Tratamiento de Hipoglicemia

Management of Diabetes andHyperglycemia in HospitalsSTEPHEN CLEMENT MD, CDE

1

SUSAN S. BRAITHWAITE, MD2

MICHELLE F. MAGEE, MD, CDE3

ANDREW AHMANN, MD4

ELIZABETH P. SMITH, RN, MS, CANP, CDE1

REBECCA G. SCHAFER, MS, RD, CDE5

IRL B. HIRSCH, MD6

ON BEHALF OF THE DIABETES IN HOSPITALS

WRITING COMMITTEE

D iabetes increases the risk for disor-ders that predispose individuals tohospitalization, including coronary

artery, cerebrovascular and peripheralvascular disease, nephropathy, infection,and lower-extremity amputations. Themanagement of diabetes in the hospital isgenerally considered secondary in impor-tance compared with the condition thatprompted admission. Recent studies (1,2)have focused attention to the possibilitythat hyperglycemia in the hospital is notnecessarily a benign condition and thataggressive treatment of diabetes and hy-perglycemia results in reduced mortalityand morbidity. The purpose of this tech-nical review is to evaluate the evidencerelating to the management of hypergly-

cemia in hospitals, with particular focuson the issue of glycemic control and itspossible impact on hospital outcomes.The scope of this review encompassesadult nonpregnant patients who do nothave diabetic ketoacidosis or hyperglyce-mic crises.

For the purposes of this review, thefollowing terms are defined (adaptedfrom the American Diabetes Association[ADA] Expert Committee on the Diagno-sis and Classification of Diabetes Mellitus)(3):

● Medical history of diabetes: diabeteshas been previously diagnosed and ac-knowledged by the patient’s treatingphysician.

● Unrecognized diabetes: hyperglycemia(fasting blood glucose �126 mg/dl orrandom blood glucose �200 mg/dl)occurring during hospitalization andconfirmed as diabetes after hospitaliza-tion by standard diagnostic criteria, butunrecognized as diabetes by the treat-ing physician during hospitalization.

● Hospital-related hyperglycemia: hyper-glycemia (fasting blood glucose �126mg/dl or random blood glucose �200mg/dl) occurring during the hospital-ization that reverts to normal after hos-pital discharge.

What is the prevalence of diabetes inhospitals?The prevalence of diabetes in hospitalizedadult patients is not known. In the year2000, 12.4% of hospital discharges in theU.S. listed diabetes as a diagnosis. Theaverage length of stay was 5.4 days (4).Diabetes was the principal diagnosis inonly 8% of these hospitalizations. The ac-curacy of using hospital discharge diag-nosis codes for identifying patients withpreviously diagnosed diabetes has beenquestioned. Discharge diagnosis codesmay underestimate the true prevalence ofdiabetes in hospitalized patients by asmuch as 40% (5,6). In addition to havinga medical history of diabetes, patients pre-senting to hospitals may have unrecog-nized diabetes or hospital-relatedhyperglycemia. Umpierrez et al. (1) re-ported a 26% prevalence of known diabe-tes in hospita l ized pat ients in acommunity teaching hospital. An addi-tional 12% of patients had unrecognizeddiabetes or hospital-related hyperglyce-mia as defined above. Levetan et al. (6)reported a 13% prevalence of laboratory-documented hyperglycemia (blood glu-cose �200 mg/dl (11.1 mmol) in 1,034consecutively hospitalized adult patients.Based on hospital chart review, 64% ofpatients with hyperglycemia had preex-isting diabetes or were recognized as hav-ing new-onse t d i abe t e s dur inghospitalization. Thirty-six percent of thehyperglycemic patients remained unrec-ognized as having diabetes in the dis-charge summary, although diabetes or“hyperglycemia” was documented in

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From the 1Georgetown University Hospital, Washington, DC; the 2University of North Carolina, Chapel Hill,North Carolina; 3Medstar Research Institute at Washington Hospital Center, Washington, DC; the 4OregonHealth and Science University, Portland, Oregon; the 5VA Medical Center, Bay Pines, Florida; and the6University of Washington, Seattle, Washington.

Address correspondence and reprint requests to Dr. Stephen Clement, MD, Georgetown UniversityHospital, Department of Endocrinology, Bldg. D, Rm. 232, 4000 Reservoir Rd., NW, Washington, DC20007. E-mail: [email protected]..

Received and accepted for publication 1 August 2003.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 fromAventis, Pfizer, Bristol Myers Squibb, Takeda, and Lilly; and has received grant support from Aventis, Pfizer,Lilly, Takeda, Novo Nordisk, Bayer, GlaxoSmithKline, and Hewlett Packard. A.A. has received honorariafrom Aventis, Bayer, BMS, GlaxoSmithKline, Johnson & Johnson, Lilly, Novo Nordisk, Pfizer, and Takedaand research support from Aventis, BMS, GlaxoSmithKline, Johnson & Johnson, Lilly, Novo Nordisk, Pfizer,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.

Additional information for this article can be found in two online appendixes at http://care.diabetesjournals.org.

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

A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversionfactors for many substances.

© 2004 by the American Diabetes Association.

R e v i e w s / C o m m e n t a r i e s / P o s i t i o n S t a t e m e n t sT E C H N I C A L R E V I E W

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 553

the progress notes for one-third of thesepatients.

Norhammar et al. (7) studied 181consecutive patients admitted to the cor-onary care units of two hospitals in Swe-den with acute myocardial infarction(AMI), no diagnosis of diabetes, and ablood glucose �200 mg/dl (�11.1mmol/l) on admission. A standard 75-gglucose tolerance test was done at dis-charge and again 3 months later. The au-thors found a 31% prevalence of diabetesat the time of hospital discharge and a25% prevalence of diabetes 3 months af-ter discharge in this group with no previ-ous diagnosis of diabetes.

Using the A1C test may be a valuablecase-finding tool for identifying diabetesin hospitalized patients. Greci et al. (8)reported that an A1C �6% was 100%specific and 57% sensitive for identifyingpersons with diabetes in a small cohort ofpatients admitted through the emergencydepartment of one hospital with a randomblood glucose �126 mg/dl (7 mmol/l)and no prior history of diabetes.

From the patient’s perspective, 24%of adult patients with known diabetes sur-veyed in 1989 reported being hospital-ized at least once in the previous year (9).The risk for hospitalization increasedwith age, duration of diabetes, and num-ber of diabetes complications. Personswith diabetes reported being hospitalizedin the previous year three times more fre-quently compared with persons withoutdiabetes. In summary, the prevalence ofdiabetes in hospitalized adults is conser-vatively estimated at 12.4–25%, depend-ing on the thoroughness used inidentifying patients.

WHAT IS THE LINKBETWEEN HIGH BLOODGLUCOSE AND POOROUTCOMES? POSSIBLEMECHANISMS — The mechanismof harm from hyperglycemia on variouscells and organ systems has been studiedin in vitro systems and animal models.This research has centered on the im-mune system, mediators of inflammation,vascular responses, and brain cell re-sponses.

Hyperglycemia and immune functionThe association of hyperglycemia and in-fection has long been recognized, al-though the overall magnitude of theproblem is still somewhat unclear

(10,11). From a mechanistic point ofview, the primary problem has been iden-tified as phagocyte dysfunction. Studieshave reported diverse defects in neutro-phil and monocyte function, includingadherence, chemotaxis, phagocytosis,bacterial killing, and respiratory burst(10–20). Bagdade et al. (14) were amongthe first to attach a glucose value to im-provement in granulocyte function whenthey demonstrated significant improve-ment in granulocyte adherence as themean fasting blood glucose was reducedfrom 293 � 20 to 198 � 29 mg/dl(16.3–11 mmol/l) in 10 poorly controlledpatients with diabetes. Other investiga-tors have demonstrated similar improve-ments in leukocyte function withtreatment of hyperglycemia (17,21–23).In vitro trials attempting to define hyper-glycemic thresholds found only rough es-timates that a mean glucose �200 mg/dl(11.1 mmol/l) causes leukocyte dysfunc-tion (13,14,16,24–26).

Alexiewicz et al. (17) demonstratedelevated basal levels of cytosolic calciumin the polymorphonuclear leukocytes(PMNs) of patients with type 2 diabetesrelative to control subjects. Elevated cyto-solic calcium was associated with reducedATP content and impaired phagocytosis.There was a direct correlation betweenPMN cytosolic calcium and fasting serumglucose. These were both inversely pro-portional to phagocytic activity. Glucosereduction with glyburide resulted in re-duced cytosolic calcium, increased ATPcontent, and improved phagocytosis.

Classic microvascular complicationsof diabetes are caused by alterations in thealdose reductase pathway, AGE pathway,reactive oxygen species pathway, and theprotein kinase C (PKC) pathway (rev. in27). Several of these pathways may con-tribute to immune dysfunction. PKC maymediate the effect of hyperglycemia onneutrophil dysfunction (28). Liu et al.(29) found that decreased phagocytic ac-tivity in diabetic mice correlated inverselywith the formation of AGEs, although adirect cause-and-effect relationship wasnot proven. Ortmeyer and Mohsenin (30)found that hyperglycemia caused im-paired superoxide formation along withsuppressed activation of phospholipaseD. Reduced superoxide formation hasbeen linked to leukocyte dysfunction. An-other recent study found a link amonghyperglycemia, inhibition of glucose-6-phosphate dehydrogenase, and reduced

superoxide production in isolated humanneutrophils (31). Sato and colleagues(32–34) used chemiluminescence to eval-uate neutrophil bactericidal function. Theauthors confirmed a relationship betweenhyperglycemia and reduced superoxideformation in neutrophils. This defect wasimproved after treatment with an aldosereductase inhibitor. This finding suggeststhat increased activity of the aldose reduc-tase pathway makes a significant contri-bution to the incidence of diabetes-related bacterial infections.

Laboratory evidence of the effect ofhyperglycemia on the immune systemgoes beyond the granulocyte. Nonenzy-matic glycation of immunoglobulins hasbeen reported (35). Normal individualsexposed to transient glucose elevationshow rapid reduction in lymphocytes, in-cluding all lymphocyte subsets (36). Inpatients with diabetes, hyperglycemia issimilarly associated with reduced T-cellpopulations for both CD-4 and CD-8 sub-sets. These abnormalities are reversedwhen glucose is lowered (37).

In summary, studies evaluating theeffect of hyperglycemia on the immunesystem comprise small groups of normalindividuals, patients with diabetes of var-ious duration and types, and animal stud-ies. These studies consistently show thathyperglycemia causes immunosuppres-sion. Reduction of glucose by a variety ofmeans reverses the immune functiondefects.

Hyperglycemia and thecardiovascular systemAcute hyperglycemia has numerouseffects on the cardiovascular system. Hy-perglycemia impairs ischemic precondi-tioning, a protective mechanism forischemic insult (38). Concomitantly, in-farct size increases in the setting of hyper-glycemia. The same investigatorsdemonstrated reduced coronary collat-eral blood flow in the setting of moder-ately severe hyperglycemia (39). Acutehyperglycemia may induce cardiac myo-cyte death through apoptosis (40) or byexaggerating ischemia-reperfusion cellu-lar injury (41).

Other vascular consequences of acutehyperglycemia relevant to inpatient out-comes include blood pressure changes,catecholamine elevations, platelet abnor-malities, and electrophysiologic changes.Streptozotocin-induced diabetes in ratsresults in significant hemodynamic

Management of diabetes and hyperglycemia in hospitals

554 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004

changes as well as QT prolongation (42).These changes were reversed with correc-tion of hyperglycemia. In humans,Marfella et al. (43) reported increased sys-tolic and diastolic blood pressure and in-creased endothelin levels with acutehyperglycemia in patients with type 2 di-abetes. The same researchers also inducedacute hyperglycemia (270 mg/dl or 15mmol/l) over 2 h in healthy men. Thisproduced elevated systolic and diastolicblood pressure, increased pulse, elevationof catecholamine levels, and QTc prolon-gation (44). Other investigators havedemonstrated an association betweenacute hyperglycemia and increased vis-cosity, blood pressure (45), and natiureticpeptide levels (46).

Hyperglycemia and thrombosisMultiple studies have identified a varietyof hyperglycemia-related abnormalities inhemostasis, favoring thrombosis (47–51).For example, hyperglycemic changes inrats rapidly reduce plasma fibrinolytic ac-tivity and tissue plasminogen activator ac-tivity while increasing plasminogenactivator inhibitor (PAI)-1 activity (52).Human studies in patients with type 2 di-abetes have shown platelet hyperactivityindicated by increased thromboxane bio-synthesis (47). Thromboxane biosynthe-sis decreases with reduction in bloodglucose. Hyperglycemia-induced eleva-tions of interleukin (IL)-6 levels havebeen linked to elevated plasma fibrinogenconcentrations and fibrinogen mRNA(53,54).

Increased platelet activation as shownby shear-induced platelet adhesion andaggregation on extracellular matrix hasbeen demonstrated in patients with dia-betes (48). As little as 4 h of acute hyper-glycemia enhances platelet activation inpatients with type 2 diabetes (51). In thiscrossover, double-blind study, 12 pa-tients were subjected to hyperglycemic(250 mg/dl, 13.9 mmol/l) and euglycemic(100 mg/dl, 5.55 mmol/l) clamps. Hyper-glycemia precipitated stress-inducedplatelet activation as well as platelet P-selectin and lysosomal integral membraneprotein (LIMP) expression. Hyperglyce-mia also caused increased plasma vonWillebrand factor antigen, von Wille-brand factor activity, and urinary 11-dehydro-thromboxane B2 (a measure ofthromboxane A2 production). Thesechanges were not seen in the euglycemicstate.

If hyperglycemia-induced platelet hy-perreactivity is particularly evident withhigh–shear stress conditions, as sug-gested in the above studies, this findingmay explain the increased thromboticevents commonly seen in hospitalized pa-tients with diabetes.

Hyperglycemia and inflammationThe connection between acute hypergly-cemia and vascular changes likely in-volves inflammatory changes. Culturedhuman peripheral blood mononuclearcells (PBMCs), when incubated in highglucose medium (594 mg/dl, 33 mmol/l)for 6 h produce increased levels of IL-6and tumor necrosis factor (TNF)-� (53).TNF-� is apparently involved in IL-6 pro-duction. Blocking TNF-� activity withanti-TNF monoclonal antibody blocksthe stimulatory effect of glucose on IL-6production by these cells. Other in vitrostudies suggest that glucose-induced ele-vations in IL-6, TNF-�, and other factorsmay cause acute inflammation. This in-flammatory response to glucose has beenseen in adipose tissue, 3T3-L1 adipocytecell lines, vascular smooth muscle cells,PBMCs, and other tissues or cell types(55–61).

In humans, moderate elevation ofglucose to 270 mg/dl (15 mmol/l) for 5 hhas been associated with increased IL-6,IL-18, and TNF-� (62). Elevations ofthese various inflammatory factors havebeen linked to detrimental vascular ef-fects. For example, TNF-� extends thearea of necrosis following left anterior de-scending coronary artery ligation in rab-bits (63). In humans, TNF-� levels areelevated in the setting of AMI and corre-late with severity of cardiac dysfunction(63,64). TNF-� may also play a role insome cases of ischemic renal injury and incongestive heart failure (CHF) (57,65).Ischemic preconditioning is associatedwith decreased postischemic myocardialTNF-� production (66). IL-18 has beenproposed to destabilize atheroscleroticplaques, leading to acute ischemic syn-dromes (67).

One of the most commonly demon-strated relationships between hyperglyce-mia and inflammatory markers is the invitro induction of the proinflammatorytranscriptional factor, nuclear factor(NF)-�B by exposure of various cell typesto 1–8 days of hyperglycemia (58,59,68–71). In patients with type 1 diabetes, ac-t ivation of NF-�B in PBMCs was

positively correlated to HbA1c level (r �0.67, P � 0.005) (72). A recent study bySchiefkofer et al. (73) demonstrated invivo exposure to hyperglycemia (180 mg/dl, 10 mmol/l) for 2 h caused NF-�B ac-tivation.

Hyperglycemia and endothelial celldysfunctionOne proposed link between hyperglyce-mia and poor cardiovascular outcomes isthe effect of acute hyperglycemia on thevascular endothelium. In addition to serv-ing as a barrier between blood and tissues,vascular endothelial cells play a criticalrole in overall homeostasis. In the healthystate, the vascular endothelium maintainsthe vasculature in a quiescent, relaxant,antithrombotic, antioxidant, and antiad-hesive state (rev. in 74,75). During illnessthe vascular endothelium is subject todysregulation, dysfunction, insufficiency,and failure (76). Endothelial cell dysfunc-tion is linked to increased cellular adhe-sion, perturbed angiogenesis, increasedcell permeability, inflammation, andthrombosis. Commonly, endothelialfunction is evaluated by measuring endo-thelial-dependent vasodilatation, lookingmost often at the brachial artery. Humanin vivo studies utilizing this parameterconfirm that acute hyperglycemia to thelevels commonly seen in the hospital set-ting (142–300 mg/dl or 7.9 –16.7mmol/l) causes endothelial dysfunction(77–82). Only one study failed to showevidence of endothelial cell dysfunctioninduced by short-term hyperglycemia(83). The degree of endothelial cell dys-function after an oral glucose challengewas positively associated with the peakglucose level, ranging from 100 to 300mg/dl (5.5–16.7 mmol/l) (78,79). Hyper-glycemia may directly alter endothelialcell function by promoting chemical inac-tivation of nitric oxide (84). Other mech-anisms include triggering production ofreactive oxygen species (ROS) or activat-ing other pathways (rev. in 27). Despitecompelling experimental data, studies ex-amining a possible association among hy-perglycemia, endothelial function, andoutcomes have not to date been done inhospitalized patients.

