exposed to high con- checked gluconeogenesis and ketogenesis. lactic acidosis. The most common risk centrations of rosiglitazone, a monolayer An additional variable that deter- factors for lactic acidosis in metformin- of pulmonary artery endothelial cells will mines total insulin needs in the hospital is treated patients are cardiac disease, in- exhibit significantly increased permeabil- an increase in insulin requirement that cluding CHF, hypoperfusion, renal ity to albumin (251). Although this is a generally accompanies acute illness. Insu- insufficiency, old age, and chronic pul- preliminary in vitro study, it raises the lin resistance occurs due to counterregu- monary disease (242). In an outpatient possibility of thiazolidinediones causing a latory hormone responses to stress (e.g., setting, using slightly variable criteria, direct effect on capillary permeability. surgery) and/or illness and the use of cor- 22–54% of patients treated with met- This process may be of greater signifi- ticosteroids, pressors, or other diabeto- formin have absolute or relative contrain- cance in the inpatient setting. On the pos- genic drugs. The net effect of these factors dications to its use (242–245). One recent itive side, thiazoladinediones may have is an increase in insulin requirement, report noted that 27% of patients on met- benefits in preventing restenosis of coro- compared with a nonsick population. formin in the hospital had at least one nary arteries after placement of coronary This proportion of insulin requirement contraindication to its use (246). In 41% stents in patients with type 2 diabetes specific to illness is referred to as “illness” of these cases, metformin was continued (252). For inpatient glucose control, or “stress-related” insulin and varies be- despite the contraindication. This study however, thiazolidinediones are not suit- tween individuals (Fig. 2). seemingly underestimates the usual fre- able for initiation in the hospital because Is the patient insulin deficient or non– quency of contraindications since it iden- the onset of effect, which is mediated insulin deficient? As in the outpatient tified no individuals with CHF, a risk through nuclear transcription, is quite setting, a key component to providing ef- factor that has been frequently noted in slow. fective insulin therapy in the hospital set- many of the outpatient studies. Not sur- In summary, each of the major classes ting is determining whether a patient has prisingly, a recent review of hospital of oral agents has significant limitations the ability to produce endogenous insu- Medicare data found that 11.2% of pa- for inpatient use. Additionally, they pro- lin. Patients who have a known history of tients with concomitant diagnoses of dia- vide little flexibility or opportunity for ti- type 1 diabetes are by definition insulin betes and CHF were discharged with a tration in a setting where acute changes deficient (3). In addition, other clinical prescription of metformin (247). demand these characteristics. Therefore, features may be helpful in determining Recent evidence continues to indicate insulin, when used properly, may have the level of insulin deficiency (Table 2). lactic acidosis is a rare complication, de- many advantages in the hospital setting. Patients determined to be insulin defi- spite the relative frequency of risk factors cient require basal insulin replacement to (248). However, in the hospital,where the Use of insulin prevent iatrogenic diabetic ketoacidosis, risk for hypoxia, hypoperfusion, and re- As in the outpatient setting, in the hospi- i.e., they must be treated with insulin at nal insufficiency is much higher, it still tal a thorough understanding of normal all times.

564 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Clement and Associates

Figure 2—Insulin requirements tinct peaks and prolonged action, can be in health and illness. Components used for both their basal and prandial in- of insulin requirement are divided sulin effects. For hospitalized patients into basal, prandial or nutritional, with severe insulin deficiency, this can and correction insulin. When writ- be a disadvantage since the timing of ing insulin orders, the basal and prandial/nutritional insulin doses meals and the quantity of food is often are written as programmed inconsistent. (scheduled) insulin, and correc- Basal insulin therapy for patients who tion-dose insulin is written as an are not eating. While not eating, pa- algorithm to supplement the tients who are not insulin deficient may scheduled insulin (see online ap- not require basal insulin. Since reduction pendix 2). Programmed and cor- of caloric intake may alter insulin resis- rection insulin are increased to tance substantially in type 2 diabetes, meet the higher daily basal and sometimes allowing previously insulin- prandial or nutritional require- requiring patients to be controlled with ments. Total insulin requirements may vary widely. endogenous insulin production alone, the basal requirement is not easily deter- mined. However, withholding basal insu- Subcutaneous insulin therapy. Subcu- lin) or of long-acting insulin analogs. lin in insulin-deficient patients results in a taneous insulin therapy may be used to Some of these methods result in peaks of rapid rise in blood glucose by 45 mg/dl attain glucose control in most hospital- insulin action that may exceed the basal (2.5 mmol/l) per hour until ketoacidosis ized patients with diabetes. The compo- needs of the patient, causing hypoglyce- occurs (rev. in 254). This situation can nents of the daily insulin dose mia. This is most likely to occur as the occur when “sliding scale” insulin therapy requirement can be met by a variety of acute illness begins to resolve and basal is the sole method of insulin coverage insulins, depending on the particular hos- insulin requirements that were elevated (255). Scheduled basal insulin therapy for pital situation. Subcutaneous insulin due to stress and/or illness begin to return patients who are not eating can be pro- therapy is subdivided into programmed to normal levels. Although selected in vided by a number of insulin types and or scheduled insulin and supplemental or part for basal coverage, NPH, lente, and to methods. correction insulin (Table 3). some extent ultralente insulin also deliver Insulin for patients with intermittent Scheduled insulin therapy. This review peaks of insulin that potentially can cover nutritional intake. Hospitalized pa- will use the term “programmed” or prandial needs, albeit with variable capa- tients may receive nutrition intermit- “scheduled insulin requirement” to refer bility for matching the timing of nutri- tently, as with patients who are being to the dose requirement in the hospital tional intake. When NPH insulin is used transitioned between NPO status and reg- necessary to cover the both basal and nu- in very low doses, it can also be adminis- ular diet, patients with anorexia or nau- sea, or patients receiving overnight tritional needs. For patients who are eat- tered four times daily as an alternate way cycling of enteral feedings. Appropriate ing discrete meals, it is appropriate to to provide basal insulin action (253). insulins used in combination therapy consider the basal and prandial compo- Prandial insulin therapy for patients might include regular, intermediate, and nents of the insulin requirement separately. who are eating. Prandial insulin re- Basal insulin therapy for patients who long-acting insulins or analogs, adminis- placement has its main effect on periph- are eating. Subcutaneous basal insulin tered to cover basal needs and also timed eral glucose disposal into muscle. Also can be provided by any one of several to match the intermittent nutritional intake. referred to as “bolus” or “mealtime” insu- strategies. These include continuous sub- Illness-related or stress dose insulin lin, prandial insulin is usually adminis- cutaneous insulin infusion (CSII) or sub- therapy. The illness-related insulin can tered before eating. There are occasional cutaneous injection of intermediate- be apportioned between the basal insulin, acting insulin (including premixed insu- situations when this insulin may be in- the nutritional or prandial insulin, and jected immediately after eating, such as the correction doses. It is important to when it is unclear how much food will be point out that illness-related insulin re- Table 2—Clinical characteristics of the pa- eaten. In such situations, the quantity of quirements decrease as the patient’s con- tient with insulin deficiency carbohydrates taken can be counted and dition improves and, thus, in many an appropriate amount of rapid-acting ● Known type 1 diabetes situations may be difficult to precisely re- ● History of pancreatectomy or pancreatic analog can be injected. The technique of place (Fig. 2). In attempting to meet the dysfunction “carbohydrate counting” may be useful illness-related insulin requirement, and ● History of wide fluctuations in blood for patients practicing insulin self- to later return to lower doses, it is impor- glucose levels management. The rapid-acting insulin tant to recall that intravenous insulin in- ● History diabetic ketoacidosis analogs, insulin lispro and aspart, are ex- fusion gives the greatest flexibility and ● History of insulin use for Ͼ5 years and/or cellent prandial insulins. Regular insulin that long-acting analog gives the least, a history of diabetes for Ͼ10 years is more accurately considered to have with other preparations or routes being Adapted from the Expert Committee on the Diagno- both basal and prandial components due intermediate. Rapid changes in illness- sis and Classification of Diabetes Mellitus (3) and to its longer duration of action. Similarly, related insulin requirements necessitate consensus from the authors. NPH and lente insulins, with their dis- close blood glucose monitoring and daily

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 565 aaeeto ibtsadhprlcmai hospitals in hyperglycemia and diabetes of Management 566 Table 3—Practical guidelines for hospital use of insulin

Programmed/scheduled insulin option(s) Supplemental/correction-insulin Clinical setting Basal Prandial and/or nutritional option(s) Comments

● Total daily insulin requirement may be calculated based on prior insulin doses or as Ϫ Ϫ 0.6 units kg 1 day 1 ● Basal insulin generally accounts for 40–50% of daily insulin requirement ● Prandial and/or nutritional or supplemental/correction doses may be calculated as 10– 20% of total daily insulin requirement for each dose ● Patients with type 1 diabetes always require continuous insulin coverage to avoid ketosis Eating meals ● Int-I bid or hs ● Reg-I or rapid-I acϪ ● Reg-I or rapid-I ac ϩ/Ϫ hs ● Give Reg-I, 30–45 min ac; rapid-I, 0–15 min ac ● LA-I hs or am B&D or B, L, and D ● Glargine given as once-daily dose, usually at hs ● Insulin drip ● Avoid/minimize Reg-I and rapid-I doses at hs to decrease risk of nocturnal hypoglycemia ● 70/30 or 75/25 insulin may be used ac breakfast and dinner to meet both basal and prandial needs ● Insulin drip is Rx of choice in severely decompensated type 1, with or without DKA, and in type 2 with HHS Not eating ● Insulin drip N/A ● Reg-I q 4–6 hours ● Int-I bid or hs ● Rapid-I q 4 hours ● LA-I hs or am Perioperative or periprocedural Will eat post-op or Base on prior insulin Rx: When resumes eating Until resumes eating: ● Usual insulin and/or oral agent doses given the night prior to surgery to assure postprocedure (e.g., cataract ● Int-I give 1/2-2/3 usual am ● Restart prior doses of Reg-I or ● Reg-I q 4–6h adequate glycemic control on the morning of the procedure extraction, cardiac dose rapid-I ac ● Rapid-Iq4h ● Patients with diabetes should be on the OR list for the early morning to minimize catheterization, endoscopy) ● LA-I glargine, continue usual amount of time that they will be kept NPO. This decreases risk of hypoglycemia and dose pm prior allows maintenance of optimum metabolic homeostasis Will not eat (e.g., major ● Insulin drip N/A Until resumes eating: ● Where a prolonged postoperative npo period is anticipated, e.g., cardiothoracic, major surgery) ● Reg-I q 4–6 hours ● Reg-I q 4–6h abdominal, CNS cases, insulin drip Rx is recommended Ϫ Ϫ ● rapid-I q 4 hours ● Rapid-Iq4h ● Starting dose for perioperative maintenance insulin drip is 0.2 units kg 1 h 1 ● Int-I, give 1⁄2 usual am dose ● LA-I glargine, give usual daily dose ICU If npo and/or clinically If npo: ● Reg-I q 4–6h ● Evidence-based outcomes studies support use of insulin drip as Rx of choice for