Hyperglycemia and the brainAcute hyperglycemia is associated withenhanced neuronal damage following in-duced brain ischemia (85–98). Explora-t ion o f genera l mechan i sms o f

Clement and Associates


hyperglycemic damage has used variousmodels of ischemia and various measuresof outcomes. Models differ according totransient versus permanent ischemia aswell as global versus localized ischemia.There is some indication from animalstudies that irreversible ischemia or endarterial ischemia is not affected by hyper-glycemia (87,99,100). The major portionof the brain that is sensitive to injury fromhyperglycemia is the ischemic penumbra.This area surrounds the ischemic core.During evolution of the stroke, the isch-emic penumbra may evolve into infarctedtissue or may recover as viable tissue(87,99,101,102). One of the primarymechanistic links between hyperglycemiaand enhanced cerebral ischemic damageappears to be increased tissue acidosisand lactate levels associated with elevatedglucose concentrations. This has beenshown in various animal models with rareexception (94,102–108). Lactate hasbeen associated with damage to neurons,astrocytes, and endothelial cells (104). Inhumans, Parsons et al. (109) demon-strated that the lactate-to-choline ratiodetermined by proton magnetic reso-nance spectroscopy (MRS) had value inpredicting clinical outcomes and final in-farct size in acute stroke. More recently,the same investigators used this methodto demonstrate a positive correlation be-tween glucose elevations and lactate pro-duction (110). Through this mechanism,hyperglycemia appears to cause hypoper-fused at-risk tissue to progress to infarction.

Animal studies have shown addi-tional association of hyperglycemia withvarious acute consequences that likelyserve as intermediaries of adverse out-comes. For example, hyperglycemiacauses accumulation of extracellular glu-tamate in the neocortex. Increased gluta-mate levels predict ensuing neuronaldamage (95). A unique hippocampal cellculture model of “in vitro ischemia” dem-onstrated a similar relationship betweenhyperglycemia, glutamate activity, andincreased intracellular calcium with en-hanced cell death (98). Hyperglycemiahas also been associated with DNA frag-mentation, disruption of the blood-brainbarrier, more rapid repolarization in se-verely hypoperfused penumbral tissue,�-amyloid precursor protein elevation, aswell as elevated superoxide levels in neu-ronal tissue (111–115).

Many of the same factors noted ear-lier, linking hyperglycemia to cardiovas-

cular event outcomes, likely contribute toacute cerebrovascular outcomes. Specifi-cally, in brain ischemia models exposedto hyperglycemia, hydroxyl free radicalsare elevated and positively correlate withtissue damage (116). Likewise, antioxi-dants have a neuroprotective effect (117).Elevated glucose levels have also beenlinked to inhibition of nitric oxide gener-ation, increased IL-6 mRNA, decreasedcerebral blood flow, and evidence of vas-cular endothelial injury (90,92,118,119).Again, the composite of evidence sup-ports scientifically viable mechanisms ofcentral nervous system injury from hy-perglycemia in the acute setting.

Hyperglycemia and oxidative stressOxidative stress occurs when the forma-tion of ROS exceeds the body’s ability tometabolize them. Attempts to identify aunifying basic mechanism for many of thediverse effects of acute hyperglycemiapoint to the ability of hyperglycemia toproduce oxidative stress (58,69,120).Acute experimental hyperglycemia tolevels commonly seen in hospitalized pa-tients induces ROS generation. Endothe-lial cells exposed to hyperglycemia invitro switch from producing nitric oxideto superoxide anion (84). Increased ROSgeneration causes activation of transcrip-tional factors, growth factors, and second-ary mediators. Through direct tissueinjury or via activation of these secondarymediators, hyperglycemia-induced oxi-dative stress causes cell and tissue injury(58,59,62,70,72,74,80,121–127). In allcases studied, abnormalities were re-versed by antioxidants or by restoring eu-glycemia (58,59,70,72,80,122,127).

Is insulin per se therapeutic?Two large, well-done prospective studiessupport the relationship between insulintherapy and improved inpatient out-comes (2,128). The prevalent assumptionhas been that insulin attained this benefitindirectly by controlling blood glucose.However, a growing body of literatureraises the question of whether insulin mayhave direct beneficial effects independentof its effect on blood glucose (121,129–132).

Multiple studies suggest cardiac andneurological benefits of glucose-insulin-potassium (GIK) infusions (133–154).One may propose that such therapy sup-ports a direct effect of the insulin sinceblood glucose control is not the goal of

these infusions and the benefits have beendisplayed in normal humans and animals.Although the direct effect of insulin mayplay a significant role in benefits of GIKtherapy, other metabolic factors are likelyto be major contributors to the mecha-nism of this therapy. The theory promot-ing this form of therapy centers on theimbalance between low glycolytic sub-strate in the hypoperfused tissue and ele-vated free fatty acids (FFAs) mobilizedthrough catecholamine-induced lipolysis(41,155–159). In ischemic cardiac tissue,there is decreased ATP and increased in-o rgan i c phospha t e p roduc t i on(148,156,159). Adequate glycolytic ATPis important for maintaining cellularmembranes, myocardial contractility, andavoidance of the negative effect of fattyacids as substrate for ischemic myocar-dium (155,158–161). FFAs are associ-ated with cardiac sympathetic overactivity,worsened ischemic damage, and possiblyarrhythmias. Accordingly, using a modelof 60-min low-flow ischemia followed by30 min of reperfusion in rat hearts, inves-tigators have demonstrated the ability ofGIK infusion to increase glycolysis, de-crease ATP depletion, and maintain lowerinorganic phosphate levels in the affectedtissue (148). These effects extrapolated toimproved systolic and diastolic functionin this model. In other animal models,GIK infusion in improved left ventricularcontractility, decreased tissue acidosis,and decreased infarct size (144,152,162).

In small studies of individuals with orwithout diabetes undergoing coronary ar-tery bypass surgery, GIK therapy is asso-ciated with shorter length of intubationand shorter length of stay (142,143,163).As therapy for patients with an AMI, GIKtherapy is associated with the expecteddecrease in FFAs, decreased heart failure,and a suggestion of improved short-termsurvival (133–135,139,164). In fol-low-up of a first myocardial infarction(MI), individuals who received GIK ther-apy reported better stress tolerance, an el-evated ischemic threshold, and improvedmyocardial perfusion by 99 m-Tc-tetrofosmin–gated single photon emis-sion computed tomography (SPECT)compared with those receiving saline in-fusion (149). These studies of classic GIKtherapy with emphasis on glucose deliv-ery have been small and more suggestivethan conclusive. No large, randomized,placebo-controlled studies have been re-ported. Even less information is available



regarding the use of GIK therapy instrokes or cerebral ischemia. Limitedstudies have demonstrated safety of GIKtherapy in the acute stroke patient, with atrend to reduced mortality, and a decreasein blood pressure (147,150). However,the data are clearly inadequate to makeany conclusions of benefit.

Beyond GIK therapy, one finds in-creasing support for a direct effect of in-sulin on many of the abnormalities thatunderlie inpatient complications. Insulintreatment, ranging in duration from briefeuglycemic-hyperinsulinemic clamps to2 months of ongoing therapy, improvesendothelial cell function (165–171).There are rare exceptions to this finding(172). Insulin also has vasodilatory prop-erties in the internal carotid and femoralarteries (165,167). The vasodilatoryproperties of insulin appear to be medi-ated at least in part by stimulating nitricoxide release (165,166). Aortic endothe-lial cell cultures have also demonstratedinsulin-induced nitric oxide synthase ac-tivity and increased nitric oxide levels(172,173). In a rat model, insulin inhibits

the upregulation of the endothelial adhe-sion molecule P-selectin expression seenas a consequence of elevated glucose lev-els (121).

Insulin infusion has anti-inflamma-tory effects (129,174,175). In a largestudy of intensive insulin infusion ther-apy in the intensive care unit, investiga-tors found decreased C-reactive protein(CRP) levels in insulin-treated patients(176). Cell culture studies have shownthe ability of insulin incubation to reduceoxidative stress and its associated apopto-sis in cardiomyocytes (177). In additionto the induction of endothelial-derivednitric oxide, human aorta cell and humanmononuclear cell culture studies haveshown dose-dependent reductions inROS, the proinflammatory transcriptionfactor NF-�B, intercellular adhesion mol-ecule (ICAM)-1, and the chemokinemonocyte chemoattractant protein(MCP)-1 (173,178–180). Insulin also in-hibits the production TNF-� and theproinflammatory transcription factorearly growth response gene (Egr)-1 (181).

These effects suggest a general anti-inflammatory action of insulin.

In an animal model of myocardialischemia, insulin given early in the acuteinsult reduced infarct size by �45%(182). This effect was mediated throughthe Akt and p70s6 kinase–dependent sig-naling pathway and was independent ofglucose. There is preliminary evidence ofinsulin’s ability to improve pulmonarydiffusion and CHF in humans (183).Studies have also suggested that insulinprotects from ischemic damage in thebrain, kidney, and lung (184–186). Incatabolic states such as severe burns, hy-perglycemia promotes muscle catabo-lism, while exogenous insulin producesan anabolic effect (187). Insulin therapyhas also been associated with an im-proved fibrinolytic profile in patients atthe time of acute coronary events, reduc-ing fibrinogen and PAI-1 levels (132). Fi-nally, insulin infusion reduces collagen-induced platelet aggregation and severalother parameters of platelet activity in hu-mans. This effect was attenuated in obeseindividuals (188).

Figure 1—Link between hyperglyce-mia and poor hospital outcomes. Hy-perglycemia and relative insulindeficiency caused by metabolic stresstriggers immune dysfunction, releaseof fuel substrates, and other mediatorssuch as ROS. Tissue and organ injuryoccur via the combined insults of in-fection, direct fuel-mediated injury,and oxidative stress and other down-stream mediators. See text for details.



In summary, the overwhelming bal-ance of evidence supports a beneficial ef-fect of insulin in the acute setting.Whether these benefits are the result of adirect pharmacologic effect of insulin orrepresent an indirect effect by improvedglucose control, enhanced glycolysis, orsuppressed lipolysis is more difficult todetermine. Studies in cell cultures controlfor glucose but have other physiologiclimitations. Nevertheless, the data areprovocative and certainly leave the im-pression that insulin therapy in the hos-pital has significant potential for benefit.Considering the numerous contraindica-tions to the use of oral agents in the hos-pital, insulin is the clear choice for glucosemanipulation in the hospitalized patient.

Potential relationships betweenmetabolic stress, hyperglycemia,hypoinsulinemia, and poor hospitaloutcomesTo explain the dual role of glucose andinsulin on hospital outcomes, Levetanand Magee (189) proposed the followingrelationships. Elevations in counterregu-larory hormones accelerate catabolism,hepatic gluconeogenesis, and lipolysis.These events elevate blood glucose, FFAs,ketones, and lactate. The rise in glucoseblunts insulin secretion via the mecha-nism of glucose toxicity (190), resultingin further hyperglycemia. The vicious cy-cle of stress-induced hyperglycemia andhypoinsulinemia subsequently causesmaladaptive responses in immune func-tion, fuel production, and synthesis ofmediators that cause further tissue and or-gan dysfunction (Fig. 1). Thus, the com-bination of hyperglycemia and relativehypoinsulinemia is mechanistically posi-tioned to provide a plausible explanationfor the poor hospital outcomes seen inobservational studies.

WHAT ARE THE TARGETBLOOD GLUCOSE LEVELSFOR THE HOSPITALIZEDPATIENT?A rapidly growing body of literature sup-ports targeted glucose control in the hos-pital setting with potential for improvedmortality, morbidity, and health care eco-nomic outcomes. The relationship of hos-pital outcomes to hyperglycemia has beenextensively examined. Hyperglycemia inthe hospital may result from stress, de-compensation of type 1 diabetes, type 2diabetes, or other forms of diabetes

and/or may be iatrogenic due to adminis-tration of pharmacologic agents, includ-ing glucocorticoids, vasopressors, etc.Distinction between decompensated dia-betes and stress hyperglycemia is oftennot made or alternatively is not clear at thetime of presentation with an acute illness.When hyperglycemia is treated alongwith other acute problems, outcomes aregenerally improved. This section will re-view the evidence for outcomes from ob-servational and interventional studies inhospitalized patients with hyperglycemia.While observational reports abound, in-terventional studies that report improvedoutcomes with targeted glucose control—though few in number—are now begin-ning to provide a source of evidence in theliterature.

To make the case for defining targetsfor glucose control in hospital settings, itis necessary to examine the literature onboth short- and long-term mortality. Dataregarding diabetes and hyperglycemia-associated morbidity have emerged fromspecific clinical settings. These data in-clude infection rates, need for intensivecare unit admission, functional recovery,and health economic outcomes such aslength of stay and hospital charges. Fortheir practical implications and for thepurpose of this review, literature on theassociation of blood glucose level withoutcomes will be grouped into the medi-cal and surgical areas in which studieshave been reported as follows: generalmedicine and surgery, cardiovascular dis-ease (CVD) and critical care, and neuro-logic disorders (Table 1).

General medicine and surgeryObservational studies suggest an associa-tion between hyperglycemia and in-creased mortality. Recently, investigatorshave reported on outcomes correlatedwith blood glucose levels in the generalmedicine and surgery setting. Pomposelliet al. (191) studied 97 patients with dia-betes undergoing general surgery proce-dures. Blood glucose testing occurredevery 6 h. The authors found that a singleblood glucose level �220 mg/dl (12.2mmol/l) on the first postoperative day wasa sensitive (85%), but relatively nonspe-cific (35%), predictor of nosocomial in-fections. Patients with a blood glucosevalue(s) �220 mg/dl (12.2 mmol/l) hadinfection rates that were 2.7 times higherthan the rate for patients with blood glu-cose values �220 mg/dl (12.2 mmol/l).

When minor infections of the urinarytract were excluded, the relative risk (RR)for serious postoperative infection, in-cluding sepsis, pneumonia, and woundinfections, was 5.7.

Umpierrez et al. (1) reviewed 1,886admissions for the presence of hypergly-cemia (fasting blood glucose �126 mg/dlor random blood glucose �200 mg/dl ontwo or more occasions). Care was pro-vided on general medicine and surgeryunits. Among these subjects, there were223 patients (12%) with new hyperglyce-mia and 495 (26%) with known diabetes.Admission blood glucose for the normo-glycemic group was 108 � 10.8 mg/dl(6 � 0.6 mmol/l); for the new hypergly-cemia group, it was 189 � 18 mg/dl(10.5 � 1 mmol/l); and for known diabe-tes, it was 230.4 � 18 mg/dl (12.8 � 1mmol/l). After adjusting for confoundingfactors, patients with new hyperglycemiahad an 18-fold increased inhospital mor-tality and patients with known diabeteshad a 2.7-fold increased inhospital mor-tality compared with normoglycemic pa-tients. Length of stay was higher for thenew hyperglycemia group compared withnormoglycemic and known diabetic pa-tients (9 � 0.7, 4.5 � 0.1, and 5.5 � 0.2days, respectively, P � 0.001). Both thenew hyperglycemia and known diabeticpatients were more likely to require inten-sive care unit (ICU) care when comparedwith normoglycemic subjects (29 vs. 14vs. 9%, respectively, P � 0.01) and weremore likely to require transitional or nurs-ing home care. There was a trend towarda higher rate of infections and neurologicevents in the two groups with hypergly-cemia (1). It is likely that the “new” hy-perglycemic patients in this report were aheterogeneous population made up of pa-tients with unrecognized diabetes, predi-abetes, and/or stress hyperglycemiasecondary to severe illness.

The observational data from these twostudies suggest that hyperglycemia fromany etiology in the hospital on general med-icine and surgery services is a significantpredictor of poor outcomes, relative to out-comes for normoglycemic subjects. Patientswith hyperglycemia, with or without diabe-tes, had increased risk of inhospital mortal-ity, postoperative infections, neurologicevents, intensive care unit admission andincreased length of stay. The Pomposelli ar-ticle (191) found that a blood glucose levelof 220 mg/dl (12.2mmol/l) separated pa-tients for risk of infection. Data from the



Tab

le1—

Evi

denc

efo

ras

soci

atio

nof

bloo

dgl

ucos

ele

velw

ith

clin

ical

outc

omes

Clin

ical

sett

ing

Thr

esho

ldBG

leve

ls[m

g/dl

,(m

mol

/l)]

Out

com

esan

dco

mm

ents

Gen

eral

med

icin

ean

dsu

rger

yM

orta

lity,

ICU

adm

its,

leng

thof

stay

,and

nurs

ing

hom

eor

tran

siti

onal

care

adm

its

corr

elat

edw

ith

BGan

dgl

ucos

eto

lera

nce

stat

us:

Nor

mog

lyce

mia

�10

8�

10.8

(6�

0.6)

;N

ewhy

perg

lyce

mia

�18

9�

18(1

0.5

�1)

;K

now

ndi

abet

es�

230.

4�

18(1

2.8

�1)

.

Rev

iew

ofBG

leve

lsof

pati

ents

onge

nera

lmed

icin

ean

dsu

rger

yw

ards

.Hyp

ergl

ycem

iade

fined

astw

oor

mor

em

easu

rem

ents

wit

hfa

stin

gBG

�12

6(7

)an

d/or

rand

om�

200

(11.

1).H

ospi

talm

orta

lity

for

norm

ogly

cem

icpa

tien

tsw

as1.

7%.W

ith

know

ndi

abet

esm

orta

lity

was

3%an

dw

ith

“new

”hy

perg

lyce

mia

itw

as16

%.A

fter

adju

stm

ent

for

vari

able

s,th

e“n

ew”

hype

rgly

cem

iagr

oup

had

an18

.3-f

old

incr

ease

dm

orta

lity

rate

com

pare

dw

ith

a2.