D unstable: ● N/A ● Rapid-Iq4h decompensated diabetes in the ICU setting including coronary care (acute IABETES ● Insulin drip If eating: myocardial infarction) and surgical intensive care units (Malmberg, Van den Berghe, ● Reg-I q 4–6h ● Reg-I or RA-I ac and hs Furnary) ● Rapid-Iq4h C

ARE If eating: ● Continue prior Int-I or LA-I ,

VOLUME Enteral tube feeding Continuous 24 h: ● Reg-I q 4–6h ● Reg-I q 4–6 hours ● Basal insulin dose generally no more than 40% of total daily insulin requirement to avoid hypoglycemia if enteral feeding interrupted

27, ● Int-I bid; ● Rapid-Iq4h ● Rapid-I q 4 hours ● Nutritional insulin requirements met with programmed doses of reg-I or rapid-I ● LA-I hs or am ● May use low-dose int-I at hs to control fasting hyperglycemia NUMBER Daytime only: During tube feeding delivery ● If tube feeding interrupted, e.g., for procedure or intolerance, increase frequency of ● Int-I am period only: fingerstick BG checks ●

,F 2, Reg-I q 4–6h ● Rapid-Iq4h EBRUARY Bolus 24 h: ● Reg-I q 4–6h ● Reg-I q 4–6h ● Give reg-I, 30–45 mins, or rapid-I, 0–15 mins prior to bolus to control post-bolus BG ● Int-I bid; ● Rapid-Iq4h ● Rapid-Iq4h excursions ● LA-I hs or am ● Check finger stick BG 2 h after reg-I or 1 h after rapid-I to determine dose adjustments

2004 for post-bolus target BG Ͻ 180 mg/dl ● May use low-dose int-I at hs to control fasting hyperglycemia Clement and Associates

changes in the scheduled insulin doses, as the blood glucose levels dictate. Correction-dose insulin therapy. Also called “supplemental” insulin, this usu- ally refers to the insulin used to treat hy- perglycemia that occurs before meals or between meals. At bedtime, correction- dose insulin is often administered in a re- duced dose compared with other times of the day in order to avoid nocturnal hypo- glycemia. Correction-dose insulin may also refer to insulin used to correct hyper-

r 1 h after rapid-I to determine prandial insulin glycemia in the NPO patient or in the pa- 15 min prior to meal to control postprandial BG –

s TPN bag as reg-I, until daily dose determined tient who is receiving scheduled ’ nutritional and basal insulin but not eat-

180 mg/dl ing discrete meals. Correction-dose insu- Ͻ rosmolar state; hs, bedtime; I, insulin; Int-I, intermediate lin should not be confused with “sliding G 2 h after reg-I o scale insulin,” which usually refers to a set 45 min or rapid-I 0 12 h following once-daily GC dose y day; rapid-I, rapid acting insulin (lispro or aspart); Reg-I, regular – amount of insulin administered for hy- – perglycemia without regard to the timing ngerstick B fi of the food, the presence or absence of preexisting insulin administration, or insulin infusion for 24 hamount to to determine subsequent daily TPN insulin bags; requirement,the or then previous add add day 2/3 2/3 to of of the total this next units day of insulin administered SQ troughs with nutrient delivery may lead to erratic BG control excursions dose adjustments may occur 8 Basal and nutritional insulin needsTo met determine with daily reg-I dose added of to insulin TPN to bag add directly to TPN bag, consider use of separate IV Use SQ insulin with caution with TPN. Lack of correlation of insulin peaks and Give reg-I, 30 Postprandial target BG Check High-dose glucocorticoids raise insulin requirements Adjust/increase insulin doses to counter postprandial hyperglycemia and BG peak that Alternate-day steroid doses require alternate-day insulin doses ● ● ● ● ● ● ● ● ● even individualization of the patient’s sensitivity to insulin.

hs The traditional sliding scale insulin 6 – Ϫ / regimens, usually consisting of regular in- ϩ sulin without any intermediate or long- acting insulins, have been shown to be ineffective at best and dangerous at worst 6h – (255–257). Problems cited with sliding scale insulin regimens are that the sliding hours if NPO Reg-I q 4 Reg-I or rapid-I ac ac

ac and hs if eating; or q 4 scale regimen prescribed on admission is ● ● ● likely to be used throughout the hospital stay without modification (255). Second, sliding scale insulin therapy treats hyper-

6hif glycemia after it has already occurred, in- – stead of preventing the occurrence of hyperglycemia. This “reactive” approach 6h – can lead to rapid changes in blood glucose Iq4h levels, exacerbating both hyperglycemia only: D) if eating; or qNPO 4 Reg-I q 4 Rapid- Reg-I or rapid-I ac and hypoglycemia. ac (B and D) or ac (B, L, and During bolus delivery period ● ● ● Reg-I or RA-I: Reg-I or rapid-I: ● Correction-dose insulin therapy is an important adjunct to scheduled insulin, both as a dose-finding strategy and as a supplement when rapid changes in insu- lin requirements lead to hyperglycemia. If correction doses are frequently required, it is recommended that the scheduled in- sulin doses be increased the following day

or am to accommodate the increased insulin Int-I am Reg-I added to TPN bags Int-I bid LA-I hs or am Insulin drip; Int-I bid; LA-I hs ● ● ● ● ● needs. Writing insulin orders. An example of an insulin order form that prompts the physician to address all three components of insulin therapy (i.e., basal, prandial, and correction dose) is provided (see on- line appendix 1 [available at http:// care.diabetesjournals.org]). The forms can be incorporated into computerized TPN Bolus (cont.) Daytime only: Transition to oral intake insulin; SQ, subcutaneous. ac, before meals; am, morning; B, breakfast; BG, blood glucose; D, dinner; DKA, diabetic ketoacidosis; GC, glucocorticoid; HHS, hyperglycemic hype acting insulin (NPH or Lente); IV, intravenous; L, lunch; LA-I, long-acting insulin (glargine or ultralente); OR, operating room; q, every; qd, ever High-dose glucocorticoid Rx order sets and other prompting methods

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 567 Management of diabetes and hyperglycemia in hospitals

Table 4—Indication for intravenous insulin infusion among nonpregnant adults with estab- long-acting insulin. The desirability of in- lished diabetes or hyperglycemia fusing dextrose simultaneously depends on the blood glucose concentration and Strength of the condition for which the insulin infu- Indication Evidence sion is being used (275,288). Mixing the insulin infusion. Depend- Diabetic ketoacidosis and nonketotic hyperosmolar state A ing on availability of infusion pumps that General preoperative, intraoperative, and postoperative care C accurately deliver very low hourly vol- Postoperative period following heart surgery B umes, intravenous insulin therapy is con- Organ transplantation E ducted with regular crystalline insulin in a MI or cardiogenic shock A solution of 1 unit per 1 ml normal saline. Stroke E The concentrated infusion is piggy- Exacerbated hyperglycemia during high-dose glucocorticoid therapy E backed into a dedicated running intrave- NPO status in type 1 diabetes E nous line. Highly concentrated solutions Critically ill surgical patient requiring mechanical ventilation A may be reserved for patients requiring Dose-finding strategy, anticipatory to initiation or reinitiating of C volume restriction; otherwise, solutions subcutaneous insulin therapy in type 1 or type 2 diabetes as dilute as 1 unit insulin per 10 ml nor- mal saline may be used (306,307). When the more dilute solutions are used, at least to reduce errors. Practice guidelines for to achieve glycemic control, and most im- 50 ml of the insulin-containing solution using insulin under various clinical cir- portantly, nonglycemic patient outcomes. should be allowed to run through the tub- cumstances are summarized in Table 3. During intravenous insulin infusion used ing before use (308). It is prudent to pre- Intravenous insulin infusion. The only to control hyperglycemic crises, hypogly- pare and label the solutions in a central method of insulin delivery specifically de- cemia (if it occurs) is short-lived, whereas institutional pharmacy, if possible using veloped for use in the hospital is contin- in the same clinical settings repeated ad- the same concentration for all adult uous intravenous infusion, using regular ministration of subcutaneous insulin may patients. crystalline insulin. There is no advantage result in “stacking” of the insulin’s effect, The use of a “priming bolus” to initi- to using insulin lispro or aspart in an in- causing protracted hypoglycemia. As an ate intravenous insulin infusion is contro- travenous insulin infusion. The medical alternative to continuous intravenous in- versial (265). The half-life of an literature supports the use of intravenous fusion, repeated intravenous bolus ther- intravenous insulin bolus is about 4–5 insulin infusion in preference to the sub- apy also has been advocated for patients min (309), and, although tissue effects are cutaneous route of insulin administration with type 2 diabetes during anesthesia somewhat delayed, by 45 min insulin for several clinical indications among (305). blood levels return virtually to baseline. nonpregnant adults, including diabetic Depending on the indication for in- Because repeated intravenous bolus insu- ketoacidosis and nonketotic hyperosmo- travenous insulin infusion, caregivers lin therapy does not maintain adequate lar state (258–275); general preoperative, may establish different glycemic thresh- blood insulin levels or target tissue action intraoperative, and postoperative care olds for initiation of intravenous insulin of insulin, the initial priming bolus of in- (257,276–290); the postoperative period therapy. For patients not hyperglycemic travenous insulin, if used, must be fol- following heart surgery (142,196,198, initially, it is best to assign a blood glucose lowed by maintenance insulin infusion 290,291); organ transplantation (297); or threshold for initiation of the insulin in- therapy (310,311). cardiogenic shock (128,194,292–296) fusion that is below the upper limit of the Insulin infusion initiation. Com- and possibly stroke (147); exacerbated target range glucose at which the infusion monly, for unstressed normoglycemic hyperglycemia during high-dose glu- protocol aims. For patients with type 1 adults of average BMI, insulin infusion is cocorticoid therapy (297); NPO status diabetes, uninterrupted intravenous insu- initiated at 1 unit/h but adjusted as (298); critical care illness (2,299–301); lin infusion perioperatively is an accept- needed to maintain normoglycemia (i.e., and as a dose-finding strategy, anticipa- able and often the preferred method of the perioperative setting). The assump- tory to initiation or reinitiation of subcu- delivering basal insulin. For these pa- tion that ϳ50% of the ambulatory daily taneous insulin therapy in type 1 or type 2 tients, intravenous insulin infusion ther- insulin dose is the basal requirement can diabetes (Table 4) (302–304). Some of apy should be started before the end of also be used to estimate initial hourly re- these settings may be characterized by, or the anticipated timeframe of action of pre- quirements for a normoglycemic, un- associated with, severe or rapidly chang- viously administered subcutaneous insu- stressed patient previously treated with ing insulin requirements, generalized pa- lin, i.e., before hyperglycemia or ketosis insulin (312). Alternatively, a weight- tient edema, impaired perfusion of can develop. For patients having elective based insulin dose may be calculated us- Ϫ Ϫ subcutaneous sites, requirement for pres- surgery, hourly measurements of capil- ing 0.02 units kg 1 h 1 as a starting sor support, and/or use of total parenteral lary blood glucose may be ordered, and rate. A lower initial insulin infusion rate nutrition. In these settings the intrave- the intravenous infusion of insulin may be may be used for patients with low body nous route for insulin administration sur- initiated at a low hourly rate when rising weight or renal or hepatic failure or if the passes the subcutaneous route with blood glucose levels (Ͼ120 mg/dl, or 6.7 infusion is started within the timeframe of respect to rapidity of onset of effect in mmol/l) indicate waning of the effects of action of previously administered subcu- controlling hyperglycemia, overall ability previously administered intermediate or taneous insulin. A higher initiation rate

568 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Clement and Associates such as Ն2 units/h may be used when mia in a timely manner, provide a method tions. The initial doses of scheduled hyperglycemia is present, when pread- to determine the insulin infusion rate re- subcutaneous insulin are based on previ- mission insulin requirements are high, or quired to maintain blood sugars within a ously established dose requirements, pre- if the patient has conditions predicting defined the target range, include a rule for vious experience for the same patient the presence of insulin resistance. Among making temporary corrective increments during similar circumstances of nutri- hyperglycemic type 1 and type 2 diabetic or decrements of insulin infusion rate tional change or drug administration, re- patients who were otherwise well and re- without under- or overcompensation, quirements during continuous insulin ceiving no concomitant intravenous dex- and allow for adjustment of the mainte- infusion (if stable), knowledge of stability trose, the prime determinants of the initial nance rate as patient insulin sensitivity or or instability of medical condition and hourly intravenous insulin requirement carbohydrate intake changes. The algo- nutritional intake, assessment of medical are the initial plasma glucose and BMI. rithm should also contain directions as to stress, and/or body weight. Correction After attainment of normoglycemia, only how to proceed if hypoglycemia or a rapid doses for various ranges of total daily in- the BMI correlates with the hourly insulin fall in blood glucose occurs, as well as sulin requirement or body weight can be infusion requirement (313). It has been instructions as to how to transition the expressed in tabular form, as a compo- argued that the maximum biologic effect patient to scheduled subcutaneous insulin. nent of standardized inpatient orders (see of insulin might be expected at infusion Physician orders to “titrate drip” to a online appendix 1). For most insulin- rates of 10 units/h or less. However, some given target blood glucose range, or pro- sensitive patients, 1 unit of rapid-acting patients benefit from higher infusion rates tocols requiring application of mathemat- insulin will lower blood glucose by 50– according to setting, and use of hourly ical rules by nursing staff, may be difficult 100 mg/dl (2.8–5.6 mmol) (320). A re- insulin infusion rates as high as 50 units/h to implement. A mathematical algorithm duction of the correction dose at bedtime has been reported, particularly in the in- can be reduced to tabular form, in which is appropriate to reduce the risk of noc- tensive care setting (2). each column indicates different insulin turnal hypoglycemia. For patients whose Assignment and adjustment of the in- infusion rates necessary to maintain target insulin requirements are unknown and travenous insulin infusion rate is deter- range control and shows appropriate in- whose nutritional intake will be adequate, mined by the caregiver, based on fusions rates necessary for correction at an assumption concerning requirement knowledge of the condition of the patient, given blood glucose levels, accompanied for scheduled insulin based on body the blood glucose level, and the response weight would be about 0.5–0.7 units/kg by a rule for shifting between columns to previous therapy. Blood glucose deter- insulin per 24-h period for patients hav- (see online appendix 2 [available at http:// minations should be performed hourly ing type 1 diabetes and 0.4–1.0 units/kg care.diabetesjournals.org]) (314). It is until stability of blood glucose level has or more for patients having type 2 diabe- prudent to provide inservice teaching of been demonstrated for 6–8 h; then, the tes, starting low and working up to the pharmacy, nursing, and physician staff on frequency of blood glucose testing can be dose to meet demonstrated needs, with the use of insulin drip protocols (307). reduced to every 2–3 h. To avoid un- assignment of a corresponding scale for wanted excursions of blood glucose, es- Transition from intravenous to subcu- correction doses. If nutritional intake is pecially when making corrective changes taneous insulin therapy. To maintain severely curtailed, for type 1 diabetes the in the insulin infusion rate, the pharmaco- effective blood levels of insulin, it is nec- amount of scheduled insulin calculated dynamics of intravenous insulin adminis- essary to administer short- or rapid-acting by body weight should be reduced by tration and delay of tissue responsiveness insulin subcutaneously 1–2 h before dis- 50%. For type 2 diabetes, a safe initial following attainment of a given blood continuation of the intravenous insulin assumption in the absence of nutritional level of insulin must be considered. If infusion (191,199,315–319). An inter- intake would be that endogenous insulin concomitant infusion of dextrose is used, mediate or long-acting insulin must be in- might meet needs, requiring supplemen- caregivers must be alert to the effects of jected 2–3 h before discontinuing the tation only with correction doses, until abrupt changes of dextrose infusion rate. insulin infusion. In transitioning from in- results of monitoring indicate the further Well-conducted insulin infusion therapy travenous insulin infusion to subcutane- need for scheduled insulin. should demonstrate progressively smaller ous therapy, the caregiver may order Perioperative insulin requirements. In oscillations of the hourly insulin infusion subcutaneous insulin with appropriate the perioperative period for all type 1 di- rate and narrower excursions of blood duration of action to be administered as a abetic patients and for those type 2 dia- glucose, as the caregiver discovers the single dose or repeatedly to maintain betic patients with demonstrated insulin hourly rate that will maintain normogly- basal effect until the time of day when the deficiency, scheduled insulin intended to cemia for a given patient. choice of insulin or analog preferred for provide basal coverage should be admin- Many institutions use insulin infusion basal effect normally would be provided. istered on the night before surgery to as- algorithms that can be implemented by For example, a patient who normally uses sure optimum fasting blood glucose for nursing staff (2,189,194,197,200,280, glargine at bedtime and lispro before the operative room. If insulin intended to 298,301,304,307,314). Algorithms meals, and whose insulin infusion will be meet basal needs is normally adminis- should incorporate the concept that stopped at lunchtime, could receive a tered in the morning, in the case of type 1 maintenance requirements differ between dose of lispro and a one-time injection of diabetes the morning basal insulin is patients and change over the course of NPH before interruption of the insulin given without dose adjustment, and in the treatment. The algorithm should facilitate infusion. case of type 2 diabetes 50–100% of the communication between physicians and Initial scheduled insulin, dose deci- basal insulin is administered on the morn- nurses, achieve correction of hyperglyce- sions, and correction-dose calcula- ing of surgery. Correction doses may be