7-fo

ldin

crea

sew

ith

know

ndi

abet

es.P

atie

nts

wit

hne

why

perg

lyce

mia

also

had

anin

crea

sed

leng

thof

stay

,wer

em

ore

likel

yto

requ

ire

ICU

care

,and

wer

em

ore

likel

yto

requ

ire

tran

siti

onal

ornu

rsin

gho

me

care

(Obs

,n�

1,88

6)(1

).In

fect

ion

rate

sco

rrel

ated

wit

hBG

abov

e22

0.5.

9-fo

ldin

crea

sein

seri

ous

infe

ctio

ns,i

nclu

ding

seps

is,p

neum

onia

,and

wou

ndin

fect

ions

for

BGov

er22

0(1

2.2)

,w

hich

was

ase

nsit

ive

(85%

)pr

edic

tor

ofno

soco

mia

linf

ecti

on(O

bs,n

�97

)(1

91).

CV

Dan

dcr

itic

alca

reA

cute

MI

Mor

talit

y,C

HF,

and

card

ioge

nic

shoc

kri

skco

rrel

ated

wit

hBG

Abo

ve10

9.8

(6),

inpa

tien

tsw

itho

utkn

own

diab

etes

;A

tor

abov

e12

4(6

.9),

wit

hdi

abet

esdi

agno

sis.

Lite

ratu

rere

view

.Rel

ativ

eri

sk(R

R)

for

inho

spit

alm

orta

lity

incr

ease

d3.

9-fo

ldin

subj

ects

wit

hout

diab

etes

wit

hBG

ator

abov

era

nge

of10

9.8–

144

(6.1

–8),

95%

CI

2.9–

5.4;

risk

ofC

HF

and

card

ioge

nic

shoc

kw

asal

soin

crea

sed.

RR

for

mod

erat

ein

crea

sein

mor

talit

yw

ith

know

ndi

abet

esw

ith

was

1.7

(14

arti

cle

revi

eww

ith

met

a-an

alys

is)

(192

).

Adm

itBG

,str

atifi

edac

cord

ing

toW

HO

crit

eria

and

corr

elat

edw

ith

mor

talit

y:I.

BGle

ssth

an10

0.8

(5.6

)to

IV.B

Ggr

eate

rth

anor

equa

lto

199.

8(1

1)

One

-yea

rm

orta

lity

was

19.3

%fo

rBG

�10

0.8

(5.6

)at

tim

eof

adm

issi

on,c

ompa

red

wit

h44

%w

hen

BG�

199.

8(1

1).

Mor

talit

yw

ashi

gher

inpa

tien

tsw

ith

diab

etes

than

inth

ose

wit

hout

(40

vs.1

6%,P

�0.

05)

(Obs

,n�

336)

(193

).M

orta

lity

corr

elat

edw

ith

BGin

inte

nsiv

ein

sulin

ther

apy

grou

pw

here

mea

nBG

�17

2.8

�59

.4(9

.6�

3.3)

com

pare

dw

ith

conv

enti

onal

ther

apy

grou

pw

here

mea

nBG

�21

0.6

�73

.8(1

1.7

�4.

1).

Inte

nsiv

ein

sulin

ther

apy

inpa

tien

tsw

ith

acut

eM

I,fo

llow

edby

mul

tish

otre

gim

enfo

r3

orm

ore

mon

ths,

wit

h29

%re

duct

ion

inm

orta

lity

at1

year

.Ben

efit

exte

nds

toat

leas

t3.

4ye

ars.

One

life

save

dfo

rni

nepa

tien

tstr

eate

d(I

nt,

n�

620)

(128

).C

ardi

acsu

rger

yM

orta

lity

posi

tive

lyco

rrel

ated

wit

hBG

ina

dose

-dep

ende

ntm

anne

r,w

ith

the

low

est

mor

talit

yin

the

grou

pw

here

mea

npo

stop

erat

ive

BG�

150

(8.3

).O

bser

vati

onal

stud

ies

usin

ghi

stor

ical

cont

rols

.Bot

hm

orta

lity

and

inci

denc

eof

DSW

Isw

ere

redu

ced

toth

eno

ndia

beti

cra

nge

afte

rim

plem

enti

ngin

sulin

infu

sion

prot

ocol

sw

ith

prog

ress

ivel

ylo

wer

BGta

rget

sov

erti

me

(196

,197

).C

riti

calc

are

Mor

talit

yan

dse

psis

risk

corr

elat

edw

ith

BG.I

nten

sive

insu

linth

erap

yar

mw

ith

mea

nBG

103

�19

(5.7

�1.

06);

conv

enti

onal

trea

tmen

tar

mw

ith

mea

nBG

153

�33

(8.5

�1.

8).

Pros

pect

ive

rand

omiz

edco

ntro

lled

stud

yof

adul

tsad

mit

ted

tosu

rgic

alIC

Uan

don

mec

hani

calv

enti

lati

on.S

ixty

perc

ent

had

had

card

iac

surg

ery,

maj

orit

yof

othe

rsal

sosu

rgic

alpa

tien

ts.I

ITto

mai

ntai

nBG

in80

–110

(4.4

–6.1

)ra

nge

com

pare

dw

ith

conv

enti

onal

ther

apy

(CT

)to

targ

etBG

to18

0–20

0(1

0–11

.1).

IIT

redu

ced

ICU

mor

talit

yby

40%

from

8.0

to4.

6%,P

�0.

04.F

orea

ch20

mg/

dlin

crea

sein

BG,r

isk

ofde

ath

was

incr

ease

dby

30%

.IIT

also

redu

ced

inci

denc

eof

seps

isby

46%

and

over

allh

ospi

talm

orta

lity

by34

%.A

grad

uald

eclin

ein

risk

for

ICU

and

hosp

ital

deat

hw

ith

decl

ine

inBG

leve

lwas

obse

rved

,wit

hno

iden

tifia

ble

thre

shol

dbe

low

whi

chth

ere

was

nofu

rthe

rri

skre

duct

ion.

Prol

onge

din

flam

mat

ion,

defin

edas

elev

atio

nin

CR

Pab

ove

150

mg/

dlfo

rov

er3

days

,w

asas

soci

ated

wit

hm

ean

BGle

vel(

per

20m

g/dl

adde

d)w

ith

orof

1.16

(95%

CI

1.06

–1.2

4),P

�0.

0006

.Th

resh

old

may

behi

gher

than

110

(6.1

)(In

t,n

�1,

548)

(2,2

00).

Neu

rolo

gic

diso

rder

sA

cute

stro

keM

orta

lity

and

func

tion

alre

cove

ryaf

ter

acut

eis

chem

icst

roke

corr

elat

edw

ith

BG.

Adm

issi

onBG

over

110

(6.1

)fo

rm

orta

lity;

over

121

for

func

tion

alre

cove

ry.

Lite

ratu

rere

view

(196

6–20

00).

Aft

eris

chem

icst

roke

,adm

issi

ongl

ucos

ele

vel�

110–

126

(�6.

1–7)

asso

ciat

edw

ith

incr

ease

dri

skof

inho

spit

alor

30-d

aym

orta

lity

inpa

tien

tsw

itho

utdi

abet

eson

ly(R

R3.

8;95

%C

I2.

32–4

.64)

.St

roke

surv

ivor

sw

itho

utdi

abet

esan

dBG

over

121–

144

(6.7

–8)

had

RR

of1.

41(1

.16–

1.73

)fo

rpo

orfu

ncti

onal

reco

very

(met

aana

lysi

s,26

stud

ies)

(96)

.N

euro

logi

cfu

ncti

onaf

ter

acut

est

roke

corr

elat

edw

ith

adm

issi

onBG

.O

dds

for

neur

olog

icim

prov

emen

tde

crea

sed

wit

hO

Rof

0.76

for

each

100

mg/

dlBG

incr

ease

.

Con

trol

led,

rand

omiz

edtr

ialo

fmol

ecul

arhe

pari

nin

acut

est

roke

.Mea

nad

mis

sion

BG14

4�

68(8

�3.

8)as

soci

ated

wit

hne

urol

ogic

impr

ovem

ent

at3

mon

ths.

Inth

ose

wit

hout

impr

ovem

ent,

BGw

as16

0�

84(8

.9�

4.7)

.As

BGin

crea

sed,

odds

for

neur

olog

icim

prov

emen

tde

crea

sed,

wit

hO

R�

0.76

per

100-

mg/

dlin

crea

sein

adm

issi

onBG

(95%

CI

0.61

–0.9

5,P

�0.

01)

(Obs

,n�

1,25

9)(2

01).

Func

tion

alou

tcom

esan

dre

turn

tow

ork

afte

rst

roke

corr

elat

edw

ith

adm

issi

onBG

.A

dmis

sion

BGun

der

120

(6.7

)w

ith

posi

tive

rela

tion

ship

.

Pros

pect

ive

data

.Str

oke-

rela

ted

defic

its

wer

em

ore

seve

rew

hen

adm

issi

ongl

ucos

eva

lues

wer

e�

120

(6.7

).O

nly

43%

ofpa

tien

tsw

ith

anad

mis

sion

gluc

ose

valu

eof

�12

0m

g/dl

able

tore

turn

tow

ork,

whe

reas

76%

ofpa

tien

tsw

ith

low

ergl

ucos

eva

lues

rega

ined

empl

oym

ent

(202

).

RtP

A-i

nduc

edhe

mor

rhag

ein

toan

infa

rct

corr

elat

edw

ith

BGov

er30

0(1

6.7)

.C

entr

alco

llect

ion

ofre

tros

pect

ive

and

pros

pect

ive

data

onac

ute

isch

emic

stro

ketr

eate

din

clin

ical

prac

tice

sw

ith

alte

plas

e.BG

�30

0m

g/dl

anin

depe

nden

tri

skfa

ctor

for

hem

orrh

age

into

anin

farc

tw

hen

trea

tmen

tw

ith

reco

mbi

nant

RtP

Ais

give

n(O

bs,n

�1,

205)

(203

).M

orta

lity,

leng

thof

stay

,and

char

ges

incr

ease

dw

ith

adm

issi

onBG

�13

0(7

.2).

Hos

pita

lizat

ion

for

acut

eis

chem

icst

roke

.Hyp

ergl

ycem

ia(r

ando

mBG

ator

abov

e13

0)pr

esen

tin

40%

atad

mis

sion

.M

ost

rem

aine

dhy

perg

lyce

mic

wit

hm

ean

BGva

lues

of20

6(1

1.4)

.Ran

dom

adm

issi

onse

rum

gluc

ose

�13

0(7

.2)

inde

pend

entl

yas

soci

ated

wit

hin

crea

sed

risk

ofde

ath

at30

days

(HR

1.87

)an

d1

year

(HR

1.75

),bo

thP

�0.

01.

Oth

ersi

gnifi

cant

corr

elat

esw

ith

hype

rgly

cem

ia,w

hen

com

pare

dw

ith

norm

alBG

,wer

ele

ngth

ofst

ay(7

vs.6

days

,P�

0.01

5)an

dch

arge

s($

5,26

2vs

.$6,

611,

P�

0.00

1)(O

bs,n

�65

6)(2

05).

Hyp

ogly

cem

iari

skan

d4

wee

km

orta

lity

wit

hBG

targ

eted

to72

–126

(4–7

).G

luco

se-i

nsul

inin

fusi

onin

acut

est

roke

wit

hm

ild-t

o-m

oder

ate

hype

rgly

cem

ia.E

xam

ined

the

safe

tyof

trea

ting

toa

targ

etgl

ucos

eof

72–1

26(4

–7).

Low

erin

gBG

was

foun

dto

bew

itho

utsi

gnifi

cant

risk

ofhy

pogl

ycem

iaor

4-w

eek

exce

ssm

orta

lity

inpa

tien

tsw

ith

acut

est

roke

and

mild

-to-

mod

erat

ehy

perg

lyce

mia

(147

).Pe

num

bral

salv

age,

final

infa

rct

size

,and

func

tion

alou

tcom

ein

pati

ents

wit

hm

edia

nac

ute

BGra

ngin

gfr

om10

4.4

to17

2.8

(5.8

–9.6

).St

udy

ofM

RI

and

MR

Sin

acut

est

roke

.Pro

spec

tive

eval

uati

onw

ith

seri

aldi

ffus

ion-

wei

ghte

dan

dpe

rfus

ion-

wei

ghte

dM

RI

and

acut

eBG

mea

sure

men

ts.M

edia

nac

ute

BGw

as13

3.2

mg/

dl(7

.4m

mol

/l),r

ange

104.

4–17

2.8

mg/

dl(5

.8–9

.6m

mol

/l).A

doub

ling

ofBG

from

5to

10m

mol

/lle

dto

a60

%re

duct

ion

inpe

num

bral

salv

age

and

a56

-cm

3in

crea

sein

final

infa

rct

size

.In

pati

ents

wit

hac

ute

perf

usio

n-di

ffus

ion

mis

mat

ch,a

cute

hype

rgly

cem

iaw

asal

soco

rrel

ated

wit

hre

duce

dsa

lvag

eof

mis

mat

chti

ssue

from

infa

rcti

on,g

reat

erfin

alin

farc

tsi

ze,a

ndw

orse

func

tion

alou

tcom

e,in

depe

nden

tof

base

line

stro

kese

veri

ty,l

esio

nsi

ze,a

nddi

abet

icst

atus

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Umpierrez study (1) and most of the litera-ture from other disciplines, as outlined else-where in this review, would suggest a lowerthreshold for optimal hospital outcomes.Evidence for a blood glucose threshold.The Umpierrez study demonstrated bet-ter outcomes for patients with fasting andadmission blood glucose �126 mg/dl (7mmol/l) and all random blood glucoselevels �200 mg/dl (11.1 mmol/l). Be-cause the Pomposelli and Umpierrezstudies are observational, a causal link be-tween hyperglycemia and poor outcomescannot be established.

CVD and critical careNumerous articles contain data linkingblood glucose level to outcomes in AMIand cardiac surgery, for which patientsreceive care predominantly in the ICUsetting. The majority of these trials are ob-servational, but the literature also in-c ludes seve ra l l a rge , l andmarkinterventional studies that have markedlyincreased awareness of the need for tar-geted glycemic control in these settings.AMI. In 2000, Capes et al. (192) re-viewed blood glucose levels and mortalityin the setting of AMI from 15 previouslypublished studies and performed a meta-analysis of the results to compare the RRof in-hospital mortality and CHF in bothhyper- and normoglycemic patients withand without diabetes. In subjects withoutknown diabetes whose admission bloodglucose was �109.8 mg/dl (6.1 mmol/l),the RR for in-hospital mortality was in-creased significantly (RR 3.9, 95% CI2.9–5.4). When diabetes was present andadmission glucose was �180 mg/dl (10mmol/l), risk of death was moderately in-creased (1.7, 1.2–2.4) compared with pa-t i ents who had diabetes but nohyperglycemia on admission.

Bolk et al. (193) analyzed admissionblood glucose values in 336 prospective,consecutive patients with AMI with aver-age follow-up to 14.2 months. Twelvepercent of this cohort had previously di-agnosed diabetes. Multivariate analysisrevealed an independent association ofadmission blood glucose and mortality.The 1-year mortality rate was 19.3% insubjects with admission plasma glucose�100.8 mg/dl (5.6 mmol/l) and rose to44% with plasma glucose �199.8 mg/dl(11 mmol/l). Mortality was higher in pa-tients with known diabetes than in thosewithout diabetes (40 vs. 16%, P � 0.05.).

From the frequently cited Diabetes

and Insulin-Glucose Infusion in AcuteMyocardial Infarction (DIGAMI) study,Malmberg and colleagues (128,194) havepublished the results of a prospective in-terventional trial of insulin-glucose infu-sion followed by subcutaneous insulintreatment in diabetic patients with AMI,reporting mortality at 1 year. Of 620 per-sons with diabetes and AMI, 306 wererandomized to intensive treatment withinsulin infusion therapy, followed by amultishot insulin regimen for 3 or moremonths. Patients randomized to conven-tional therapy received standard diabetestherapy and did not receive insulin unlessclinically indicated. Baseline blood glu-cose values were similar in the intensivetreatment group, 277.2 � 73.8 mg/dl(15.4 � 4.1 mmol/l), and the conven-tional treatment group, 282.6 � 75.6mg/dl (15.7 � 4.2 mmol/l). Blood glucoselevels decreased in the first 24 h in theintervention group to 172.8 � 59.4 mg/dl(9.6 � 3.3 mmol/l; P � 0.001 vs. conven-tional treatment), whereas blood glucosedeclined to 210.6 � 73.8 mg/dl (11.7 �4.1mmol/l). The blood glucose range foreach group was wide: 116.4–232.2 mg/dl(6.5–12.9 mmol/l) in the intensive treat-ment group and 136.8 –284.4 mg/dl(7.6–15.8 mmol/l) in the conventionaltreatment group. Mortality at 1 year in theintensive treatment group was 18.6%,and for the conventional treatment groupit was 26.1%, a 29% reduction in mortal-ity for the intervention arm (P � 0.027).At 3.4 (1.6–5.6) years follow-up, mortal-ity was 33% in the intensive treatmentgroup and 44% in the conventional treat-ment group (RR 0.72, 95% CI 0.55–0.92;P � 0.011), consistent with persistent re-duction in mortality. The benefit of inten-sive control was most pronounced in 272patients who had not had prior insulintherapy and had a less risk for CVD (0.49,0.30–0.80; P � 0.004).

In the DIGAMI study, insulin infu-sion in AMI followed by intensive subcu-taneous insulin therapy for 3 or moremonths improved long-term survival,with a benefit that extends to at least 3.4years (128). An absolute reduction inmortality of 11% was observed, meaningthat one life was saved for every ninetreated patients. The observation thathigher mean glucose levels were associ-ated with increased mortality betweengroups of patients with diabetes wouldsuggest that stress hyperglycemia plays anindependent role in the determination of

outcomes. In addition, it is of interest thatin spite of the observation that blood glu-cose levels between the intensive and con-ventional treatment groups were similar,a significant difference in mortality be-tween these groups was found. A rela-tively modest reduction in blood glucosein the intensive treatment group com-pared with the conventional treatmentgroup produced a statistically significantimprovement in mortality. This suggeststhe possibility that the beneficial effect ofimproved control may be mediatedthrough mechanisms other than a directeffect of hyperglycemia, such as a directeffect of insulin.Evidence for a blood glucose thresholdfor increased mortality in AMI.● The metaanalysis of Capes et al. (192)

reported a blood glucose threshold of�109.8 mg/dl (6.1 mmol/l) for patientswithout diabetes and �180 mg/dl (10mmol/l) for known diabetes.

● The observational study of Bolk et al.(193) identified threshold blood glu-coses, divided by World Health Orga-nization (WHO) classification criteria,with mortality risk of 19.3% for normo-glycemia (blood glucose �100.8 mg/dl[5.6 mmol/l]), which rose progressivelyto 44% for blood glucose �199.8mg/dl (11 mmol/l).

● In the DIGAMI study, mean blood glu-cose in the intensive insulin interven-tion arm was 172.8 mg/dl (9.6 mmol/l),where lower mortality risk was ob-served. In the conventional treatmentarm, mean blood glucose was 210.6mg/dl (11.7 mmol/l). The broad rangeof blood glucose levels within each armlimits the ability to define specific bloodglucose target thresholds.

Cardiac surgery. Attainment of targetedglucose control in the setting of cardiacsurgery is associated with reduced mor-tality and risk of deep sternal wound in-fect ions. Furnary and col leagues(196,197) treated cardiac surgery pa-tients with diabetes with either subcuta-neous insulin (years 1987–1991) or withintravenous insulin (years 1992–2003) inthe perioperative period. From 1991–1998, the target glucose range was 150�200 mg/dl (8.3–11.1 mmol/l); in 1999it was dropped to 125–175 mg/dl (6.9–9.7 mmol/l), and in 2001 it was againlowered to 100 –150 mg/dl (5.5– 8.3mmol/l). Following implementation ofthe protocol in 1991, the authors re-



ported a decrease in blood glucose levelfor the first 2 days after surgery and a con-comitant decrease in the proportion of pa-tients with deep wound infections, from2.4% (24 of 990) to 1.5% (5 of 595) (P �0.02) (198). A recent analysis or the co-hort found a positive correlation betweenthe average postoperative glucose leveland mortality, with the lowest mortalityin patients with average postoperativeblood glucose �150 mg/dl (8.3 mmol/l)(197).

Golden et al. (199) performed a non-concurrent prospective cohort chart re-view study in cardiac surgery patientswith diabetes (n � 411). Perioperativeglucose control was assessed by the meanof six capillary blood glucose measuresperformed during the first 36 h followingsurgery. The overall infectious complica-tion rate was 24.3%. After adjustment forvariables, patients with higher mean cap-illary glucose readings were at increasedrisk of developing infections. Comparedwith subjects in the lowest quartile forblood glucose, those in quartiles 2– 4were at progressively increased risk forinfection (RR 1.17, 1.86, and 1.78 forquartiles 2, 3, and 4, respectively, P �0.05 for trend). These data support theconcept that perioperative hyperglycemiais an independent predictor of infection inpatients with diabetes.Critical care. Van den Berghe et al. (200)performed a prospective, randomizedcontrolled study of 1,548 adults whowere admitted to a surgical intensive careunit and were receiving mechanical ven-tilation. Reasons for ICU admission werecardiac surgery (60%) and noncardiacindications, including neurologic disease(cerebral trauma or brain surgery), otherthoracic surgery, abdominal surgery orperitonitis, vascular surgery, multipletrauma, or burns and transplant (4–9%each group). Patients were randomized toreceive intensive insulin therapy (IIT) tomaintain target blood glucose in the 80–110 mg/dl (4.4–6.1) range or conven-tional therapy to maintain target bloodglucose between 180 and 200 mg/dl (10–11.1 mmol/l). Insulin infusion was initi-ated in the conventional treatment grouponly if blood glucose exceeded 215 mg/dl(11.9 mmol/l), and the infusion was ad-justed to maintain the blood glucose levelbetween 180 and 200 mg/dl (10.0 and11.1 mmol/l). After the patients left theICU they received standard care in thehospital with a target blood glucose of

180 and 200 mg/dl (10.0 and 11.1 mmol/l).

Ninety-nine percent of patients in theIIT group received insulin infusion, ascompared with 39% of the patients in theconventional treatment group. In the IITarm, blood glucose levels were 103 � 19mg/dl (5.7 � 1.1 mmol/l) and in conven-tional treatment 153 � 33 mg/dl (8.5 �1.8 mmol/l). IIT reduced mortality duringICU care from 8.0% with conventionaltreatment to 4.6% (P � 0.04). The benefitof IIT was attributable to its effect on mor-tality among patients who remained in theunit for more than 5 days (20.2% withconventional treatment vs. 10.6% withIIT, P � 0.005). IIT also reduced overallinhospital mortality by 34% (2). In a sub-sequent analysis, Van den Berghe (200)demonstrated that for each 20 mg/dl (1.1mmol/l), glucose was elevated �100mg/dl (5.5 mmol/l) and the risk of ICUdeath increased by 30% (P � 0.0001).Daily insulin dose (per 10 units added)was found as a positive rather than nega-tive risk factor, suggesting that it was notthe amount of insulin that produced theobserved reduction in mortality. Hospitaland ICU survival were linearly associatedwith ICU glucose levels, with the highestsurvival rates occurring in patientsachieving an average blood glucose �110mg/dl (6.1 mmol). An improvement inoutcomes was found in patients who hadprior diabetes as well as in those who hadno history of diabetes.Evidence for a blood glucose thresholdin cardiac surgery and critical care.● Furnary et al. (196) and Zerr et al. (198)

identified a reduction in mortalitythroughout the blood glucose spectrumwith the lowest mortality in patientswith blood glucose �150 mg/dl (8.3mmol/l).

● Van den Berghe et al. (2), using inten-sive intravenous insulin therapy, re-ported a 45% reduction in ICUmortality with a mean blood glucose of103 mg/dl (5.7 mmol/l), as comparedwith the conventional treatment arm,where mean blood glucose was 153mg/dl (8.5 mmol/l) in a mixed group ofpatients with and without diabetes.

Acute neurologic illness and stroke. Inthe setting of acute neurologic illness,stroke, and head injury, data support aweak association between hyperglycemiaand increased mortality and are scanty forpatients with known diabetes. In these

clinical settings, available data, with oneexception, are observational. Capes et al.(96) reported on mortality after stroke inrelation to admission glucose level from26 studies, published between 1996 and2000, where RRs for prespecified out-comes were reported or could be calcu-lated. After ischemic stroke, admissionglucose level �110–126 mg/dl (�6.1–7mmol/l) was associated with increasedrisk of inhospital or 30-day mortality inpatients without diabetes only (RR 3.8,95% CI 2.32– 4.64). Stroke survivorswithout diabetes and blood glucose�121–144 mg/dl (6.7–8 mmol/l) had anRR of 1.41 (1.16–1.73) for poor func-tional recovery. After hemorrhagic stroke,admission hyperglycemia was not associ-ated with higher mortality in either thediabetes or nondiabetes groups.

Several of the studies that were in-cluded in the analysis of Capes et al. (96)contain additional data that support anassociation between blood glucose andoutcomes in stroke. In the Acute StrokeTreatment Trial (TOAST), a controlled,randomized study of the efficacy of a low–molecular weight heparinoid in acuteischemic stroke (n � 1,259), neurologicimprovement at 3 months (a decrease byfour or more points on the National Insti-tutes of Health [NIH] Stroke Scale or afinal score of 0) was seen in 63% of sub-jects. Those with improvement had amean admission glucose of 144 � 68 mg/dl, and those without improvement hadblood glucose of 160 � 84 mg/dl. In mul-tivariate analysis, as admission blood glu-cose increased, the odds for neurologicimprovement decreased with an OR of0.76 per 100 mg/dl increase in admissionglucose (95% CI 0.61–0.95, P � 0.01)(201). Subgroup analysis for patientswith or without a history of diabetes wasnot done. Pulsinelli et al. (202) reportedworse outcomes for both patients with di-abetes and hyperglycemic patients with-out an established diagnosis of diabetescompared with those who were normo-glycemic. Stroke-related deficits weremore severe when admission glucose val-ues were �120 mg/dl (6.7 mmol/l). Only43% of the patients with an admissionglucose value of �120 mg/dl were able toreturn to work, whereas 76% of patientswith lower glucose values regainedemployment.

Demchuk et al. (203) studied the ef-fect of admission glucose level and risk forintracerebral hemorrhage into an infarct



when treatment with recombinant tissueplasminogen activator was given to 138patients presenting with stroke. Twenty-three percent of the cohort had knowndiabetes. The authors reported admissionblood glucose and/or history of diabetesas the only independent predictors ofhemorrhage. Kiers et al. (204) prospec-tively studied 176 sequential acute strokepatients and grouped them by admissionblood glucose level, HbA1c level, and his-tory of diabetes. Threshold blood glucosefor euglycemia was defined as fastingblood glucose �140 mg/dl (7.8 mmol/l).The authors divided patients into one offour groups: euglycemia with no historyof diabetes, patients with “stress hyper-glycemia” (blood glucose �140 mg/dl,7.8 mmol/l, and HbA1c �8%), newly di-agnosed diabetes (blood glucose �140mg/dl, 7.8 mmol/l, and HbA1c �8%), andknown diabetes. No difference was foundin the type or site of stroke among the fourgroups. Compared with the euglycemic,nondiabetic patients, mortality was in-creased in all three groups of hyperglyce-mic patients.

Williams et al. (205) reported on theassociation of hyperglycemia and out-comes in a group of 656 acute stroke pa-tients. Fifty-two percent of the cohort hada known history of diabetes. Hyperglyce-mia, defined as a random blood glucose�130 mg/dl (7.22 mmol/l), was presentin 40% of patients at the time of admis-sion. Hyperglycemia was an independentpredictor of death at 30 days (RR 1.87)and at 1 year (RR 1.75) (both P � 0.01).Other outcomes that were significantlycorrelated with hyperglycemia, whencompared with normal blood glucose,were length of stay (7 vs. 6 days, P �0.015) and charges ($6,611 vs. $5,262,P � 0.001).

Recently, Parsons et al. (110) re-ported a study of magnetic resonance im-aging (MRI) and MRS in acute stroke.Sixty-three acute stroke patients wereprospectively evaluated with serial diffu-sion-weighted and perfusion-weightedMRI and acute blood glucose measure-ments. Median acute blood glucose was133.2 mg/dl (7.4 mmol/l), range 104.4–172.8 mg/dl (5.8–9.6 mmol/l). A dou-bling of blood glucose from 90 to 180mg/dl (5�10 mmol/l) led to a 60% reduc-tion in penumbral salvage and a 56 cm3

increase in final infarct size. For patientswith acute perfusion-diffusion mismatch,acute hyperglycemia was correlated with

reduced salvage of mismatch tissue frominfarction, greater final infarct size, andworse functional outcome, independentof baseline stroke severity, lesion size, anddiabetes status. Furthermore, higheracute blood glucose in patients with per-fusion-diffusion mismatch was associatedwith greater acute-subacute lactate pro-duction, which, in turn, was indepen-dently associated with reduced salvage ofmismatch tissue. Acute hyperglycemia in-creases brain lactate production and facil-itates conversion of hypoperfused at-risktissue into infarction, which may ad-versely affect stroke outcome.

These numerous observational stud-ies further support the need for random-ized controlled trials that aggressivelytarget glucose control in acute stroke. Todate, there is just one report of a treat-to-target intervention in stroke patients. TheGlucose Insulin in Stroke Trial (GIST) ex-amined the safety of GIK infusion in treat-ing to a target glucose of 72–126 mg/dl(4–7 mmol/l). Lowering plasma glucoselevels was found to be without significantrisk of hypoglycemia or excess mortalityin patients with acute stroke and mild-to-moderate hyperglycemia (206). No dataon functional recovery were reported.While it is promising that these investiga-tors were able to lower plasma glucosewithout increasing risk of hypoglycemiaor mortality for stroke patients, until fur-ther studies test the effectiveness of thisapproach and possible impact on out-comes, it cannot be considered standardpractice.

Hyperglycemia is associated withworsened outcomes in patients with acutestroke and head injury, as evidenced bythe large number of observational studiesin the literature. It seems likely that thehyperglycemia associated with theseacute neurologic conditions results fromthe effects of stress and release of insulincounterregulatory hormones. The ele-vated blood glucose may well be a markerof the level of stress the patient is experi-encing. The hyperglycemia can bemarked in these patients. Studies areneeded to assess the role of antihypergly-cemic pharmacotherapy in these settingsfor possible impact on outcomes. Clinicaltrials to investigate the impact of targetedglycemic control on outcomes in patientswith stress hyperglycemia and/or knowndiabetes and acute neurologic illness areneeded.

Evidence for a blood glucose thresholdin acute neurologic disorders. Obser-vational studies suggest a correlation be-tween blood glucose level, mortality,morbidity, and health outcomes in pa-tients with stroke.

● Capes et al.’s (96) metaanalysis identi-fied an admission blood glucose �110mg/dl (6.1 mmol/l) for increased mor-tality for acute stroke.

● Studies by Pulsinelli, Jorgenson, andWeir et al. (202) identified an admis-sion blood glucose �120 mg/dl (6.67mmol/l), 108 mg/dl (6 mmol/l), and144 mg/dl (8 mmol/l), respectively, forincreased severity ad mortality for acutestroke.

● Williams et al. (205) reported a thresh-old admission blood glucose �130mg/dl (7.2 mmol/l) for increased mor-tality, length of stay, and charges inacute stroke.

● Scott et al. (206) demonstrated accept-able hypoglycemia risk and no excess4-week mortality with glucose-insulininfusion treatment targeted to bloodglucose range of 72–126 mg/dl (4–7mmol/l) in acute stroke.

● Parsons et al. (110) reported that a dou-bling of blood glucose from 90 to 180mg/dl (5–10 mmol/l) was associatedwith 60% worsening of penumbral sal-vage and a 56-cm3 increase in infarctsize.

HOW ARE TARGET BLOODGLUCOSE LEVELS BESTACHIEVED IN THEHOSPITAL?

Role of oral diabetes agentsNo large studies have investigated the po-tential roles of various oral agents on out-comes in hospitalized patients withdiabetes. A number of observational stud-ies have commented on the outcomes ofpatients treated as outpatients with dietalone, oral agents, or insulin. However,the results are variable and the methodscannot account for patient characteristicsthat would influence clinician selection ofthe various therapies in the hospital set-ting. Of the three primary categories oforal agents, secretagogues (sulfonylureasand meglitinides), biguanides, and thia-zolidinediones, none have been systemat-ically studied for inpatient use. However,all three groups have characteristics thatcould impact acute care.



SulfonylureasConcern about inpatient use of sulfonyl-ureas centers on vascular effects(207,208). Over 30 years ago the report ofthe University Group Diabetes Programproposed increased cardiovascular eventsin patients treated with sulfonylureas(209). This report resulted in an ongoinglabeling caution for sulfonylureas andheart disease, although the findings havebeen questioned and have had very lim-ited influence on prescribing habits. Re-sidual fears seemingly were allayed withthe findings of the U.K. Prospective Dia-betes Study (UKPDS) (210). This largeprospective trial did not find any evidenceof increased frequency of MI among indi-viduals treated with sulfonylureas.Rather, the trend was in the direction ofreduced events. However, questions re-main. For instance, it is possible that con-trol of hyperglycemia by any meansreduces the frequency of vascular eventsto a greater extent than any effect sulfo-nylureas may have to increase vascularevents. A variety of studies have served tofuel continued controversy.

Ischemic preconditioning appears tobe an adaptive, protective mechanismserving to reduce ischemic injury in hu-mans (211,212). Sulfonylureas inhibitATP-sensitive potassium channels, result-ing in cell membrane depolarization, ele-vation of intracellular calcium, andcellular response (213,214). This mecha-nism may inhibit ischemic precondition-ing (215–217). Various methodsevaluating cardiac ischemic precondi-tioning have been used to compare cer-tain of the available sulfonylureas. Forexample, using isolated rabbit hearts, re-searchers found that glyburide but notglimepiride reversed the beneficial effectsof ischemic preconditioning and diazox-ide in reducing infarct size (218). Otherstudies using similar animal heart modelsor cell cultures have found differencesamong the sulfonylureas, usually show-ing glyburide to be potentially moreharmful than other agents studied (219–222). A unique, double-blind, placebo-controlled study using acute balloonocclusion of high-grade coronary steno-ses in humans looked at the relative ef-fects of intravenously administeredplacebo, glimepiride, or glyburide (223).The researchers measured mean ST seg-ment shifts and time to angina. The re-sults again demonstrated suppression ofthe myocardial preconditioning by gly-

buride but not by glimepiride. In per-fused animal heart models, bothglimepiride and glyburide also appear toreduce baseline coronary blood flow athigh doses (220,224).