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 569 Management of diabetes and hyperglycemia in hospitals applied on the morning of surgery if the self-management is appropriate under the Table 5—Components for safe diabetes self- morning glucose concentration exceeds conditions of hospitalization. Compo- management in the hospital 180 mg/dl. nents of the program can include a phy- ● Perform simultaneous laboratory- Appropriate use of insulin self- sician order for self-management with measured capillary or venous blood test management. Recognition of the patient respect to selection of food from a general and patient-performed capillary blood rights, patient responsibilities, and the diet, self-monitoring of blood glucose, glucose test. The capillary blood glucose importance of patient-oriented care are self-determination and administration of test should be Ϯ15% of the laboratory critical to the care of diabetes (321–323). insulin dose, and ranges of insulin to be test. In the ambulatory setting, patient self- taken. Patient record-keeping, sharing of ● Demonstration that the patient can self- management has a favorable impact on results with nursing staff, and charting by administer insulin accurately. glycemic control and quality of life nursing staff of self-determined glucose ● Patient is alert and is able to make (324,325). Using the tools of multiple results and insulin administration should appropriate decisions on insulin dose. daily injections of insulin or CSII, patient occur. If a subcutaneous insulin pump is ● All insulin administered by the patient self-management has been shown to be used, provisions for assistance in trouble- and nurse is recorded in the medication capable of improving glycemic control shooting pump problems need to be in record. and microvascular outcomes (326–328). place. Assistance might be required if ● Physician writes order that the patient In multiple-dose insulin therapy, meal- equipment familiar to the patient is un- may perform insulin self-management. time treatment with rapid-acting insulin available, if refrigeration is required, or if analog improves hypoglycemia and post- physical autonomy is imperfect. For ex- prandial hyperglycemia in comparison ample, decision making about dosage type 1 and type 2 diabetes (343–347). In with conventional therapy in both type 2 may be intact, but manual dexterity or the hospital, multiple additional risk fac- (329) and type 1 diabetes (253,330– availability of easily reached injection tors for hypoglycemia are present, even 332). In comparison with conventional sites may be altered by the conditions of among patients who are neither “brittle” management using intermediate-acting hospitalization. Additionally, help may be nor tightly controlled. Patients who do insulin for basal effect, patients using required in a situation of increasing insu- not have diabetes may experience hypo- long-acting insulin analog for basal insu- lin resistance or period of NPO where the glycemia in the hospital, in association lin effect experience less overall or noctur- patient may not know how to adjust his or with factors such as altered nutritional nal hypoglycemia (333–336), better her insulin doses appropriately. state, heart failure, renal or liver disease, control of fasting plasma glucose levels Although the program should be de- malignancy, infection, or sepsis (348). Pa- (333,337), and lower HbA1c levels (333). veloped in compliance with institutional tients having diabetes may develop hypo- In CSII therapy, rapid-acting analogs im- and external regulatory requirements, glycemia in association with the same prove control for most patients (338– consideration should be given to permit- conditions (349). Additional triggering 340). Use of advanced carbohydrate ting self-use of equipment and drugs al- events leading to iatrogenic hypoglycemia counting and an insulin-to-carbohydrate ready in the possession of the patient but include sudden reduction of corticoste- ratio have markedly enhanced the success not normally on formulary. The program roid dose; altered ability of the patient to of patients to implement intensive self- should not create additional burdens for self-report symptoms; reduction of oral management (341). Patients familiar with dietary or nursing staff. As one of the intake; emesis; new NPO status; reduc- their own needs sometimes have experi- likely barriers to implementation, institu- tion of rate of administration of intra- enced adverse events or, perceiving threat tions should recognize that fear of not venous dextrose; and unexpected inter- of adverse events, express frustration with only causing patient harm, but also of ex- ruption of enteral feedings or parenteral rigidity of hospital routine and delegation posure of deficiencies of knowledge and nutrition. Under-prescribing needed of decision making to providers who are skill, may underlie staff resistance to pa- maintenance antihyperglycemic therapy less likely to understand their immediate tient self-management programs. Staff is not always fully protective against such needs. may be trained in advance to understand causes of hypoglycemia. Nevertheless, Self-management in the hospital may that proficiency in making intensive man- fear of hypoglycemia may contribute to be appropriate for competent adult pa- agement decisions or using specialized inadequate prescribing of scheduled dia- tients who have stable level of conscious- equipment is not expected of them by ei- betes therapy or inappropriate reliance ness and reasonably stable known daily ther their employer or the patient. Orders upon “sliding scale” monotherapy insulin requirements and successfully to replace self-management with provid- (255,256,350). conduct self-management of diabetes at er-directed care should be written when Despite the preventable nature of home, have physical skills appropriate to changing the condition of the patient many inpatient episodes of hypoglyce- successfully self-administer insulin, per- makes self-management inappropriate mia, institutions are more likely to have form self-monitoring of blood glucose, (342). Table 5 summarizes the compo- nursing protocols for treatment of hypo- and have adequate oral intake. Appropri- nents necessary for diabetes self- glycemia than for its prevention (351– ate patients are those already proficient in management. 359). Nursing and pharmacy staff must carbohydrate counting, use of multiple remain alert to the effects of antihypergly- daily injections of insulin or insulin pump Preventing hypoglycemia cemic therapy that may have been admin- therapy, and sick-day management. The Hypoglycemia, especially in insulin- istered on a previous shift. Various patient and physician in consultation treated patients, is the leading limiting conditions creating a high risk for hypo- with nursing staff must agree that patient factor in the glycemic management of glycemia are listed in Table 6. If identified,

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Table 6—Conditions creating high risk for problem. Although in some patients the For most institutionalized patients, it is hypoglycemia in patients receiving scheduled hyperglycemia, if present, may be mild, in recommended that protein intake should Ϫ Ϫ (programmed) insulin others the glucocorticoids may be respon- be 1.2–1.5 g kg 1 day 1 (375). Most ● Sudden NPO status or reduction in oral sible for hyperosmolar hyperglycemic currently available standard formulas intake syndrome (371). The best predictors of contain 25–40% of total calories from fat. ● Enteral feeding discontinued glucocorticoid-induced diabetes are fam- There is current controversy as to how ● TPN or intravenous dextrose ily history of diabetes, increasing age, and much of this fat source should be from discontinued glucocorticoid dose. n-3 compared with n-6 fatty acids. Not ● Premeal insulin given and meal not There are few studies examining how surprisingly, products that are lower in ingested to best treat glucocorticoid-induced hy- carbohydrate and higher in dietary fiber ● Unexpected transport from nursing unit perglycemia. Thiazolidinediones may be and fat have less of an impact on diabetes after rapid-action insulin given effective for long-term treatment with control (376,377). ● Reduction in corticosteroid dose glucocorticoids (372), but no insulin sen- There is only one study reporting gly- sitizer would be appropriate for the initial cemic outcomes for people with type 2 management of acute hyperglycemia in diabetes receiving different enteral for- preventive strategies could potentially the hospital due to the fact their antihy- mulas (378). Thirty-four patients were include a provision, under protocol or by perglycemic effects will take weeks to oc- randomized to a reduced-carbohydrate, physician order, to perform blood glucose cur. There is also an uncontrolled report modified fat enteral formula or a standard testing more frequently and, for falling suggesting that chromium may be benefi- high-carbohydrate feeding. After 3 levels, to take preventive action. cial for this population (373). Insulin is months, HbA1c levels were lower for the recommended as the drug of choice for group receiving the reduced-carbohy- Special situations: TPN the treatment of glucocorticoid-induced drate formula, but this did not reach Hyperglycemia in patients without diabe- hyperglycemia. Although data are not statistical significance. For those random- tes from TPN is based on a variety of fac- available, due to the effect of glucocorti- ized to the high-carbohydrate formula, tors—age (360), severity of illness (361), coids on postprandial glucose, an empha- HDL cholesterol levels were lower and tri- and the rate of dextrose infusion (362)— sis on the use of prandial insulin would be glyceride concentrations were higher. In- all of which affect the degree of hypergly- expected to have the best results. For pa- terestingly, in this small study, the group cemia. In individuals with preexisting tients receiving high-dose intravenous receiving the reduced-carbohydrate for- type 2 diabetes not previously receiving glucocorticoids, an intravenous insulin mula had 10% fewer infections. insulin therapy, 77% of patients required infusion may be appropriate (306). The There are no clinical trial data exam- insulin to control glycemia during TPN insulin dose requirements are extremely ining different strategies of insulin re- (363). Insulin doses in this group aver- difficult to predict, but with the insulin placement for this population. For aged 100 Ϯ 8 units/day. infusion it is possible to quickly reach the intermittent enteral feedings such as noc- There are no controlled trials examin- required insulin dosing. Furthermore, for turnal tube feeding, NPH insulin, usually ing which strategies are best for this situ- short glucocorticoid boluses of no more with a small dose of regular insulin, works ation. Adding incremental doses of than 2 or 3 days, the insulin infusion al- well. The NPH insulin provides basal in- insulin to the TPN is one option, but this lows appropriate tapering of insulin infu- sulin coverage, while the regular insulin is may require days to determine the correct sion rates so that glycemic control is not administered before each tube feeding to insulin dose (306). The use of a separate compromised and hypoglycemic risks control postprandial glucose levels. Doses intravenous insulin infusion brings most can be minimized as steroid doses are re- should be calculated based on capillary patients within target within 24 h (364). duced. It should be emphasized that if glucose testing before and 2 h after each Two-thirds to 100% of the total number intravenous insulin is not used, there will enteral feeding period. Continuous feed- of units of insulin used in the variable rate be a greater increase in prandial com- ing may be managed by several different infusion over the previous 24-h period pared with basal insulin doses. There are strategies; again, however, there are no can subsequently be added to the subse- no trials comparing the use of insulin lis- data that have examined these manage- quent TPN bag(s) (306,365). pro or insulin aspart to regular insulin for ment strategies. One could use once- or this situation. twice-daily insulin glargine. Ideally, one Special situations: glucocorticoid would start with a small basal dose and therapy Special situations: enteral feeding use correction-dose insulin as needed Glucocorticoids are well known to affect Current enteral nutrition formulas are while the glargine dose is being increased. carbohydrate metabolism. They increase generally high in carbohydrate (with an Alternatively, the initial dose could be es- hepatic glucose production, inhibit glu- emphasis on low–molecular weight car- timated by the amount of insulin required cose uptake into muscle, and have a com- bohydrates) and low in fat and dietary fi- from a 24-h intravenous insulin infusion. plex effect on ␤-cell function (366–368). ber. Carbohydrates contribute 45–92% of This, however, may not be an accurate The decrease in glucose uptake with glu- calories (374). There are a variety of dif- assessment of actual subcutaneous insu- cocorticoids seems to be the major early ferent protein sources in these enteral lin needs. The major concern about using defect (369,370), and thus it is not sur- feedings, and there are no contraindica- insulin glargine or ultralente insulin for prising that for hospitalized patients with tions for use of any of these in people with this population is that when the enteral well-controlled type 2 diabetes, postpran- diabetes. Generally, enteral formulas con- feeding is discontinued, whether planned dial hyperglycemia is the most significant tain 7–16% of total calories from protein. or not, the subcutaneous insulin depot