Cardiac effects of sulfonylureas havealso been compared with other classes oforal diabetes medications. In individualswith type 2 diabetes, investigators foundthat glyburide increased QT dispersion(225). This effect, proposed to reflect riskfor arrhythmias, was measured after 2months of therapy with glyburide or met-formin. Glyburide also increased QTc,while metformin produced no negativeeffects. This study is in contradiction tothe conclusions of a study using isolatedrabbit hearts, where glyburide exerted anantiarrhythmic effect despite repeat evi-dence that it interfered with postischemichyperemia (226). There have been fewother comparisons of sulfonylureas andmetformin with regard to direct cardiaceffects. In a study of rat ventricular myo-cytes, hyperglycemia induced abnormali-ties of myocyte relaxation. Theseabnormalities were improved when myo-cytes were incubated with metformin, butglyburide had no beneficial effect (227).Finally, one experiment recently evalu-ated the relative functional cardiac effectsof glyburide versus insulin (228). In thisstudy of patients with type 2 diabetes, leftventricular function was measured byechocardiography after 12-week treat-ment periods with each agent, attainingsimilar metabolic control. Neither treat-ment influenced resting cardiac function.However, after receiving dipyridamole,glyburide-treated patients experienceddecreased left ventricular ejection fractionand increased wall motion score index.Insulin treatment did not produce thesedeleterious effects on contractility.

Although these various findings usingdifferent research models raise questionsabout potential adverse cardiovascular ef-fects of sulfonylureas in general and gly-buride in particular, they do notnecessarily extrapolate to clinical rele-vancy. A series of observational studieshave attempted to add to our knowledgeabout whether any of the negative effectsof sulfonylureas impact on vascularevents, but they have yielded mixed re-sults. For example, outcomes of directballoon angioplasty after AMI were eval-uated comparing 67 patients taking sulfo-nylureas with 118 patients on otherdiabetes therapies (229). Logistic regres-

sion found sulfonylurea use to be inde-pendently associated with increasedhospital mortality. Others have reportedsimilar trends in patients receiving angio-plasty (230). A third observational studyinvestigated 636 elderly patients with di-abetes (mean age 80 years) and previousMI. The researchers looked for subse-quent coronary events, including fataland nonfatal MI or sudden coronarydeath (231). They found sulfonylureatherapy to be a predictor of new coronaryevents compared with insulin or to diettherapy (82 vs. 69 and 70%, respectively).Not enough metformin-treated patientswere included to comment statistically ona comparison with sulfonylureas.

Conversely, other observational stud-ies have failed to support a relationshipbetween sulfonylurea use and vascularevents. Klaman et al. (232) found no dif-ferences in mortality or creatinine kinase(CK) elevations after acute MI in 245 pa-tients with type 2 diabetes when compar-ing those treated with insulin, thosetreated with oral agents, or those newlydiagnosed. Others have reported a similarlack of association with MI outcomes andsulfonylureas (233–236). In one study,ventricular fibrillation was found to beless associated with sulfonylurea therapythan with gliclazide or insulin (234). Fi-nally, in a related vascular consideration,there was no evidence of increased strokemortality or severity in patients with type2 diabetes treated with sulfonylureas ver-sus other therapies (237).

None of the studies looking at sulfo-nylurea effects on vascular inpatient mor-tality have been prospective. Investigatorshave not made attempts to separate outduration of therapy or whether sulfonyl-ureas were continued after presentationto the hospital. The one prospective studylooking at treatment after admission forAMI indicated a benefit for insulin ther-apy over conventional therapy with sulfo-nylureas, but the improved outcomeswere proposed to occur as a benefit ofimproved glucose control (238). No sug-gestion was made that sulfonylurea ther-apy had specific negative effects.

Despite a spectrum of data raisingconcern about potential adverse effects ofsulfonylureas in the inpatient setting,where cardiac or cerebral ischemia is afrequent problem in an at-risk popula-tion, there are insufficient data to specifi-cally recommend against the use ofsulfonylureas in this setting. However,



sulfonylureas have other limitations in theinpatient setting. Their long action andpredisposition to hypoglycemia in pa-tients not consuming their normal nutri-tion serve as relative contraindications toroutine use in the hospital for many pa-tients (239). Sulfonylureas do not gener-ally allow rapid dose adjustment to meetthe changing inpatient needs. Sulfonyl-ureas also vary in duration of action be-tween individuals and likely vary in thefrequency with which they induce hypo-glycemia (240).

MetforminMetformin represents a second agent thatindividuals are likely to be using as anoutpatient, with potential for continua-tion as an inpatient. There is a suggestionfrom the UKPDS that metformin mayhave cardioprotective effects, althoughthe study was not powered to allow for acomparison with sulfonylureas (241).

The major limitation to metforminuse in the hospital is a number of specificcontraindications to its use, many ofwhich occur in the hospital. All of thesecontraindications relate to a potentiallyfatal complication of metformin therapy,lactic acidosis. The most common riskfactors for lactic acidosis in metformin-treated patients are cardiac disease, in-cluding CHF, hypoperfusion, renalinsufficiency, old age, and chronic pul-monary disease (242). In an outpatientsetting, using slightly variable criteria,22–54% of patients treated with met-formin have absolute or relative contrain-dications to its use (242–245). One recentreport noted that 27% of patients on met-formin in the hospital had at least onecontraindication to its use (246). In 41%of these cases, metformin was continueddespite the contraindication. This studyseemingly underestimates the usual fre-quency of contraindications since it iden-tified no individuals with CHF, a riskfactor that has been frequently noted inmany of the outpatient studies. Not sur-prisingly, a recent review of hospitalMedicare data found that 11.2% of pa-tients with concomitant diagnoses of dia-betes and CHF were discharged with aprescription of metformin (247).

Recent evidence continues to indicatelactic acidosis is a rare complication, de-spite the relative frequency of risk factors(248). However, in the hospital,where therisk for hypoxia, hypoperfusion, and re-nal insufficiency is much higher, it still

seems prudent to avoid the use of met-formin in most patients. In addition to therisk of lactic acidosis, metformin hasadded side effects of nausea, diarrhea, anddecreased appetite, all of which may beproblematic during acute illness in thehospital.

ThiazolidinedionesAlthough thiazolidinediones have veryfew acute adverse effects (249,250), theydo increase intravascular volume, a par-ticular problem in those predisposed toCHF and potentially a problem for pa-tients with hemodynamic changes relatedto admission diagnoses (e.g., acute coro-nary ischemia) or interventions commonin hospitalized patients. The same studyof Medicare patient hospital data citedabove (247) found that 16.1% of patientswith diabetes and CHF received a pre-scription for a thiazolidinedione at thetime of discharge. Twenty-four percent ofpatients with these combined diagnosesreceived either metformin or a thiazo-lidinedione, both drugs carrying contra-indications in this setting.

Most recently it has been demon-strated that when exposed to high con-centrations of rosiglitazone, a monolayerof pulmonary artery endothelial cells willexhibit significantly increased permeabil-ity to albumin (251). Although this is apreliminary in vitro study, it raises thepossibility of thiazolidinediones causing adirect effect on capillary permeability.This process may be of greater signifi-cance in the inpatient setting. On the pos-itive side, thiazoladinediones may havebenefits in preventing restenosis of coro-nary arteries after placement of coronarystents in patients with type 2 diabetes(252). For inpatient glucose control,however, thiazolidinediones are not suit-able for initiation in the hospital becausethe onset of effect, which is mediatedthrough nuclear transcription, is quiteslow.

In summary, each of the major classesof oral agents has significant limitationsfor inpatient use. Additionally, they pro-vide little flexibility or opportunity for ti-tration in a setting where acute changesdemand these characteristics. Therefore,insulin, when used properly, may havemany advantages in the hospital setting.

Use of insulinAs in the outpatient setting, in the hospi-tal a thorough understanding of normal

insulin physiology and the pharmacoki-netics of exogenous insulin is essential forproviding effective insulin therapy. Theinpatient insulin regimen must bematched or tailored to the specific clinicalcircumstance of the individual patient.Components of the insulin dose re-quirement defined physiologically. Inthe outpatient setting, it is convenient tothink of the insulin dose requirement inphysiologic terms as consisting of “basal”and “prandial” needs. In the hospital, nu-tritional intake is not necessarily providedas discrete meals. The insulin dose re-quirement may be thought of as consist-ing of “basal” and “nutritional” needs. Theterm “nutritional insulin requirement” re-fers to the amount of insulin necessary tocover intravenous dextrose, TPN, enteralfeedings, nutritional supplements admin-istered, or discrete meals. When patientseat discrete meals without receiving othernutritional supplementation, the nutri-tional insulin requirement is the same asthe “prandial” requirement. The term“basal insulin requirement” is used to re-fer to the amount of exogenous insulinper unit of time necessary to prevent un-checked gluconeogenesis and ketogenesis.

An additional variable that deter-mines total insulin needs in the hospital isan increase in insulin requirement thatgenerally accompanies acute illness. Insu-lin resistance occurs due to counterregu-latory hormone responses to stress (e.g.,surgery) and/or illness and the use of cor-ticosteroids, pressors, or other diabeto-genic drugs. The net effect of these factorsis an increase in insulin requirement,compared with a nonsick population.This proportion of insulin requirementspecific to illness is referred to as “illness”or “stress-related” insulin and varies be-tween individuals (Fig. 2).Is the patient insulin deficient or non–insulin deficient? As in the outpatientsetting, a key component to providing ef-fective insulin therapy in the hospital set-ting is determining whether a patient hasthe ability to produce endogenous insu-lin. Patients who have a known history oftype 1 diabetes are by definition insulindeficient (3). In addition, other clinicalfeatures may be helpful in determiningthe level of insulin deficiency (Table 2).Patients determined to be insulin defi-cient require basal insulin replacement toprevent iatrogenic diabetic ketoacidosis,i.e., they must be treated with insulin atall times.



Subcutaneous insulin therapy. Subcu-taneous insulin therapy may be used toattain glucose control in most hospital-ized patients with diabetes. The compo-nents o f the da i ly insu l in doserequirement can be met by a variety ofinsulins, depending on the particular hos-pital situation. Subcutaneous insulintherapy is subdivided into programmedor scheduled insulin and supplemental orcorrection insulin (Table 3).Scheduled insulin therapy. This reviewwill use the term “programmed” or“scheduled insulin requirement” to referto the dose requirement in the hospitalnecessary to cover the both basal and nu-tritional needs. For patients who are eat-ing discrete meals, it is appropriate toconsider the basal and prandial compo-nents of the insulin requirement separately.Basal insulin therapy for patients whoare eating. Subcutaneous basal insulincan be provided by any one of severalstrategies. These include continuous sub-cutaneous insulin infusion (CSII) or sub-cutaneous injection of intermediate-acting insulin (including premixed insu-

lin) or of long-acting insulin analogs.Some of these methods result in peaks ofinsulin action that may exceed the basalneeds of the patient, causing hypoglyce-mia. This is most likely to occur as theacute illness begins to resolve and basalinsulin requirements that were elevateddue to stress and/or illness begin to returnto normal levels. Although selected inpart for basal coverage, NPH, lente, and tosome extent ultralente insulin also deliverpeaks of insulin that potentially can coverprandial needs, albeit with variable capa-bility for matching the timing of nutri-tional intake. When NPH insulin is usedin very low doses, it can also be adminis-tered four times daily as an alternate wayto provide basal insulin action (253).Prandial insulin therapy for patientswho are eating. Prandial insulin re-placement has its main effect on periph-eral glucose disposal into muscle. Alsoreferred to as “bolus” or “mealtime” insu-lin, prandial insulin is usually adminis-tered before eating. There are occasionalsituations when this insulin may be in-jected immediately after eating, such aswhen it is unclear how much food will beeaten. In such situations, the quantity ofcarbohydrates taken can be counted andan appropriate amount of rapid-actinganalog can be injected. The technique of“carbohydrate counting” may be usefulfor patients practicing insulin self-management. The rapid-acting insulinanalogs, insulin lispro and aspart, are ex-cellent prandial insulins. Regular insulinis more accurately considered to haveboth basal and prandial components dueto its longer duration of action. Similarly,NPH and lente insulins, with their dis-

tinct peaks and prolonged action, can beused for both their basal and prandial in-sulin effects. For hospitalized patientswith severe insulin deficiency, this canbe a disadvantage since the timing ofmeals and the quantity of food is ofteninconsistent.Basal insulin therapy for patients whoare not eating. While not eating, pa-tients who are not insulin deficient maynot require basal insulin. Since reductionof caloric intake may alter insulin resis-tance substantially in type 2 diabetes,sometimes allowing previously insulin-requiring patients to be controlled withendogenous insulin production alone, thebasal requirement is not easily deter-mined. However, withholding basal insu-lin in insulin-deficient patients results in arapid rise in blood glucose by 45 mg/dl(2.5 mmol/l) per hour until ketoacidosisoccurs (rev. in 254). This situation canoccur when “sliding scale” insulin therapyis the sole method of insulin coverage(255). Scheduled basal insulin therapy forpatients who are not eating can be pro-vided by a number of insulin types andmethods.Insulin for patients with intermittentnutritional intake. Hospitalized pa-tients may receive nutrition intermit-tently, as with patients who are beingtransitioned between NPO status and reg-ular diet, patients with anorexia or nau-sea, or patients receiving overnightcycling of enteral feedings. Appropriateinsulins used in combination therapymight include regular, intermediate, andlong-acting insulins or analogs, adminis-tered to cover basal needs and also timedto match the intermittent nutritional intake.Illness-related or stress dose insulintherapy. The illness-related insulin canbe apportioned between the basal insulin,the nutritional or prandial insulin, andthe correction doses. It is important topoint out that illness-related insulin re-quirements decrease as the patient’s con-dition improves and, thus, in manysituations may be difficult to precisely re-place (Fig. 2). In attempting to meet theillness-related insulin requirement, andto later return to lower doses, it is impor-tant to recall that intravenous insulin in-fusion gives the greatest flexibility andthat long-acting analog gives the least,with other preparations or routes beingintermediate. Rapid changes in illness-related insulin requirements necessitateclose blood glucose monitoring and daily

Figure 2—Insulin requirementsin health and illness. Componentsof insulin requirement are dividedinto basal, prandial or nutritional,and correction insulin. When writ-ing insulin orders, the basal andprandial/nutritional insulin dosesare written as programmed(scheduled) insulin, and correc-tion-dose insulin is written as analgorithm to supplement thescheduled insulin (see online ap-pendix 2). Programmed and cor-rection insulin are increased tomeet the higher daily basal andprandial or nutritional require-ments. Total insulin requirementsmay vary widely.

Table 2—Clinical characteristics of the pa-tient with insulin deficiency

● Known type 1 diabetes● History of pancreatectomy or pancreatic

dysfunction● History of wide fluctuations in blood

glucose levels● History diabetic ketoacidosis● History of insulin use for �5 years and/or

a history of diabetes for �10 years

Adapted from the Expert Committee on the Diagno-sis and Classification of Diabetes Mellitus (3) andconsensus from the authors.



Tab

le3—

Prac

tica

lgui

deli

nes

for

hosp

ital

use

ofin

suli

n

Clin

ical

sett

ing

Prog

ram

med

/sch

edul

edin

sulin

opti

on(s

)Su

pple

men

tal/c

orre

ctio

n-in

sulin

opti

on(s

)C

omm

ents

Basa

lPr

andi

alan

d/or

nutr

itio

nal

●T

otal

daily

insu

linre

quir

emen

tm

aybe

calc

ulat

edba

sed

onpr

ior

insu

lindo

ses

oras

0.6

unit

s�

kg�

1�

day�

1

●Ba

sali

nsul

inge

nera

llyac

coun

tsfo

r40

–50%

ofda

ilyin

sulin

requ

irem

ent

●Pr

andi

alan

d/or

nutr

itio

nalo

rsu

pple

men

tal/c

orre

ctio

ndo

ses

may

beca

lcul

ated

as10

–20

%of

tota

ldai

lyin

sulin

requ

irem

ent

for

each

dose

●Pa

tien

tsw

ith

type

1di

abet

esal

way

sre

quir

eco

ntin

uous

insu

linco

vera

geto

avoi

dke

tosi

sE

atin

gm

eals

●In

t-I

bid

orhs

●R

eg-I

orra

pid-

Iac

�B&

Dor

B,L,

and

D●

Reg

-Ior

rapi

d-I

ac

/�hs

●G

ive

Reg

-I,3

0–45

min

ac;r

apid

-I,0

–15

min

ac●

LA-I

hsor

am●

Gla

rgin

egi

ven

ason

ce-d

aily

dose

,usu

ally

aths

●In

sulin

drip

●A

void

/min

imiz

eR

eg-I

and

rapi

d-I

dose

sat

hsto

decr

ease

risk

ofno

ctur

nal

hypo

glyc

emia

●70

/30

or75

/25

insu

linm

aybe

used

acbr

eakf

ast

and

dinn

erto

mee

tbo

thba

sala

ndpr

andi

alne

eds

●In

sulin

drip

isR

xof

choi

cein

seve

rely

deco

mpe

nsat

edty

pe1,

wit

hor

wit

hout

DK

A,

and

inty

pe2

wit

hH

HS

Not

eati

ng●

Insu

lindr

ipN

/A●

Reg

-Iq

4–6

hour

s●

Int-

Ibi

dor

hs●

Rap

id-I

q4

hour

s●

LA-I

hsor

amPe

riop

erat

ive

orpe

ripr

oced

ural

Will

eat

post

-op

orpo

stpr

oced

ure

(e.g

.,ca

tara

ctex

trac

tion

,car

diac

cath

eter

izat

ion,

endo

scop

y)