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 571 Management of diabetes and hyperglycemia in hospitals will result in a high risk of hypoglycemia, tion (391), and insulin has been identified identify instances of hyperglycemia, at particularly if large doses of insulin are as one of several medications that deserve many institutions point-of-care measure- required. The use of NPH or regular insu- high alert status (392,393). Hypoglyce- ments will escape detection unless values lin for this situation is also problematic mia may result from drug-dispensing er- are scanned into an electronic databank since the peaks and troughs of insulin do rors, including mistaken administration (417). Severe hyperglycemia (at least one not match the insulin requirements ne- of hypoglycemic agents to nondiabetic glucose level Ͼ400– 450 mg/dl), pro- cessitated by the carbohydrate infusion. patients. For diabetic patients, frank pre- longed hyperglycemia (at least three con- Although there is no ideal way to manage scribing errors, the use of trailing zeros secutive glucose levels Ͼ250 mg/dl), and this problem, the safest appears to main- after decimal points, or misinterpreted ketosis all can be used as quality-control tain target blood glucose at the high end abbreviations for insulin may compro- indicators. The time from presentation to of the target range using basal insulins. mise patient safety (394–397). Because the emergency room with hyperglycemic When the tube feeding is discontinued, capital “U” can be mistaken for a numeral emergency to the initiation of an insulin either enteral or parenteral glucose must when handwritten, the word “units”s- infusion may be viewed as a quality issue be infused until the subcutaneous insulin hould be spelled out in physician orders (268). The use of a balanced emphasis on has dissipated. (391,398). The erroneous administration both hypoglycemia and hyperglycemia by of a large dose of rapid-acting insulin in hospital quality-improvement programs HOW CAN SYSTEM DESIGN place of insulin glargine can easily occur, has been linked to changes in practice AND IMPLEMENTATION since insulin glargine and rapid-acting in- patterns that result in improved control IMPROVE DIABETES CARE sulins look the same in the vial (both are (418–420). IN THE HOSPITAL? — The design clear). Barcoding of drugs and pharmacist and implementation of protocols for participation in rounds and in surveil- WHAT IS THE ROLE OF maintaining glucose control in the hospi- lance of prescribing patterns may help re- DIABETES SELF- tal may provide useful guidance to the duce errors (399–404). Although some MANAGEMENT EDUCATION treating physician. Diabetes management emphasis has been placed on institutional FOR THE HOSPITALIZED may be offered effectively by primary care standardization of sliding scales PATIENT? — Teaching diabetes self- physicians or hospitalists, but involve- (382,405), sliding scale monotherapy it- management to patients in hospitals is a ment of appropriately trained specialists self has been considered to be both inef- difficult and challenging task. Patients are or specialty teams may reduce length of fective compared with anticipatory hospitalized because they are ill, are un- stay, improve glycemic control, and im- management and frequently dangerous. A der increased stress related to their hospi- prove outcomes (314,379–381). For a computerized order entry system can re- talization and diagnosis, and are in an variety of conditions, outcomes under duce utilization of sliding scale manage- environment that is not conducive to standardized pathways or dose titration ment (406). With present-day learning. In addition, patients are often protocols are superior to those achieved monitoring techniques, the inhouse de- unable to get the optimal amount of rest by individualization of care (382). In eval- velopment of ketoacidosis or hyperglyce- because of various distractions, such as uation of institutional performance, vari- mic hyperosmolar state is generally the telephone, TV, personnel, meal times, ability of treatment strategies among preventable, and any occurrence should testing, and procedures. The shock of di- providers may itself be interpreted as a suggest the need for a root cause analysis agnosis, denial, anger, grief, and many risk factor for unsafe practices, and “stan- (407–415). By tracking transfers or read- emotions frequently prevent or impair the dardization to excellence” may be inter- missions to the intensive care unit, it is person’s ability to meaningfully partici- preted as a surrogate for patient safety sometimes possible to detect an opportu- pate in the educational process. Ideally, (322,383). In the care of diabetes, imple- nity for improvement, such as a recurrent people with diabetes should be taught at a mentation of standardized order sets for pattern of failure to administer scheduled time and place conducive to learning: as scheduled and correction-dose insulin subcutaneous insulin at the termination an outpatient in a nationally recognized may reduce reliance on sliding scale man- of insulin infusion leading to develop- program of diabetes education classes. agement (307). A team approach is ment of metabolic emergency. For the hospitalized patient, diabetes needed to establish hospital pathways. To Both hypoglycemia and hyperglyce- “survival skills” education is generally implement intravenous infusion of insu- mia are patient safety issues appropriate considered a feasible approach. Patients lin for the majority of patients having pro- for continuous quality improvement are taught sufficient information to enable longed NPO status, hospitals will need (CQI) analysis. Nevertheless, as a focus them to go home safely. Those newly di- multidisciplinary support for using insu- for institutional CQI activities, hypogly- agnosed with diabetes or who are new to lin infusion therapy outside of critical care cemia receives more attention, and hypo- insulin and or blood glucose monitoring units. glycemic events are more readily defined need to be instructed before discharge to Patient safety, quality of care, vari- and ascertained. Pharmacies can readily help ensure safe care upon returning ability of practice, and medical error have track for example the dispensing of D50 home. Those patients hospitalized be- been the subjects of increasing national as an “antidote,” administered by nursing cause of a crisis related to diabetes man- concern (384–390). Quality assessment staff without physician orders, or detect agement or poor care at home need programs that strive to promote a “culture hypoglycemia through analysis of reports education to hopefully prevent subse- of safety” commonly focus on diabetes. It of adverse drug reactions (416). In con- quent episodes of hospitalization. Goals has been reported that 11% of medication trast, although computer searches of the of inpatient diabetes self-management ed- errors result from insulin misadministra- laboratory databank may be used to help ucation (DSME) are listed in Table 7.

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Table 7—Goals of inpatient DSME on topics immediately relevant to the pa- ● Assess current knowledge and practices of diabetes self-management and how they impact tient’s diabetes management. Registered patient’s health status and reason for hospitalization dietitians should be consulted for medical ● Initiate diabetes education for patients newly diagnosed with diabetes nutritional therapy and patient teaching. ● Provide information on basic self-management skills to help ensure safe care postdischarge Social workers and case managers should ● Team approach with other health professionals (e.g., physicians, nurses, dietitians, case be involved with discharge planning and managers, and social workers) coordinating care in the hospital and post discharge orders for home-health-nurse follow up ● Provide information on community resources and diabetes education programs for upon discharge. Those likely in need of continuing education home health nursing referrals include ● The diabetes educator serves as a resource for nursing staff and other health care providers newly diagnosed diabetic patients, pa- tients new to insulin, the aged or infirm, and those for whom there are compliance The efficacy of hospital-based DSME on a follow-up questionnaire, the experi- concerns. on outcomes has not been tested in ran- mental group reported better adherence domized prospective studies. Performing for all self-care behaviors than the control such a study that denies the basics of group. Four months postdischarge, the Patient assessment DSME to a control group is considered experimental group had significantly Patient assessment assists with defining unethical (421). Given the limitations and fewer emergency room visits compared the patient’s problems and acknowledg- ethics of study design, several studies sug- with the control group (2 vs. 20 visits, ing his or her concerns. When seeing an gest hospital-based DSME has substantial respectively, P ϭ 0.005). inpatient for an initial consultation, it is benefits in outcomes. Using historical imperative to be able to focus on the controls, Muhlhauser et al. (422) re- Writing DSME consult requests greatest needs of the patient at that time. ported a 66% reduction in hospitalization When writing a request for consultation Knowing the reason for the consultation days and an 86% reduction in episodes of for diabetes education, the referral should allows the educator to direct precious diabetic ketoacidosis after implementing state the specific reason for the referral time and energy to those specific educa- an intensive inpatient-based education (not just state “Diabetes Education”), any tional needs and to bring any necessary program for patients with type 1 diabetes. pertinent details regarding the patient sta- teaching materials/supplies to the bed- Four deaths occurred in the control tus, the discharge plan and person refer- side. Before actually seeing the patient, group, compared with no deaths in the ring for consult, and how to contact them the diabetes educator should review the treatment group. All deaths were from (Table 8). Early referral is encouraged, es- chart and, if necessary, speak with the re- acute diabetes-related complications. pecially for those patients newly diag- ferring physician or registered nurse who Fedderson and Lockwood (423) con- nosed with diabetes. Patients should be is caring for the patient in order to obtain ducted a prospective nonrandomized medically stable and able to participate in additional information. Assessment criti- study at a single 713-bed teaching hospi- the educational process. Patients who are cal to patient teaching includes: tal. Within the hospital, four similar pa- in pain or sedated should not be referred tient care units (PCUs) were identified for for DSME until their medical condition the study intervention. Two units were improves. Including various disciplines ● Knowledge, psychomotor skills, and af- designated as the treatment units and two in the plan of care is equally important. If fective domains as the control units. For the control units, caregivers are involved, it is important ● Current level of self care DSME was provided by the regular nurs- that they be identified and included in the ● Preferred learning styles ing staff. For the experimental units, a cer- teaching process. Patients who are cogni- ● Psychological status tified diabetes educator (CDE) was tively impaired are not good candidates ● Stress factors that impair learning employed to provide education to both for teaching and should have alternative ● Social/cultural/religious beliefs the staff nurses and directly to diabetic options of care considered. Topics to be ● Literacy skills patients. The nurse CDE conducted three covered should be relevant to the plan of ● Readiness to learn separate teaching sessions for the staff care and ready to implement at the time of ● Assessment of abilities—age, mobility, nurses in the experimental PCUs on infor- discharge. visual acuity, hearing loss, and dexter- mation that an insulin-requiring patient It is best to maximize the time spent ity with diabetes needs before discharge. The nurse CDE also provided direct patient education. The authors reported a mean Table 8—Writing the DSME consult request reduction in hospital length of stay of 1.3 days in the experimental group versus the Component of request Example control group (P Ͻ 0.005). Wood (424) compared the efficacy of Specific reason for consult and Diabetes education for insulin administration teaching individualized DSME (control group) to diagnosis for patient with new-onset type 2 diabetes individualized DSME supplemented by Discharge medication plan Lantus 30 units hs, Novolog 6 units ac 2-h group classes held weekly (experi- Specific comments/instructions Spanish-speaking patient; lives with daughter mental group). Patients medically unsta- Contact information John Smith, MD, pager # ble were excluded from the study. Based ac, before meals; hs, bedtime.