Base

onpr

ior

insu

linR

x:●

Int-

Igi

ve1/

2-2/

3us

uala

mdo

se●

LA-I

glar

gine

,con

tinu

eus

ual

dose

pmpr

ior

Whe

nre

sum

esea

ting

●R

esta

rtpr

ior

dose

sof

Reg

-Ior

rapi

d-I

ac

Unt

ilre

sum

esea

ting

:●

Reg

-Iq

4–6

h●

Rap

id-I

q4

h

●U

sual

insu

linan

d/or

oral

agen

tdo

ses

give

nth

eni

ght

prio

rto

surg

ery

toas

sure

adeq

uate

glyc

emic

cont

rolo

nth

em

orni

ngof

the

proc

edur

e●

Pati

ents

wit

hdi

abet

essh

ould

beon

the

OR

list

for

the

earl

ym

orni

ngto

min

imiz

eam

ount

ofti

me

that

they

will

beke

ptN

PO.T

his

decr

ease

sri

skof

hypo

glyc

emia

and

allo

ws

mai

nten

ance

ofop

tim

umm

etab

olic

hom

eost

asis

Will

not

eat

(e.g

.,m

ajor

surg

ery)

●In

sulin

drip

●R

eg-I

q4–

6ho

urs

●ra

pid-

Iq

4ho

urs

●In

t-I,

give

1⁄2

usua

lam

dose

●LA

-Igl

argi

ne,g

ive

usua

ldai

lydo

se

N/A

Unt

ilre

sum

esea

ting

:●

Reg

-Iq

4–6

h●

Rap

id-I

q4

h

●W

here

apr

olon

ged

post

oper

ativ

enp

ope

riod

isan

tici

pate

d,e.

g.,c

ardi

otho

raci

c,m

ajor

abdo

min

al,C

NS

case

s,in

sulin

drip

Rx

isre

com

men

ded

●St

arti

ngdo

sefo

rpe

riop

erat

ive

mai

nten

ance

insu

lindr

ipis

0.2

unit

s�

kg�

1�

h�1

ICU

Ifnp

oan

d/or

clin

ical

lyun

stab

le:

●In

sulin

drip

●R

eg-I

q4–

6h

●R

apid

-Iq

4h

Ifea

ting

:●

Con

tinu

epr

ior

Int-

Ior

LA-I

Ifnp

o:●

N/A

Ifea

ting

:●

Reg

-Ior

RA

-Iac

and

hs

●R

eg-I

q4–

6h

●R

apid

-Iq

4h

●E

vide

nce-

base

dou

tcom

esst

udie

ssu

ppor

tus

eof

insu

lindr

ipas

Rx

ofch

oice

for

deco

mpe

nsat

eddi

abet

esin

the

ICU

sett

ing

incl

udin

gco

rona

ryca

re(a

cute

myo

card

iali

nfar

ctio

n)an

dsu

rgic

alin

tens

ive

care

unit

s(M

alm

berg

,Van

den

Berg

he,

Furn

ary)

Ent

eral

tube

feed

ing

Con

tinu

ous

24h:

●R

eg-I

q4–

6h

●R

eg-I

q4–

6ho

urs

●Ba

sali

nsul

indo

sege

nera

llyno

mor

eth

an40

%of

tota

ldai

lyin

sulin

requ

irem

ent

toav

oid

hypo

glyc

emia

ifen

tera

lfee

ding

inte

rrup

ted

●In

t-I

bid;

●R

apid

-Iq

4h

●R

apid

-Iq

4ho

urs

●N

utri

tion

alin

sulin

requ

irem

ents

met

wit

hpr

ogra

mm

eddo

ses

ofre

g-I

orra

pid-

I●

LA-I

hsor

am●

May

use

low

-dos

ein

t-I

aths

toco

ntro

lfas

ting

hype

rgly

cem

iaD

ayti

me

only

:●

Int-

Iam

Dur

ing

tube

feed

ing

deliv

ery

peri

odon

ly:

●If

tube

feed

ing

inte

rrup

ted,

e.g.

,for

proc

edur

eor

into

lera

nce,

incr

ease

freq

uenc

yof

finge

rsti

ckBG

chec

ks●

Reg

-Iq

4–6

h●

Rap

id-I

q4

hBo

lus

24h:

●In

t-I

bid;

●LA

-Ihs

oram

●R

eg-I

q4–

6h

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apid

-Iq

4h

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eg-I

q4–

6h

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apid

-Iq

4h

●G

ive

reg-

I,30

–45

min

s,or

rapi

d-I,

0–15

min

spr

ior

tobo

lus

toco

ntro

lpos

t-bo

lus

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curs

ions

●C

heck

finge

rst

ick

BG2

haf

ter

reg-

Ior

1h

afte

rra

pid-

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dete

rmin

edo

sead

just

men

tsfo

rpo

st-b

olus

targ

etBG

�18

0m

g/dl

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ayus

elo

w-d

ose

int-

Iat

hsto

cont

rolf

asti

nghy

perg

lyce

mia



changes in the scheduled insulin doses, asthe blood glucose levels dictate.Correction-dose insulin therapy. Alsocalled “supplemental” insulin, this usu-ally refers to the insulin used to treat hy-perglycemia that occurs before meals orbetween meals. At bedtime, correction-dose insulin is often administered in a re-duced dose compared with other times ofthe day in order to avoid nocturnal hypo-glycemia. Correction-dose insulin mayalso refer to insulin used to correct hyper-glycemia in the NPO patient or in the pa-t ient who is receiving schedulednutritional and basal insulin but not eat-ing discrete meals. Correction-dose insu-lin should not be confused with “slidingscale insulin,” which usually refers to a setamount of insulin administered for hy-perglycemia without regard to the timingof the food, the presence or absence ofpreexisting insulin administration, oreven individualization of the patient’ssensitivity to insulin.

The traditional sliding scale insulinregimens, usually consisting of regular in-sulin without any intermediate or long-acting insulins, have been shown to beineffective at best and dangerous at worst(255–257). Problems cited with slidingscale insulin regimens are that the slidingscale regimen prescribed on admission islikely to be used throughout the hospitalstay without modification (255). Second,sliding scale insulin therapy treats hyper-glycemia after it has already occurred, in-stead of preventing the occurrence ofhyperglycemia. This “reactive” approachcan lead to rapid changes in blood glucoselevels, exacerbating both hyperglycemiaand hypoglycemia.

Correction-dose insulin therapy is animportant adjunct to scheduled insulin,both as a dose-finding strategy and as asupplement when rapid changes in insu-lin requirements lead to hyperglycemia. Ifcorrection doses are frequently required,it is recommended that the scheduled in-sulin doses be increased the following dayto accommodate the increased insulinneeds.Writing insulin orders. An example ofan insulin order form that prompts thephysician to address all three componentsof insulin therapy (i.e., basal, prandial,and correction dose) is provided (see on-line appendix 1 [available at http://care.diabetesjournals.org]). The formscan be incorporated into computerizedorder sets and other prompting methodsBo

lus

(con

t.)

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tim

eon

ly:

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t-I

amD

urin

gbo

lus

deliv

ery

peri

odon

ly:

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eg-I

q4–

6h

●R

apid

-Iq

4h

TPN

●R

eg-I

adde

dto

TPN

bags

●R

eg-I

q4–

6h

●Ba

sala

ndnu

trit

iona

lins

ulin

need

sm

etw

ith

reg-

Iad

ded

toT

PNba

gdi

rect

ly●

To

dete

rmin

eda

ilydo

seof

insu

linto

add

toT

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g,co

nsid

erus

eof

sepa

rate

IVin

sulin

infu

sion

for

24h

tode

term

ine

daily

insu

linre

quir

emen

t,th

enad

d2/

3of

this

amou

ntto

subs

eque

ntT

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gs;o

rad

d2/

3of

tota

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tsof

insu

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min

iste

red

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epr

evio

usda

yto

the

next

day’

sT

PNba

gas

reg-

I,un

tild

aily

dose

dete

rmin

ed●

Use

SQin

sulin

wit

hca

utio

nw

ith

TPN

.Lac

kof

corr

elat

ion

ofin

sulin

peak

san

dtr

ough

sw

ith

nutr

ient

deliv

ery

may

lead

toer

rati

cBG

cont

rol

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nsit

ion

toor

alin

take

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t-I

bid

●LA

-Ihs

oram

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eg-I

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pid-

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pid-

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ac

/�hs

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reg-

I,30

–45

min

orra

pid-

I0–

15m

inpr

ior

tom

ealt

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ntro

lpos

tpra

ndia

lBG

excu

rsio

ns●

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pran

dial

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etBG

�18

0m

g/dl

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rsti

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2h

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rre

g-I

or1

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ter

rapi

d-I

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tsH

igh-

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ter

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that

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12h

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ine

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);O

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ting

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very

;qd,

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ngin

sulin

(lis

pro

oras

part

);R

eg-I

,reg

ular

insu

lin;S

Q,s

ubcu

tane

ous.



to reduce errors. Practice guidelines forusing insulin under various clinical cir-cumstances are summarized in Table 3.Intravenous insulin infusion. The onlymethod of insulin delivery specifically de-veloped for use in the hospital is contin-uous intravenous infusion, using regularcrystalline insulin. There is no advantageto using insulin lispro or aspart in an in-travenous insulin infusion. The medicalliterature supports the use of intravenousinsulin infusion in preference to the sub-cutaneous route of insulin administrationfor several clinical indications amongnonpregnant adults, including diabeticketoacidosis and nonketotic hyperosmo-lar state (258–275); general preoperative,intraoperative, and postoperative care(257,276–290); the postoperative periodfollowing heart surgery (142,196,198,290,291); organ transplantation (297); orcardiogenic shock (128,194,292–296)and possibly stroke (147); exacerbatedhyperglycemia during high-dose glu-cocorticoid therapy (297); NPO status(298); critical care illness (2,299–301);and as a dose-finding strategy, anticipa-tory to initiation or reinitiation of subcu-taneous insulin therapy in type 1 or type 2diabetes (Table 4) (302–304). Some ofthese settings may be characterized by, orassociated with, severe or rapidly chang-ing insulin requirements, generalized pa-tient edema, impaired perfusion ofsubcutaneous sites, requirement for pres-sor support, and/or use of total parenteralnutrition. In these settings the intrave-nous route for insulin administration sur-passes the subcutaneous route withrespect to rapidity of onset of effect incontrolling hyperglycemia, overall ability

to achieve glycemic control, and most im-portantly, nonglycemic patient outcomes.During intravenous insulin infusion usedto control hyperglycemic crises, hypogly-cemia (if it occurs) is short-lived, whereasin the same clinical settings repeated ad-ministration of subcutaneous insulin mayresult in “stacking” of the insulin’s effect,causing protracted hypoglycemia. As analternative to continuous intravenous in-fusion, repeated intravenous bolus ther-apy also has been advocated for patientswith type 2 diabetes during anesthesia(305).

Depending on the indication for in-travenous insulin infusion, caregiversmay establish different glycemic thresh-olds for initiation of intravenous insulintherapy. For patients not hyperglycemicinitially, it is best to assign a blood glucosethreshold for initiation of the insulin in-fusion that is below the upper limit of thetarget range glucose at which the infusionprotocol aims. For patients with type 1diabetes, uninterrupted intravenous insu-lin infusion perioperatively is an accept-able and often the preferred method ofdelivering basal insulin. For these pa-tients, intravenous insulin infusion ther-apy should be started before the end ofthe anticipated timeframe of action of pre-viously administered subcutaneous insu-lin, i.e., before hyperglycemia or ketosiscan develop. For patients having electivesurgery, hourly measurements of capil-lary blood glucose may be ordered, andthe intravenous infusion of insulin may beinitiated at a low hourly rate when risingblood glucose levels (�120 mg/dl, or 6.7mmol/l) indicate waning of the effects ofpreviously administered intermediate or

long-acting insulin. The desirability of in-fusing dextrose simultaneously dependson the blood glucose concentration andthe condition for which the insulin infu-sion is being used (275,288).Mixing the insulin infusion. Depend-ing on availability of infusion pumps thataccurately deliver very low hourly vol-umes, intravenous insulin therapy is con-ducted with regular crystalline insulin in asolution of 1 unit per 1 ml normal saline.The concentrated infusion is piggy-backed into a dedicated running intrave-nous line. Highly concentrated solutionsmay be reserved for patients requiringvolume restriction; otherwise, solutionsas dilute as 1 unit insulin per 10 ml nor-mal saline may be used (306,307). Whenthe more dilute solutions are used, at least50 ml of the insulin-containing solutionshould be allowed to run through the tub-ing before use (308). It is prudent to pre-pare and label the solutions in a centralinstitutional pharmacy, if possible usingthe same concentration for all adultpatients.

The use of a “priming bolus” to initi-ate intravenous insulin infusion is contro-versial (265). The half-l i fe of anintravenous insulin bolus is about 4–5min (309), and, although tissue effects aresomewhat delayed, by 45 min insulinblood levels return virtually to baseline.Because repeated intravenous bolus insu-lin therapy does not maintain adequateblood insulin levels or target tissue actionof insulin, the initial priming bolus of in-travenous insulin, if used, must be fol-lowed by maintenance insulin infusiontherapy (310,311).Insulin infusion initiation. Com-monly, for unstressed normoglycemicadults of average BMI, insulin infusion isinitiated at 1 unit/h but adjusted asneeded to maintain normoglycemia (i.e.,the perioperative setting). The assump-tion that 50% of the ambulatory dailyinsulin dose is the basal requirement canalso be used to estimate initial hourly re-quirements for a normoglycemic, un-stressed patient previously treated withinsulin (312). Alternatively, a weight-based insulin dose may be calculated us-ing 0.02 units � kg�1 � h�1 as a startingrate. A lower initial insulin infusion ratemay be used for patients with low bodyweight or renal or hepatic failure or if theinfusion is started within the timeframe ofaction of previously administered subcu-taneous insulin. A higher initiation rate

Table 4—Indication for intravenous insulin infusion among nonpregnant adults with estab-lished diabetes or hyperglycemia

IndicationStrength ofEvidence

Diabetic ketoacidosis and nonketotic hyperosmolar state AGeneral preoperative, intraoperative, and postoperative care CPostoperative period following heart surgery BOrgan transplantation EMI or cardiogenic shock AStroke EExacerbated hyperglycemia during high-dose glucocorticoid therapy ENPO status in type 1 diabetes ECritically ill surgical patient requiring mechanical ventilation ADose-finding strategy, anticipatory to initiation or reinitiating of

subcutaneous insulin therapy in type 1 or type 2 diabetesC



such as �2 units/h may be used whenhyperglycemia is present, when pread-mission insulin requirements are high, orif the patient has conditions predictingthe presence of insulin resistance. Amonghyperglycemic type 1 and type 2 diabeticpatients who were otherwise well and re-ceiving no concomitant intravenous dex-trose, the prime determinants of the initialhourly intravenous insulin requirementare the initial plasma glucose and BMI.After attainment of normoglycemia, onlythe BMI correlates with the hourly insulininfusion requirement (313). It has beenargued that the maximum biologic effectof insulin might be expected at infusionrates of 10 units/h or less. However, somepatients benefit from higher infusion ratesaccording to setting, and use of hourlyinsulin infusion rates as high as 50 units/hhas been reported, particularly in the in-tensive care setting (2).

Assignment and adjustment of the in-travenous insulin infusion rate is deter-mined by the caregiver, based onknowledge of the condition of the patient,the blood glucose level, and the responseto previous therapy. Blood glucose deter-minations should be performed hourlyuntil stability of blood glucose level hasbeen demonstrated for 6–8 h; then, thefrequency of blood glucose testing can bereduced to every 2–3 h. To avoid un-wanted excursions of blood glucose, es-pecially when making corrective changesin the insulin infusion rate, the pharmaco-dynamics of intravenous insulin adminis-tration and delay of tissue responsivenessfollowing attainment of a given bloodlevel of insulin must be considered. Ifconcomitant infusion of dextrose is used,caregivers must be alert to the effects ofabrupt changes of dextrose infusion rate.Well-conducted insulin infusion therapyshould demonstrate progressively smalleroscillations of the hourly insulin infusionrate and narrower excursions of bloodglucose, as the caregiver discovers thehourly rate that will maintain normogly-cemia for a given patient.

Many institutions use insulin infusionalgorithms that can be implemented bynursing staff (2,189,194,197,200,280,298,301,304,307,314). Algorithmsshould incorporate the concept thatmaintenance requirements differ betweenpatients and change over the course oftreatment. The algorithm should facilitatecommunication between physicians andnurses, achieve correction of hyperglyce-

mia in a timely manner, provide a methodto determine the insulin infusion rate re-quired to maintain blood sugars within adefined the target range, include a rule formaking temporary corrective incrementsor decrements of insulin infusion ratewithout under- or overcompensation,and allow for adjustment of the mainte-nance rate as patient insulin sensitivity orcarbohydrate intake changes. The algo-rithm should also contain directions as tohow to proceed if hypoglycemia or a rapidfall in blood glucose occurs, as well asinstructions as to how to transition thepatient to scheduled subcutaneous insulin.