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 573 Management of diabetes and hyperglycemia in hospitals

Characteristics of adult learners vital to coordinating care with successful has been recommended that the term In preparing to teach, it is good to keep in outcomes for hospitalized patients with “ADA diet” no longer be used (427). Since mind some of the characteristics of adult diabetes. Staff nurses need to work with 1994, the ADA has not endorsed any sin- learners: patients on developing their skills and re- gle meal plan or specified percentages of inforcing knowledge of diabetes manage- macronutrients. Current nutrition rec- ● Usually self-directed ment. Medical orders and the discharge ommendations advise individualization ● Must be receptive to learning plan of care need to be appropriate, based on treatment goals, physiologic pa- ● Tend to be problem-focused rather achievable, and agreeable to the patient rameters, and medication usage; these than subject-oriented and family. For effective discharge plan- recommendations apply primarily to per- ● Inclusive of past experiences with dia- ning, collaboration among the treating sons living in a home setting who, in con- betes physician, nurses, and the diabetes nurse junction with a team of health ● Active participation educator is essential for providing conti- professionals, self-manage their diabetes. nuity of care back to the outpatient set- The question is, then, how do you use Deciding what to teach patients ting. During discharge planning, the medical nutrition therapy appropriately Deciding what to teach patients in a lim- following questions should be addressed: in the hospital? Nutrient needs often dif- ited timespan is determined mostly by fer in the home versus the hospital setting. medical necessity but also by the patient’s ● Does the patient require outpatient The diabetes treatment plan used in the previous experiences and desires. The pa- DSME? hospital may differ from home, e.g., insu- tient must be psychologically and emo- ● Can the patient prepare his or her own lin may be used instead of oral medica- tionally ready for teaching. Listening to meals? tions. The types of food a person can eat concerns and acknowledging the patient’s ● Can the patient perform self- may change, or the route of administra- feelings without being judgmental is an monitoring of blood glucose at the pre- tion may differ, e.g., enteral or parenteral important aspect of changing behavior. scribed frequency? feedings may be used instead of solid When patients are newly diagnosed with ● Can the patient take his or her diabetes foods. And lastly, the ability of institu- diabetes, teaching “survival skills” is the medications or insulin accurately? tions to individualize meal plans is greatly first step to outlining the principles of di- ● Is there a family member who can assist decreased. Because of the complexity of abetes management. These may include: with tasks that the patient cannot per- nutrition issues, it is recommended that a form? registered dietitian, knowledgeable and ● What is diabetes? Principles of treat- ● Is a visiting nurse needed to facilitate skilled in medical nutrition therapy, serve ment and prevention of complications transition to the home? as the team member who provides medi- ● Norms for blood glucose and target glu- cal nutrition therapy. The dietitian is re- cose levels for the individual Discharge diabetes medications sponsible for integrating information ● Recognition, treatment, and prevention When arranging for hospital discharge, about the patient’s clinical condition, eat- of hyperglycemia and hypoglycemia caution should be taken in prescribing ing, and lifestyle habits and for establish- ● Medical nutrition therapy (instructed antihyperglycemic therapy, especially for ing treatment goals in order to determine by a registered dietitian who, prefera- the elderly. A recent hospital discharge is a realistic plan for nutrition therapy bly, is a CDE) a strong predictor of subsequent serious (428). Registered dietitians who special- ● Medication outpatient hypoglycemia (425). This ob- ize in nutrition support can play an in- ● Self-monitoring of blood glucose servation should lead to caution in the valuable role in the management of ● Insulin administration (if going home planning of antihyperglycemic therapy at critically ill patients. However, it is essen- on insulin) discharge and careful planning for follow- tial that all members of the interdiscipli- ● Sick-day management up. Prescribing patterns should take into nary team are knowledgeable of nutrition ● Community resources consideration the evidence that among therapy. ● Universal precautions for caregivers the sulfonylureas, glipizide is associated with less hypoglycemia than glyburide in Patients previously diagnosed with the elderly (426). Goals of medical nutrition therapy diabetes need to have specific needs iden- For the hospitalized patient, the goals of tified, and their instruction must be tar- WHAT IS THE ROLE OF nutrition therapy are multiple: geted to those needs. Diabetes education MEDICAL NUTRITION in a hospital setting is not meant to pro- THERAPY IN THE ● Attain and maintain optimal metabolic vide comprehensive in-depth knowledge HOSPITALIZED PATIENT control of blood glucose levels, lipid of diabetes management, but is intended WITH DIABETES? — Determining levels, and blood pressure to enhance to provide basic information for people to the nutritional needs of hospitalized pa- recovery from illness and disease start a life-long process of continuing di- tients with diabetes, writing a diet order ● Incorporate nutrition therapies to treat abetes education. to provide for those needs, and incorpo- the complications of diabetes, includ- rating the current nutrition principles and ing hypertension, CVD, dyslipidemia, Communication and discharge recommendations for persons with diabe- and nephropathy planning tes can be a daunting task. Even though ● Provide adequate calories, as needs are Documentation, reviewing chart notes/ hospital diets are commonly ordered by often increased in illness and during re- suggestions, and oral communication are calorie levels based on the “ADA diet,” it covery from surgery

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● Improve health through use of nutri- drate is similar (430). Sucrose does not derstanding and support affect the choice tious foods increase glycemia to a greater extent than of a meal planning system (432). Many ● Address individual needs based on per- isocaloric amounts of starch. The prandial institutions are familiar with exchange di- sonal, cultural, religious, and ethnic (mealtime) insulin dose is based on the ets and, therefore, some facilities still use food preferences meal’s carbohydrate content. Current rec- them as a system for planning meals. In- ● Provide a plan for continuing self- ommendations for fat modification (430) troduction of the consistent carbohydrate management education and follow-up are incorporated by basing the meals on a system requires a multidisciplinary effort, care cardiac, heart-healthy menu when devis- staff education, and patient education for ing the consistent carbohydrate meal the program to succeed, but it can offer Nutritional needs of hospitalized plan. clear benefits when implemented. Institu- patients An advantage to the use of this system tions can adapt the consistent carbohy- The caloric needs of most hospitalized pa- is that prandial insulin dosages can be or- drate system to meet their needs. A review tients can be met through provision of dered on the basis of the known carbohy- of the implementation of the consistent 25–35 kcal/kg body wt (429,430). Pro- drate content of the meal. For patients carbohydrate system in institutions re- tein needs vary on the basis of physiologic with a poor appetite and poor intake, the vealed some variations developed by var- stress. Mildly stressed patients require 1.0 prandial insulin can be given after the ious facilities (431), as described below. g/kg body wt; moderately to severely meal based on the amount eaten. Using a One hospital terms the diet the “con- stressed patients may need 1.5 g/kg body consistent carbohydrate menu makes this sistent carbohydrate diabetes diet.” Calo- wt. These levels are for patients with nor- easy to determine. Providing meals with rie levels are not specified. Menus with mal hepatic and renal function. The pre- this system eases the burden on the health food selections instruct patients to choose ferred route of feeding is the oral route. If care team of trying to individualize diets, three to five carbohydrate foods at each intake is inadequate or if medical condi- especially when it is not practical, such as meal, identifying the carbohydrate foods. tions prohibit oral feeding, then enteral of during a short hospital stay. Meals for pa- Each contains 15 g carbohydrate. Dessert parenteral feedings will be needed. tients with type 1 diabetes can easily be items with 30 g carbohydrate (two carbo- adjusted by altering the number of carbo- hydrate choices) or 15 g are included at Consistent carbohydrate diabetes hydrate servings and snacks (428). Effi- lunch and dinner. Another facility uses meal-planning system ciencies in food service are realized and the consistent carbohydrate menu with The consistent carbohydrate diabetes patient satisfaction is enhanced with this calorie ranges from low to very high. All meal-planning system was developed to system (428,431). Another advantage is carbohydrate-containing foods are provide institutions with an up-to-date that the system reinforces carbohydrate grouped in one list on the menu. Other way of providing food service to patients counting meal planning taught to many modifications of nutrients or textures can in those settings. The system is not based persons with diabetes, particularly type 1 be added. Since no universal guideline ex- on specific calorie levels, but rather on the diabetic individuals using advanced car- ists for consistent carbohydrate diabetes amount of carbohydrate offered at each bohydrate counting. It serves as a basis for diet ordering, it is encouraged that hospi- meal. This amount is consistent from teaching newly diagnosed patients with tal nutrition committees specify their own meal to meal and day to day. Meals are diabetes about meal planning and can ordering guidelines that meet the unique based on heart-healthy diet principles— serve as a reference for home meals. needs of their patients and capabilities of saturated fats and cholesterol are limited, The meals served to patients with di- their nutrition staff. and protein content falls within a usual abetes certainly affect glucose control, but Regardless of the type of meal plan- diet’s content of 15–20% of calories. In- it should be remembered it is not the only ning system selected, the use of meal stead of focusing on the type of carbohy- factor influencing glycemia. Hospitalized plans such as no concentrated sweets, no drate foods served, the emphasis is on the patients often have poor appetites and in- sugar added, low sugar, and liberal dia- total amount of carbohydrate contained take is suboptimal. Meals can be delayed betic diets are no longer appropriate. in the meal. The majority of carbohydrate or missed entirely due to tests and proce- These diets unnecessarily restrict sucrose foods should be whole grains, fruits, veg- dures. Other causes of poor glucose con- and do not reflect the current evidence- etables, and low-fat milk, but some su- trol include erratic absorption of insulin, based nutrition recommendations (433). crose-containing foods can be included as counterregulatory hormone stress re- part of the total carbohydrate allowance sponses, increased insulin requirements, Special nutrition issues (430). A typical day’s menu provides the length of time between premeal insu- Liquid diets. Sugar-free liquid diets are ϳ1,500–2,000 calories, with a range of lin and food consumption, and impaired not appropriate for patients with diabetes. 12–15 carbohydrate servings (187–259 gut motility caused by diabetic gastropa- Calories and carbohydrates are needed to g) divided among meals and snacks. resis and medications, particularly nar- provide for normal physiologic processes. Central to the rationale for this system cotics (300). Patients given clear or full liquid diets is that the glycemic effect of carbohydrate should receive ϳ200 g carbohydrate, relates more to the total amount of carbo- How to order consistent spread equally throughout the day in hydrate rather than the source. While a carbohydrate diets meals and snacks (428). number of factors influence glycemic re- There is no single meal-planning system Surgery and progression diets. After sponse to individual foods, ingestion of a that meets the needs of all institutions. surgery it is desirable to initiate feeding as variety of foods does not acutely alter gly- Budgetary issues, food-service employee soon as possible in order to protect intes- cemic response if the amount of carbohy- time, local factors, and administration un- tinal integrity (428). Advancement from