Physician orders to “titrate drip” to agiven target blood glucose range, or pro-tocols requiring application of mathemat-ical rules by nursing staff, may be difficultto implement. A mathematical algorithmcan be reduced to tabular form, in whicheach column indicates different insulininfusion rates necessary to maintain targetrange control and shows appropriate in-fusions rates necessary for correction atgiven blood glucose levels, accompaniedby a rule for shifting between columns(see online appendix 2 [available at http://care.diabetesjournals.org]) (314). It isprudent to provide inservice teaching ofpharmacy, nursing, and physician staff onthe use of insulin drip protocols (307).Transition from intravenous to subcu-taneous insulin therapy. To maintaineffective blood levels of insulin, it is nec-essary to administer short- or rapid-actinginsulin subcutaneously 1–2 h before dis-continuation of the intravenous insulininfusion (191,199,315–319). An inter-mediate or long-acting insulin must be in-jected 2–3 h before discontinuing theinsulin infusion. In transitioning from in-travenous insulin infusion to subcutane-ous therapy, the caregiver may ordersubcutaneous insulin with appropriateduration of action to be administered as asingle dose or repeatedly to maintainbasal effect until the time of day when thechoice of insulin or analog preferred forbasal effect normally would be provided.For example, a patient who normally usesglargine at bedtime and lispro beforemeals, and whose insulin infusion will bestopped at lunchtime, could receive adose of lispro and a one-time injection ofNPH before interruption of the insulininfusion.Initial scheduled insulin, dose deci-sions, and correction-dose calcula-

tions. The initial doses of scheduledsubcutaneous insulin are based on previ-ously established dose requirements, pre-vious experience for the same patientduring similar circumstances of nutri-tional change or drug administration, re-quirements during continuous insulininfusion (if stable), knowledge of stabilityor instability of medical condition andnutritional intake, assessment of medicalstress, and/or body weight. Correctiondoses for various ranges of total daily in-sulin requirement or body weight can beexpressed in tabular form, as a compo-nent of standardized inpatient orders (seeonline appendix 1). For most insulin-sensitive patients, 1 unit of rapid-actinginsulin will lower blood glucose by 50–100 mg/dl (2.8–5.6 mmol) (320). A re-duction of the correction dose at bedtimeis appropriate to reduce the risk of noc-turnal hypoglycemia. For patients whoseinsulin requirements are unknown andwhose nutritional intake will be adequate,an assumption concerning requirementfor scheduled insulin based on bodyweight would be about 0.5–0.7 units/kginsulin per 24-h period for patients hav-ing type 1 diabetes and 0.4–1.0 units/kgor more for patients having type 2 diabe-tes, starting low and working up to thedose to meet demonstrated needs, withassignment of a corresponding scale forcorrection doses. If nutritional intake isseverely curtailed, for type 1 diabetes theamount of scheduled insulin calculatedby body weight should be reduced by50%. For type 2 diabetes, a safe initialassumption in the absence of nutritionalintake would be that endogenous insulinmight meet needs, requiring supplemen-tation only with correction doses, untilresults of monitoring indicate the furtherneed for scheduled insulin.Perioperative insulin requirements. Inthe perioperative period for all type 1 di-abetic patients and for those type 2 dia-betic patients with demonstrated insulindeficiency, scheduled insulin intended toprovide basal coverage should be admin-istered on the night before surgery to as-sure optimum fasting blood glucose forthe operative room. If insulin intended tomeet basal needs is normally adminis-tered in the morning, in the case of type 1diabetes the morning basal insulin isgiven without dose adjustment, and in thecase of type 2 diabetes 50–100% of thebasal insulin is administered on the morn-ing of surgery. Correction doses may be



applied on the morning of surgery if themorning glucose concentration exceeds180 mg/dl.Appropriate use of insulin self-management. Recognition of the patientrights, patient responsibilities, and theimportance of patient-oriented care arecritical to the care of diabetes (321–323).In the ambulatory setting, patient self-management has a favorable impact onglycemic control and quality of life(324,325). Using the tools of multipledaily injections of insulin or CSII, patientself-management has been shown to becapable of improving glycemic controland microvascular outcomes (326–328).In multiple-dose insulin therapy, meal-time treatment with rapid-acting insulinanalog improves hypoglycemia and post-prandial hyperglycemia in comparisonwith conventional therapy in both type 2(329) and type 1 diabetes (253,330 –332). In comparison with conventionalmanagement using intermediate-actinginsulin for basal effect, patients usinglong-acting insulin analog for basal insu-lin effect experience less overall or noctur-nal hypoglycemia (333–336), bettercontrol of fasting plasma glucose levels(333,337), and lower HbA1c levels (333).In CSII therapy, rapid-acting analogs im-prove control for most patients (338 –340). Use of advanced carbohydratecounting and an insulin-to-carbohydrateratio have markedly enhanced the successof patients to implement intensive self-management (341). Patients familiar withtheir own needs sometimes have experi-enced adverse events or, perceiving threatof adverse events, express frustration withrigidity of hospital routine and delegationof decision making to providers who areless likely to understand their immediateneeds.

Self-management in the hospital maybe appropriate for competent adult pa-tients who have stable level of conscious-ness and reasonably stable known dailyinsulin requirements and successfullyconduct self-management of diabetes athome, have physical skills appropriate tosuccessfully self-administer insulin, per-form self-monitoring of blood glucose,and have adequate oral intake. Appropri-ate patients are those already proficient incarbohydrate counting, use of multipledaily injections of insulin or insulin pumptherapy, and sick-day management. Thepatient and physician in consultationwith nursing staff must agree that patient

self-management is appropriate under theconditions of hospitalization. Compo-nents of the program can include a phy-sician order for self-management withrespect to selection of food from a generaldiet, self-monitoring of blood glucose,self-determination and administration ofinsulin dose, and ranges of insulin to betaken. Patient record-keeping, sharing ofresults with nursing staff, and charting bynursing staff of self-determined glucoseresults and insulin administration shouldoccur. If a subcutaneous insulin pump isused, provisions for assistance in trouble-shooting pump problems need to be inplace. Assistance might be required ifequipment familiar to the patient is un-available, if refrigeration is required, or ifphysical autonomy is imperfect. For ex-ample, decision making about dosagemay be intact, but manual dexterity oravailability of easily reached injectionsites may be altered by the conditions ofhospitalization. Additionally, help may berequired in a situation of increasing insu-lin resistance or period of NPO where thepatient may not know how to adjust his orher insulin doses appropriately.

Although the program should be de-veloped in compliance with institutionaland external regulatory requirements,consideration should be given to permit-ting self-use of equipment and drugs al-ready in the possession of the patient butnot normally on formulary. The programshould not create additional burdens fordietary or nursing staff. As one of thelikely barriers to implementation, institu-tions should recognize that fear of notonly causing patient harm, but also of ex-posure of deficiencies of knowledge andskill, may underlie staff resistance to pa-tient self-management programs. Staffmay be trained in advance to understandthat proficiency in making intensive man-agement decisions or using specializedequipment is not expected of them by ei-ther their employer or the patient. Ordersto replace self-management with provid-er-directed care should be written whenchanging the condition of the patientmakes self-management inappropriate(342). Table 5 summarizes the compo-nents necessary for diabetes self-management.

Preventing hypoglycemiaHypoglycemia, especially in insulin-treated patients, is the leading limitingfactor in the glycemic management of

type 1 and type 2 diabetes (343–347). Inthe hospital, multiple additional risk fac-tors for hypoglycemia are present, evenamong patients who are neither “brittle”nor tightly controlled. Patients who donot have diabetes may experience hypo-glycemia in the hospital, in associationwith factors such as altered nutritionalstate, heart failure, renal or liver disease,malignancy, infection, or sepsis (348). Pa-tients having diabetes may develop hypo-glycemia in association with the sameconditions (349). Additional triggeringevents leading to iatrogenic hypoglycemiainclude sudden reduction of corticoste-roid dose; altered ability of the patient toself-report symptoms; reduction of oralintake; emesis; new NPO status; reduc-tion of rate of administration of intra-venous dextrose; and unexpected inter-ruption of enteral feedings or parenteralnutrition. Under-prescribing neededmaintenance antihyperglycemic therapyis not always fully protective against suchcauses of hypoglycemia. Nevertheless,fear of hypoglycemia may contribute toinadequate prescribing of scheduled dia-betes therapy or inappropriate relianceupon “sliding scale” monotherapy(255,256,350).

Despite the preventable nature ofmany inpatient episodes of hypoglyce-mia, institutions are more likely to havenursing protocols for treatment of hypo-glycemia than for its prevention (351–359). Nursing and pharmacy staff mustremain alert to the effects of antihypergly-cemic therapy that may have been admin-istered on a previous shift. Variousconditions creating a high risk for hypo-glycemia are listed in Table 6. If identified,

Table 5—Components for safe diabetes self-management in the hospital

● Perform simultaneous laboratory-measured capillary or venous blood testand patient-performed capillary bloodglucose test. The capillary blood glucosetest should be �15% of the laboratorytest.

● Demonstration that the patient can self-administer insulin accurately.

● Patient is alert and is able to makeappropriate decisions on insulin dose.

● All insulin administered by the patientand nurse is recorded in the medicationrecord.

● Physician writes order that the patientmay perform insulin self-management.



preventive strategies could potentiallyinclude a provision, under protocol or byphysician order, to perform blood glucosetesting more frequently and, for fallinglevels, to take preventive action.

Special situations: TPNHyperglycemia in patients without diabe-tes from TPN is based on a variety of fac-tors—age (360), severity of illness (361),and the rate of dextrose infusion (362)—all of which affect the degree of hypergly-cemia. In individuals with preexistingtype 2 diabetes not previously receivinginsulin therapy, 77% of patients requiredinsulin to control glycemia during TPN(363). Insulin doses in this group aver-aged 100 � 8 units/day.

There are no controlled trials examin-ing which strategies are best for this situ-ation. Adding incremental doses ofinsulin to the TPN is one option, but thismay require days to determine the correctinsulin dose (306). The use of a separateintravenous insulin infusion brings mostpatients within target within 24 h (364).Two-thirds to 100% of the total numberof units of insulin used in the variable rateinfusion over the previous 24-h periodcan subsequently be added to the subse-quent TPN bag(s) (306,365).

Special situations: glucocorticoidtherapyGlucocorticoids are well known to affectcarbohydrate metabolism. They increasehepatic glucose production, inhibit glu-cose uptake into muscle, and have a com-plex effect on �-cell function (366–368).The decrease in glucose uptake with glu-cocorticoids seems to be the major earlydefect (369,370), and thus it is not sur-prising that for hospitalized patients withwell-controlled type 2 diabetes, postpran-dial hyperglycemia is the most significant

problem. Although in some patients thehyperglycemia, if present, may be mild, inothers the glucocorticoids may be respon-sible for hyperosmolar hyperglycemicsyndrome (371). The best predictors ofglucocorticoid-induced diabetes are fam-ily history of diabetes, increasing age, andglucocorticoid dose.

There are few studies examining howto best treat glucocorticoid-induced hy-perglycemia. Thiazolidinediones may beeffective for long-term treatment withglucocorticoids (372), but no insulin sen-sitizer would be appropriate for the initialmanagement of acute hyperglycemia inthe hospital due to the fact their antihy-perglycemic effects will take weeks to oc-cur. There is also an uncontrolled reportsuggesting that chromium may be benefi-cial for this population (373). Insulin isrecommended as the drug of choice forthe treatment of glucocorticoid-inducedhyperglycemia. Although data are notavailable, due to the effect of glucocorti-coids on postprandial glucose, an empha-sis on the use of prandial insulin would beexpected to have the best results. For pa-tients receiving high-dose intravenousglucocorticoids, an intravenous insulininfusion may be appropriate (306). Theinsulin dose requirements are extremelydifficult to predict, but with the insulininfusion it is possible to quickly reach therequired insulin dosing. Furthermore, forshort glucocorticoid boluses of no morethan 2 or 3 days, the insulin infusion al-lows appropriate tapering of insulin infu-sion rates so that glycemic control is notcompromised and hypoglycemic riskscan be minimized as steroid doses are re-duced. It should be emphasized that ifintravenous insulin is not used, there willbe a greater increase in prandial com-pared with basal insulin doses. There areno trials comparing the use of insulin lis-pro or insulin aspart to regular insulin forthis situation.

Special situations: enteral feedingCurrent enteral nutrition formulas aregenerally high in carbohydrate (with anemphasis on low–molecular weight car-bohydrates) and low in fat and dietary fi-ber. Carbohydrates contribute 45–92% ofcalories (374). There are a variety of dif-ferent protein sources in these enteralfeedings, and there are no contraindica-tions for use of any of these in people withdiabetes. Generally, enteral formulas con-tain 7–16% of total calories from protein.

For most institutionalized patients, it isrecommended that protein intake shouldbe 1.2–1.5 g � kg�1 � day�1 (375). Mostcurrently available standard formulascontain 25–40% of total calories from fat.There is current controversy as to howmuch of this fat source should be fromn-3 compared with n-6 fatty acids. Notsurprisingly, products that are lower incarbohydrate and higher in dietary fiberand fat have less of an impact on diabetescontrol (376,377).

There is only one study reporting gly-cemic outcomes for people with type 2diabetes receiving different enteral for-mulas (378). Thirty-four patients wererandomized to a reduced-carbohydrate,modified fat enteral formula or a standardhigh-carbohydrate feeding. After 3months, HbA1c levels were lower for thegroup receiving the reduced-carbohy-drate formula, but this did not reachstatistical significance. For those random-ized to the high-carbohydrate formula,HDL cholesterol levels were lower and tri-glyceride concentrations were higher. In-terestingly, in this small study, the groupreceiving the reduced-carbohydrate for-mula had 10% fewer infections.

There are no clinical trial data exam-ining different strategies of insulin re-placement for this population. Forintermittent enteral feedings such as noc-turnal tube feeding, NPH insulin, usuallywith a small dose of regular insulin, workswell. The NPH insulin provides basal in-sulin coverage, while the regular insulin isadministered before each tube feeding tocontrol postprandial glucose levels. Dosesshould be calculated based on capillaryglucose testing before and 2 h after eachenteral feeding period. Continuous feed-ing may be managed by several differentstrategies; again, however, there are nodata that have examined these manage-ment strategies. One could use once- ortwice-daily insulin glargine. Ideally, onewould start with a small basal dose anduse correction-dose insulin as neededwhile the glargine dose is being increased.Alternatively, the initial dose could be es-timated by the amount of insulin requiredfrom a 24-h intravenous insulin infusion.This, however, may not be an accurateassessment of actual subcutaneous insu-lin needs. The major concern about usinginsulin glargine or ultralente insulin forthis population is that when the enteralfeeding is discontinued, whether plannedor not, the subcutaneous insulin depot

Table 6—Conditions creating high risk forhypoglycemia in patients receiving scheduled(programmed) insulin

● Sudden NPO status or reduction in oralintake

● Enteral feeding discontinued● TPN or intravenous dextrose

discontinued● Premeal insulin given and meal not

ingested● Unexpected transport from nursing unit

after rapid-action insulin given● Reduction in corticosteroid dose



will result in a high risk of hypoglycemia,particularly if large doses of insulin arerequired. The use of NPH or regular insu-lin for this situation is also problematicsince the peaks and troughs of insulin donot match the insulin requirements ne-cessitated by the carbohydrate infusion.Although there is no ideal way to managethis problem, the safest appears to main-tain target blood glucose at the high endof the target range using basal insulins.When the tube feeding is discontinued,either enteral or parenteral glucose mustbe infused until the subcutaneous insulinhas dissipated.

HOW CAN SYSTEM DESIGNAND IMPLEMENTATIONIMPROVE DIABETES CAREIN THE HOSPITAL? — The designand implementation of protocols formaintaining glucose control in the hospi-tal may provide useful guidance to thetreating physician. Diabetes managementmay be offered effectively by primary carephysicians or hospitalists, but involve-ment of appropriately trained specialistsor specialty teams may reduce length ofstay, improve glycemic control, and im-prove outcomes (314,379–381). For avariety of conditions, outcomes understandardized pathways or dose titrationprotocols are superior to those achievedby individualization of care (382). In eval-uation of institutional performance, vari-ability of treatment strategies amongproviders may itself be interpreted as arisk factor for unsafe practices, and “stan-dardization to excellence” may be inter-preted as a surrogate for patient safety(322,383). In the care of diabetes, imple-mentation of standardized order sets forscheduled and correction-dose insulinmay reduce reliance on sliding scale man-agement (307). A team approach isneeded to establish hospital pathways. Toimplement intravenous infusion of insu-lin for the majority of patients having pro-longed NPO status, hospitals will needmultidisciplinary support for using insu-lin infusion therapy outside of critical careunits.

Patient safety, quality of care, vari-ability of practice, and medical error havebeen the subjects of increasing nationalconcern (384–390). Quality assessmentprograms that strive to promote a “cultureof safety” commonly focus on diabetes. Ithas been reported that 11% of medicationerrors result from insulin misadministra-

tion (391), and insulin has been identifiedas one of several medications that deservehigh alert status (392,393). Hypoglyce-mia may result from drug-dispensing er-rors, including mistaken administrationof hypoglycemic agents to nondiabeticpatients. For diabetic patients, frank pre-scribing errors, the use of trailing zerosafter decimal points, or misinterpretedabbreviations for insulin may compro-mise patient safety (394–397). Becausecapital “U” can be mistaken for a numeralwhen handwritten, the word “units”s-hould be spelled out in physician orders(391,398). The erroneous administrationof a large dose of rapid-acting insulin inplace of insulin glargine can easily occur,since insulin glargine and rapid-acting in-sulins look the same in the vial (both areclear). Barcoding of drugs and pharmacistparticipation in rounds and in surveil-lance of prescribing patterns may help re-duce errors (399–404). Although someemphasis has been placed on institutionals tandardizat ion of s l iding scales(382,405), sliding scale monotherapy it-self has been considered to be both inef-fective compared with anticipatorymanagement and frequently dangerous. Acomputerized order entry system can re-duce utilization of sliding scale manage-ment (406) . Wi th pre sen t -daymonitoring techniques, the inhouse de-velopment of ketoacidosis or hyperglyce-mic hyperosmolar state is generallypreventable, and any occurrence shouldsuggest the need for a root cause analysis(407–415). By tracking transfers or read-missions to the intensive care unit, it issometimes possible to detect an opportu-nity for improvement, such as a recurrentpattern of failure to administer scheduledsubcutaneous insulin at the terminationof insulin infusion leading to develop-ment of metabolic emergency.