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 575 Management of diabetes and hyperglycemia in hospitals clear liquid to full liquid to solid foods patients receiving nutrition support, as based only on expert and consensus opin- should be done as quickly as tolerated. overfeeding can exacerbate hyperglyce- ion. For patients who are eating, com- Approximately 200 g carbohydrate mia, cause abnormal liver function tests, monly recommended testing frequencies should be provided daily in evenly di- and increase oxygen consumption and are premeal and at bedtime. For patients vided doses at meals and snacks. During carbon dioxide production (429). not eating, testing every 4–6 h is usually illness and surgery, glucose requirements sufficient for determining correction in- increase. Hypoglycemia can occur with- Nutrition guidelines for health care sulin doses. Patients controlled with con- out sufficient glucose (428). institutions tinuous intravenous insulin typically In 1997 the “Translation of the Diabetes require hourly blood glucose testing until Catabolic illness and nutrition Nutrition Recommendations for Health the blood glucose levels are stable, then support Care Institutions” technical review (428) every 2 h. During catabolic illness, nutritional needs and position statement (427) were pub- Bedside blood glucose testing is usu- are altered. Careful continuous monitor- lished. The position statement has been ally performed with portable glucose de- ing of various nutrition parameters and republished without any substantive vices that are identical or similar to glycemic status is essential so that nutri- modifications (433). The original paper devices for home self-monitoring of blood tional needs are met and glycemic control was based on the nutrition recommenda- glucose. Characteristics unique to the is maintained. Catabolic illness can alter tions current at that time, but both the hospitalized patient and common to the fluid balance and can lead to shrinkage of original and updated position statements nonhospitalized patient can lead to erro- body fat and body cell mass, making nu- conform to the current evidence-based neous bedside blood glucose testing re- trition assessment difficult. A recent nutrition recommendations (430). sults (Table 9). Most of these errors can be weight loss of 10% indicates a need for prevented by implementing and main- thorough nutrition assessment. Moderate Discharge planning taining a strong hospital quality-control protein-calorie malnutrition can occur Patients with newly recognized diabetes program (434,435). The impact of spe- with an unintentional weight loss of 10– require DSME during hospitalization and cific interfering substances or hematocrit 20%; if the loss is Ͼ20%, severe malnu- need detailed discharge planning for dia- are device-specific (436–440). Elevated trition is likely present (430). The time betes care. Discharge planning includes levels of multiple interfering substances period over which the weight loss has oc- assessment of the patient’s ability to pay may alter bedside glucose results, al- curred bears investigation, since a more for diabetes supplies and medications. Of though each substance, by itself, may be rapid weight loss is more hazardous. The patients with no prior history of diabetes below the interference threshold specified magnitude of recent weight loss with con- who are found to have hyperglycemia by the manufacturer (441). sideration of the presence of excess fluid (random blood glucose Ͼ125 mg/dl or New bedside glucose devices allow often present in critically ill patients, the 6.9 mmol/l) during hospitalization, 60% for identification of both patient and pro- presence or absence of clinical markers of are likely to have diabetes at follow-up vider by reading a unique barcode. The stress, and the amount of time the patient testing (8). For this reason, follow-up glucose results can also be automatically will be unable to eat should determine the testing for diabetes based on ADA criteria downloaded into the hospital’s central lab need for nutrition intervention (429). A (3) is recommended within 1 month of database, allowing for easier access and consultation to the registered dietitian is hospital discharge. monitoring for quality-control purposes. warranted in these cases. Most currently used bedside glucose Enteral feedings have several advan- WHAT IS THE ROLE OF meters, though designed for capillary tages over parenteral feedings, including BEDSIDE GLUCOSE whole-blood testing, are calibrated to re- lower costs, avoidance of catheter-related MONITORING IN THE port results compatible to plasma, which complications, the trophic effect on gas- HOSPITALIZED PATIENT? — allows for reliable comparison to the lab- trointestinal cells, and the more physio- Implementing intensive diabetes therapy oratory glucose test. For critically ill pa- logic route (429). While parenteral in the hospital setting requires frequent tients, hypotension, dehydration, nutrition is necessary in certain situa- and accurate blood glucose data. This anemia, and interfering substances in the tions, it is beneficial to progress to enteral measure is analogous to an additional “vi- blood may render capillary blood glucose tube feedings or oral intake as soon as tal sign” for hospitalized patients with di- testing inaccurate (437). Using arterial or possible. As with solid-food diets, the abetes. Bedside glucose monitoring using venous blood with bedside glucose amount of carbohydrate present will have capillary blood has advantages over labo- meters in these situations is likely more the greatest impact on blood glucose re- ratory venous glucose testing because the reliable, but frequent comparison with sponse (428). Medications, particularly results can be obtained rapidly at the the laboratory glucose test is recom- insulin, can be adjusted to maintain gly- “point of care,” where therapeutic deci- mended to avoid errors in insulin ther- cemic control based on frequent blood sions are made. For this reason, the terms apy. Arterial concentrations are ϳ5 mg/dl glucose monitoring. The dietitian, in con- bedside and point-of-care glucose moni- (0.3 mmol) higher than capillary concen- sultation with other members of the inter- toring are used interchangeably. trations and ϳ10 mg/dl (0.5 mmol) disciplinary team, determines the best To date, no study has been conducted higher than venous concentrations. In the method of feeding, the appropriate en- testing the effect of frequency of bedside study by Van den Berghe et al. (2), in teral formula, and the amounts of protein, glucose testing on the incidence of hyper- which very strict glucose targets were lipid, and carbohydrate in parenteral for- glycemia or hypoglycemia in the hospital. maintained in critically ill patients, all mulations. It is important to not overfeed Without such data, recommendations are glucose samples were performed with a

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Table 9—Conditions causing erroneous bedside blood glucose results

Sources of analytical error Sources of user error Low hematocrit* Inadequate meter calibration High hematocrit† Using a test strip that does not match the meter code or that has passed the expiration date Shock and dehydration‡ Inadequate quality-control testing Hypoxia‡ Poor meter maintenance Hyperbilirubinemia, severe lipemia* Poor technique in performing fingerprick Specimen additives: sodium flouride† Poor technique of applying drop of blood to the test strip Drugs—acetaminophen overdose, ascorbic acid, Failure to record results in patient’s chart or to take action if dopamine, fluorescein, mannitol, salicylate‡ blood glucose is out of target range *Falsely elevates result; †falsely lowers result; ‡can either falsely lower or elevate result, depending on the device used. glucose analyzer at 1- to 4-h intervals. The out diabetes—a cost ratio of 2.1. Similar chronic care, home care, or loss of wages use of alternate-site glucose testing (i.e., increased hospital-related cost for dia- due to illness or mortality has not as yet arm, leg, or palm) in the hospital has not betic patients is reported in Europe (446). been reported. been studied. The use of alternate-site This increased cost for hospital care is due Levetan et al. (379) reported the im- glucose testing may cause erroneous re- to increased frequency of hospital admis- pact of obtaining an endocrinology con- sults when the blood glucose level is rap- sions (447), increased length of stay, and sultation, either alone or as part of idly rising or falling and when increased cost per hospital day due to multidisciplinary diabetes team (endocri- hypoglycemia occurs (442). higher utilization of intensive care and nologist, diabetes nurse educator, and a As with any procedure handling procedures (448). registered dietitian), on hospital length of blood, protective glove use is essential for Furnary and colleagues (196,290) stay in patients admitted with the princi- health care personnel performing bedside performed a cost-effectiveness analysis pal diagnosis of diabetes, including hy- glucose monitoring. The use of self- following implementation of a continu- perosmolar state, diabetic ketoacidosis, retracting lancet devices has the potential ous intravenous insulin infusion program and uncontrolled diabetes. In this non- to eliminate the chance of needlestick in- for the first 3 days after cardiac surgical randomized observational study, the av- jury and risk for infection. Table 10 out- procedures in diabetic patients. Com- erage length of stay of the diabetes team Ϯ lines specific elements of a quality-control pared with historical control subjects, the patients was 3.6 1.7 days as compared program deemed to be necessary for ap- with 8.2 Ϯ 6.2 days for patients in the incidence of deep sternal wound infec- Ϯ propriate use of bedside blood glucose tions (DSWIs) was reduced from 1.9 to no-consultation group and 5.5 3.4 days testing in the hospital (443). Key partici- 0.8%, and mortality from DSWIs reduced for the patients who received a traditional pants in the program are clinical labora- decreased from 19 to 3.8% after imple- individual endocrine consultation. Possi- tory representatives, nurses, physicians, mentation of the protocol. The average ble reasons for shortened length of stay and hospital administrators. Additional were more rapid normalization of glucose excess length of stay from DSWI was 16 guidelines are published by the National levels, more efficient transition from in- days, generating an average $26,400 in Committee for Clinical Laboratory Stan- travenous to subcutaneous insulin, faster additional hospital charges. Furnary et al. dards (444). For patients practicing dia- transition to a definitive insulin or oral (449) estimated the additional expense of betes self-management in the hospital, a medication regimen, and more effective insulin infusion at $125–150 per patient. quality-control program to test the pa- teaching of diabetes survival skills. Esti- tient’s blood glucose device and the pa- Of 1,499 patients in the intervention mated cost savings from reduction in tient’s testing technique is necessary to group, the number of DWSIs prevented length of stay for the 34 patients seen by ensure accurate results. was 10, resulting in an average cost to the diabetes team was $120,000 com- prevent one DSWI at approximately pared with the cost in salaries of $40,000. $21,000. This estimate does not incorpo- In summary, the potential opportu- IS IMPROVED DIABETES rate the potential effects of the interven- nity for cost savings from improved hos- CARE IN HOSPITALS COST tion on other outcomes, such as a pital outcomes, reduced mortality, and EFFECTIVE? — Of the $91.8 billion reduction in mortality, cost for chronic shortened length of stay for patients with spent annually in the U.S. for direct med- care, and lost income from work. diabetes and hospital-related hyperglyce- ical expenditures for diabetes, hospital Van den Berghe et al. (2) reported a mia is substantial. Future studies using care accounts for the single largest com- 34% reduction in hospital mortality in randomized prospective design are ponent of expenditures, comprising $40 critically ill patients treated with intensive needed to verify these results. billion, or 43.9%, of the total cost (445). insulin therapy. Intensive insulin therapy After adjustment for age, sex, and race/ reduced the duration of intensive care but ethnicity, annual per capita costs for hos- not the overall length of stay in the hospi- SUGGESTIONS FOR FUTURE pital care is $6,309 for persons with tal. Subsequent comparison of costs be- RESEARCH — While outcomes stud- diabetes versus $2,971 for persons with- tween the groups for rehabilitation, ies that provide evidence for a clear role

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 577 Management of diabetes and hyperglycemia in hospitals

Table 10—Characteristics of an effective Table 11—Summary of major recommendations for hospital management of hyperglycemia bedside glucose monitoring (BGM) quality- control program Level of Recommendation evidence Characteristic ● Good metabolic control is associated with improved hospital outcomes. Target B ● A specifically designated responsible plasma glucose levels are: individual, preferably a laboratory •Ͻ110 mg/dl preprandial and Ͻ180 mg/dl peak postprandial. professional, is involved in the ● Intensive insulin therapy with intravenous insulin, with the goal of A administration and quality assurance of maintaining blood glucose 80–110 mg/dl, reduces morbidity and mortality the BGM program. among critically ill patients in the surgical ICU. ● A written procedure for the BGM ● Intravenous insulin infusion is safe and effective for achieving metabolic B program. control during major surgery, hemodynamic instability, and NPO status. ● An organized training program that ● Intravenous insulin infusion is safe and effective for patients who have poorly B involves laboratory personnel and controlled diabetes and widely fluctuating blood glucose levels or who are nursing staff. insulin deficient or severely insulin resistant. ● Defined frequencies and requirements for ● Intravenous insulin infusion, followed by multidose subcutaneous insulin A maintenance and cleaning of BGM therapy, improves survival in diabetic patients after myocardial infarction. instruments. ● For insulin-deficient patients, despite reductions or the absence of caloric B ● Regular performance of quality control intake, basal insulin must be provided to prevent diabetic ketoacidosis. testing on each instrument (daily or by ● Use of scheduled insulin improves blood glucose control compared with B shift), depending on the frequency of orders based on sliding scale insulin coverage alone. patient testing. ● For patients who are alert and demonstrate accurate insulin self-administration E ● A policy to regularly compare the BGM and glucose monitoring, insulin self-management should be allowed as an results from each operator and adjunct to standard nurse-delivered diabetes management. instrument with results from a ● Patients with no prior history of diabetes who are found to have hyperglycemia E corresponding sample tested in the (random blood glucose Ͼ125 mg/dl or 6.9 mmol/l) during hospitalization clinical laboratory. Suggest that all BGM should have follow-up testing for diabetes within 1 month of hospital results are, at least, within Ϯ15% discharge. variation from the clinical laboratory ● Establishing a multidisciplinary team that sets and implements institutional B results. guidelines, protocols, and standardized order sets for the hospital results in ● Participation in an external proficiency reduced hypoglycemic and hyperglycemic events. testing program. ● Diabetes education, medical nutrition therapy, and timely diabetes-specific C ● Acknowledgment of the limitations of discharge planning are essential components of hospital-based diabetes care. BGM and requirement of a clinical laboratory glucose determination when a BGM result is outside a defined range. Health care outcomes related to ● Define the impact of diabetes educa- ● Acknowledgment of the effect of glycemic control tion. hematocrit value variation on BGM Few studies in the literature contain ran- results and establishment of hematocrit domized, controlled evidence to support Specific strategies for insulin value limitations for the instrument in specific interventions that target glucose delivery use. control in various clinical settings. Work Development and implementation of spe- ● Determination of the bias of the is clearly needed to provide rigorous evi- cific strategies for insulin delivery, based instrument in use and communication of dence in the hospital management of dia- on knowledge of the pharmacokinetics of this information to the physicians and the betes in order to: institutional quality assurance program. the currently available insulins, will allow physicians and nurses to overcome barri- Adapted from Jones et al. (443). ● Further define the role of targeted glu- ers to its effective use in managing blood cose control and the threshold for im- glucose. Such strategies will need to dem- for targeted glucose control in the hospi- pact of blood glucose level on health onstrate safety and efficacy of specific ap- tal management of diabetes are beginning care outcomes in diverse clinical set- plications of insulin therapies that to accumulate in the scientific literature, tings, such as general medicine and sur- address known areas of need, including: numerous questions related to how to gery patients, and in specific best manage diabetes in this hospital set- circumstances, such as stroke, neuro- ting remain to be addressed. These ques- surgery, and CVDs ● Optimum methods for delivering basal tions may be grouped into three main ● Examine clinical outcomes insulin under various clinical condi- areas: health care outcomes attributable ● Examine health care economic out- tions to glycemic control, specific strategies for comes such as length of stay and cost ● Feasibility of using subcutaneous insulin delivery, and processes for opti- effectiveness glargine or detemir insulin to meet mizing diabetes care and education in the ● Further examine the impact of special- basal insulin requirements (e.g., for hospital setting. ist care and diabetes team management medicine services) in the operating

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room and for periprocedural manage- the severity of illness or if hyperglycemia with acute myocardial infarction and no ment itself, in conjunction with relative hypo- previous diagnosis of diabetes mellitus: a ● The role of standardization of diabetes insulinemia, is pathogenic for tissue in- prospective study. Lancet 359:2140– management and algorithmic care and jury and poor hospital outcomes. Based 2144, 2002 validation of such pathways and tools on limited interventional studies in se- 8. Greci LS, Kailasam M, Malkani S, Katz DL, Hulinsky I, Ahmadi R, Nawaz H: ● Safety and practicality of delivering in- lected settings, aggressive control of Utility of HbA1c levels for diabetes case sulin infusion therapy outside the in- blood glucose in the hospital may provide finding in hospitalized patients with hy- tensive care unit an opportunity to improve patient out- perglycemia. Diabetes Care 26:1064– ● Simple algorithms for subcutaneous comes. Clinical trials are needed to an- 1068, 2003 delivery of programmed basal, prandi- swer these questions. The target blood 9. Aubert R, Geiss L, Ballard D, Coca- al/nutritional, and correction doses of glucose threshold to optimize outcomes nougher B, Herman W: Diabetes-Related insulin and insulin infusion algorithms. in the hospital is not clearly defined but Hospitalization and Hospital Utilization. may be lower than previously thought. 2nd ed. Bethesda, MD, National Insti- Improved methods for glucose From a cost perspective, research and tutes of Health, 1995, p. 555–556 strategies targeting glucose control and 10. Joshi N, Caputo G, Weitekamp M, monitoring Karchmer A: Infections in patients with Current methods for blood glucose mon- diabetes care in the hospital have the diabetes mellitus. N Engl J Med 341: itoring are painful and time consuming. potential to translate to substantial cost 1906–1912, 1999 Improved methods for frequent and accu- savings. 11. Wheat L: Infection and diabetes melli- rate blood glucose monitoring would en- tus. Diabetes Care 3:187–197, 1980 hance the ability to reach target blood 12. Mowat A, Baum J: Chemotaxis of poly- glucose levels safely. Development of con- Acknowledgments— Support for this Tech- morphonuclear leukocytes from pa- tinuous glucose monitoring systems that nical Review was provided by an unrestricted tients with diabetes mellitus. N Engl educational grant from Novo Nordisk. are safe and accurate is encouraged. J Med 284:621–627, 1971 The authors thank the members of the ADA 13. Bagdade J, Root R, Bulger R: Impaired Professional Practice Committee for their leukocyte function in patients with Processes for optimizing diabetes thoughtful review of the manuscript. The au- poorly controlled diabetes. Diabetes 23: care and education in the hospital thors also thank Drs. James Lenhard and Ste- 9–15, 1974 setting phen Hodak for their helpful comments. 14. 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