Both hypoglycemia and hyperglyce-mia are patient safety issues appropriatefor continuous quality improvement(CQI) analysis. Nevertheless, as a focusfor institutional CQI activities, hypogly-cemia receives more attention, and hypo-glycemic events are more readily definedand ascertained. Pharmacies can readilytrack for example the dispensing of D50as an “antidote,” administered by nursingstaff without physician orders, or detecthypoglycemia through analysis of reportsof adverse drug reactions (416). In con-trast, although computer searches of thelaboratory databank may be used to help

identify instances of hyperglycemia, atmany institutions point-of-care measure-ments will escape detection unless valuesare scanned into an electronic databank(417). Severe hyperglycemia (at least oneglucose level �400 – 450 mg/dl), pro-longed hyperglycemia (at least three con-secutive glucose levels �250 mg/dl), andketosis all can be used as quality-controlindicators. The time from presentation tothe emergency room with hyperglycemicemergency to the initiation of an insulininfusion may be viewed as a quality issue(268). The use of a balanced emphasis onboth hypoglycemia and hyperglycemia byhospital quality-improvement programshas been linked to changes in practicepatterns that result in improved control(418–420).

WHAT IS THE ROLE OFDIABETES SELF-MANAGEMENT EDUCATIONFOR THE HOSPITALIZEDPATIENT? — Teaching diabetes self-management to patients in hospitals is adifficult and challenging task. Patients arehospitalized because they are ill, are un-der increased stress related to their hospi-talization and diagnosis, and are in anenvironment that is not conducive tolearning. In addition, patients are oftenunable to get the optimal amount of restbecause of various distractions, such asthe telephone, TV, personnel, meal times,testing, and procedures. The shock of di-agnosis, denial, anger, grief, and manyemotions frequently prevent or impair theperson’s ability to meaningfully partici-pate in the educational process. Ideally,people with diabetes should be taught at atime and place conducive to learning: asan outpatient in a nationally recognizedprogram of diabetes education classes.

For the hospitalized patient, diabetes“survival skills” education is generallyconsidered a feasible approach. Patientsare taught sufficient information to enablethem to go home safely. Those newly di-agnosed with diabetes or who are new toinsulin and or blood glucose monitoringneed to be instructed before discharge tohelp ensure safe care upon returninghome. Those patients hospitalized be-cause of a crisis related to diabetes man-agement or poor care at home neededucation to hopefully prevent subse-quent episodes of hospitalization. Goalsof inpatient diabetes self-management ed-ucation (DSME) are listed in Table 7.



The efficacy of hospital-based DSMEon outcomes has not been tested in ran-domized prospective studies. Performingsuch a study that denies the basics ofDSME to a control group is consideredunethical (421). Given the limitations andethics of study design, several studies sug-gest hospital-based DSME has substantialbenefits in outcomes. Using historicalcontrols, Muhlhauser et al. (422) re-ported a 66% reduction in hospitalizationdays and an 86% reduction in episodes ofdiabetic ketoacidosis after implementingan intensive inpatient-based educationprogram for patients with type 1 diabetes.Four deaths occurred in the controlgroup, compared with no deaths in thetreatment group. All deaths were fromacute diabetes-related complications.

Fedderson and Lockwood (423) con-ducted a prospective nonrandomizedstudy at a single 713-bed teaching hospi-tal. Within the hospital, four similar pa-tient care units (PCUs) were identified forthe study intervention. Two units weredesignated as the treatment units and twoas the control units. For the control units,DSME was provided by the regular nurs-ing staff. For the experimental units, a cer-tified diabetes educator (CDE) wasemployed to provide education to boththe staff nurses and directly to diabeticpatients. The nurse CDE conducted threeseparate teaching sessions for the staffnurses in the experimental PCUs on infor-mation that an insulin-requiring patientwith diabetes needs before discharge. Thenurse CDE also provided direct patienteducation. The authors reported a meanreduction in hospital length of stay of 1.3days in the experimental group versus thecontrol group (P � 0.005).

Wood (424) compared the efficacy ofindividualized DSME (control group) toindividualized DSME supplemented by2-h group classes held weekly (experi-mental group). Patients medically unsta-ble were excluded from the study. Based

on a follow-up questionnaire, the experi-mental group reported better adherencefor all self-care behaviors than the controlgroup. Four months postdischarge, theexperimental group had significantlyfewer emergency room visits comparedwith the control group (2 vs. 20 visits,respectively, P � 0.005).

Writing DSME consult requestsWhen writing a request for consultationfor diabetes education, the referral shouldstate the specific reason for the referral(not just state “Diabetes Education”), anypertinent details regarding the patient sta-tus, the discharge plan and person refer-ring for consult, and how to contact them(Table 8). Early referral is encouraged, es-pecially for those patients newly diag-nosed with diabetes. Patients should bemedically stable and able to participate inthe educational process. Patients who arein pain or sedated should not be referredfor DSME until their medical conditionimproves. Including various disciplinesin the plan of care is equally important. Ifcaregivers are involved, it is importantthat they be identified and included in theteaching process. Patients who are cogni-tively impaired are not good candidatesfor teaching and should have alternativeoptions of care considered. Topics to becovered should be relevant to the plan ofcare and ready to implement at the time ofdischarge.

It is best to maximize the time spent

on topics immediately relevant to the pa-tient’s diabetes management. Registereddietitians should be consulted for medicalnutritional therapy and patient teaching.Social workers and case managers shouldbe involved with discharge planning andorders for home-health-nurse follow upupon discharge. Those likely in need ofhome health nursing referrals includenewly diagnosed diabetic patients, pa-tients new to insulin, the aged or infirm,and those for whom there are complianceconcerns.

Patient assessmentPatient assessment assists with definingthe patient’s problems and acknowledg-ing his or her concerns. When seeing aninpatient for an initial consultation, it isimperative to be able to focus on thegreatest needs of the patient at that time.Knowing the reason for the consultationallows the educator to direct precioustime and energy to those specific educa-tional needs and to bring any necessaryteaching materials/supplies to the bed-side. Before actually seeing the patient,the diabetes educator should review thechart and, if necessary, speak with the re-ferring physician or registered nurse whois caring for the patient in order to obtainadditional information. Assessment criti-cal to patient teaching includes:

● Knowledge, psychomotor skills, and af-fective domains

● Current level of self care● Preferred learning styles● Psychological status● Stress factors that impair learning● Social/cultural/religious beliefs● Literacy skills● Readiness to learn● Assessment of abilities—age, mobility,

visual acuity, hearing loss, and dexter-ity

Table 7—Goals of inpatient DSME

● Assess current knowledge and practices of diabetes self-management and how they impactpatient’s health status and reason for hospitalization

● Initiate diabetes education for patients newly diagnosed with diabetes● Provide information on basic self-management skills to help ensure safe care postdischarge● Team approach with other health professionals (e.g., physicians, nurses, dietitians, case

managers, and social workers) coordinating care in the hospital and post discharge● Provide information on community resources and diabetes education programs for

continuing education● The diabetes educator serves as a resource for nursing staff and other health care providers

Table 8—Writing the DSME consult request

Component of request Example

Specific reason for consult anddiagnosis

Diabetes education for insulin administration teachingfor patient with new-onset type 2 diabetes

Discharge medication plan Lantus 30 units hs, Novolog 6 units acSpecific comments/instructions Spanish-speaking patient; lives with daughterContact information John Smith, MD, pager #

ac, before meals; hs, bedtime.



Characteristics of adult learnersIn preparing to teach, it is good to keep inmind some of the characteristics of adultlearners:

● Usually self-directed● Must be receptive to learning● Tend to be problem-focused rather

than subject-oriented● Inclusive of past experiences with dia-

betes● Active participation

Deciding what to teach patientsDeciding what to teach patients in a lim-ited timespan is determined mostly bymedical necessity but also by the patient’sprevious experiences and desires. The pa-tient must be psychologically and emo-tionally ready for teaching. Listening toconcerns and acknowledging the patient’sfeelings without being judgmental is animportant aspect of changing behavior.When patients are newly diagnosed withdiabetes, teaching “survival skills” is thefirst step to outlining the principles of di-abetes management. These may include:

● What is diabetes? Principles of treat-ment and prevention of complications

● Norms for blood glucose and target glu-cose levels for the individual

● Recognition, treatment, and preventionof hyperglycemia and hypoglycemia

● Medical nutrition therapy (instructedby a registered dietitian who, prefera-bly, is a CDE)

● Medication● Self-monitoring of blood glucose● Insulin administration (if going home

on insulin)● Sick-day management● Community resources● Universal precautions for caregivers

Patients previously diagnosed withdiabetes need to have specific needs iden-tified, and their instruction must be tar-geted to those needs. Diabetes educationin a hospital setting is not meant to pro-vide comprehensive in-depth knowledgeof diabetes management, but is intendedto provide basic information for people tostart a life-long process of continuing di-abetes education.

Communication and dischargeplanningDocumentation, reviewing chart notes/suggestions, and oral communication are

vital to coordinating care with successfuloutcomes for hospitalized patients withdiabetes. Staff nurses need to work withpatients on developing their skills and re-inforcing knowledge of diabetes manage-ment. Medical orders and the dischargeplan of care need to be appropriate,achievable, and agreeable to the patientand family. For effective discharge plan-ning, collaboration among the treatingphysician, nurses, and the diabetes nurseeducator is essential for providing conti-nuity of care back to the outpatient set-ting. During discharge planning, thefollowing questions should be addressed:

● Does the patient require outpatientDSME?

● Can the patient prepare his or her ownmeals?

● Can the pat ient per form se l f -monitoring of blood glucose at the pre-scribed frequency?

● Can the patient take his or her diabetesmedications or insulin accurately?

● Is there a family member who can assistwith tasks that the patient cannot per-form?

● Is a visiting nurse needed to facilitatetransition to the home?

Discharge diabetes medicationsWhen arranging for hospital discharge,caution should be taken in prescribingantihyperglycemic therapy, especially forthe elderly. A recent hospital discharge isa strong predictor of subsequent seriousoutpatient hypoglycemia (425). This ob-servation should lead to caution in theplanning of antihyperglycemic therapy atdischarge and careful planning for follow-up. Prescribing patterns should take intoconsideration the evidence that amongthe sulfonylureas, glipizide is associatedwith less hypoglycemia than glyburide inthe elderly (426).

WHAT IS THE ROLE OFMEDICAL NUTRITIONTHERAPY IN THEHOSPITALIZED PATIENTWITH DIABETES? — Determiningthe nutritional needs of hospitalized pa-tients with diabetes, writing a diet orderto provide for those needs, and incorpo-rating the current nutrition principles andrecommendations for persons with diabe-tes can be a daunting task. Even thoughhospital diets are commonly ordered bycalorie levels based on the “ADA diet,” it

has been recommended that the term“ADA diet” no longer be used (427). Since1994, the ADA has not endorsed any sin-gle meal plan or specified percentages ofmacronutrients. Current nutrition rec-ommendations advise individualizationbased on treatment goals, physiologic pa-rameters, and medication usage; theserecommendations apply primarily to per-sons living in a home setting who, in con-junct ion wi th a team of hea l thprofessionals, self-manage their diabetes.

The question is, then, how do you usemedical nutrition therapy appropriatelyin the hospital? Nutrient needs often dif-fer in the home versus the hospital setting.The diabetes treatment plan used in thehospital may differ from home, e.g., insu-lin may be used instead of oral medica-tions. The types of food a person can eatmay change, or the route of administra-tion may differ, e.g., enteral or parenteralfeedings may be used instead of solidfoods. And lastly, the ability of institu-tions to individualize meal plans is greatlydecreased. Because of the complexity ofnutrition issues, it is recommended that aregistered dietitian, knowledgeable andskilled in medical nutrition therapy, serveas the team member who provides medi-cal nutrition therapy. The dietitian is re-sponsible for integrating informationabout the patient’s clinical condition, eat-ing, and lifestyle habits and for establish-ing treatment goals in order to determinea realistic plan for nutrition therapy(428). Registered dietitians who special-ize in nutrition support can play an in-valuable role in the management ofcritically ill patients. However, it is essen-tial that all members of the interdiscipli-nary team are knowledgeable of nutritiontherapy.

Goals of medical nutrition therapyFor the hospitalized patient, the goals ofnutrition therapy are multiple:

● Attain and maintain optimal metaboliccontrol of blood glucose levels, lipidlevels, and blood pressure to enhancerecovery from illness and disease

● Incorporate nutrition therapies to treatthe complications of diabetes, includ-ing hypertension, CVD, dyslipidemia,and nephropathy

● Provide adequate calories, as needs areoften increased in illness and during re-covery from surgery



● Improve health through use of nutri-tious foods

● Address individual needs based on per-sonal, cultural, religious, and ethnicfood preferences

● Provide a plan for continuing self-management education and follow-upcare

Nutritional needs of hospitalizedpatientsThe caloric needs of most hospitalized pa-tients can be met through provision of25–35 kcal/kg body wt (429,430). Pro-tein needs vary on the basis of physiologicstress. Mildly stressed patients require 1.0g/kg body wt; moderately to severelystressed patients may need 1.5 g/kg bodywt. These levels are for patients with nor-mal hepatic and renal function. The pre-ferred route of feeding is the oral route. Ifintake is inadequate or if medical condi-tions prohibit oral feeding, then enteral ofparenteral feedings will be needed.

Consistent carbohydrate diabetesmeal-planning systemThe consistent carbohydrate diabetesmeal-planning system was developed toprovide institutions with an up-to-dateway of providing food service to patientsin those settings. The system is not basedon specific calorie levels, but rather on theamount of carbohydrate offered at eachmeal. This amount is consistent frommeal to meal and day to day. Meals arebased on heart-healthy diet principles—saturated fats and cholesterol are limited,and protein content falls within a usualdiet’s content of 15–20% of calories. In-stead of focusing on the type of carbohy-drate foods served, the emphasis is on thetotal amount of carbohydrate containedin the meal. The majority of carbohydratefoods should be whole grains, fruits, veg-etables, and low-fat milk, but some su-crose-containing foods can be included aspart of the total carbohydrate allowance(430). A typical day’s menu provides1,500–2,000 calories, with a range of12–15 carbohydrate servings (187–259g) divided among meals and snacks.

Central to the rationale for this systemis that the glycemic effect of carbohydraterelates more to the total amount of carbo-hydrate rather than the source. While anumber of factors influence glycemic re-sponse to individual foods, ingestion of avariety of foods does not acutely alter gly-cemic response if the amount of carbohy-

drate is similar (430). Sucrose does notincrease glycemia to a greater extent thanisocaloric amounts of starch. The prandial(mealtime) insulin dose is based on themeal’s carbohydrate content. Current rec-ommendations for fat modification (430)are incorporated by basing the meals on acardiac, heart-healthy menu when devis-ing the consistent carbohydrate mealplan.

An advantage to the use of this systemis that prandial insulin dosages can be or-dered on the basis of the known carbohy-drate content of the meal. For patientswith a poor appetite and poor intake, theprandial insulin can be given after themeal based on the amount eaten. Using aconsistent carbohydrate menu makes thiseasy to determine. Providing meals withthis system eases the burden on the healthcare team of trying to individualize diets,especially when it is not practical, such asduring a short hospital stay. Meals for pa-tients with type 1 diabetes can easily beadjusted by altering the number of carbo-hydrate servings and snacks (428). Effi-ciencies in food service are realized andpatient satisfaction is enhanced with thissystem (428,431). Another advantage isthat the system reinforces carbohydratecounting meal planning taught to manypersons with diabetes, particularly type 1diabetic individuals using advanced car-bohydrate counting. It serves as a basis forteaching newly diagnosed patients withdiabetes about meal planning and canserve as a reference for home meals.

The meals served to patients with di-abetes certainly affect glucose control, butit should be remembered it is not the onlyfactor influencing glycemia. Hospitalizedpatients often have poor appetites and in-take is suboptimal. Meals can be delayedor missed entirely due to tests and proce-dures. Other causes of poor glucose con-trol include erratic absorption of insulin,counterregulatory hormone stress re-sponses, increased insulin requirements,the length of time between premeal insu-lin and food consumption, and impairedgut motility caused by diabetic gastropa-resis and medications, particularly nar-cotics (300).

How to order consistentcarbohydrate dietsThere is no single meal-planning systemthat meets the needs of all institutions.Budgetary issues, food-service employeetime, local factors, and administration un-

derstanding and support affect the choiceof a meal planning system (432). Manyinstitutions are familiar with exchange di-ets and, therefore, some facilities still usethem as a system for planning meals. In-troduction of the consistent carbohydratesystem requires a multidisciplinary effort,staff education, and patient education forthe program to succeed, but it can offerclear benefits when implemented. Institu-tions can adapt the consistent carbohy-drate system to meet their needs. A reviewof the implementation of the consistentcarbohydrate system in institutions re-vealed some variations developed by var-ious facilities (431), as described below.

One hospital terms the diet the “con-sistent carbohydrate diabetes diet.” Calo-rie levels are not specified. Menus withfood selections instruct patients to choosethree to five carbohydrate foods at eachmeal, identifying the carbohydrate foods.Each contains 15 g carbohydrate. Dessertitems with 30 g carbohydrate (two carbo-hydrate choices) or 15 g are included atlunch and dinner. Another facility usesthe consistent carbohydrate menu withcalorie ranges from low to very high. Allcarbohydrate-containing foods aregrouped in one list on the menu. Othermodifications of nutrients or textures canbe added. Since no universal guideline ex-ists for consistent carbohydrate diabetesdiet ordering, it is encouraged that hospi-tal nutrition committees specify their ownordering guidelines that meet the uniqueneeds of their patients and capabilities oftheir nutrition staff.

Regardless of the type of meal plan-ning system selected, the use of mealplans such as no concentrated sweets, nosugar added, low sugar, and liberal dia-betic diets are no longer appropriate.These diets unnecessarily restrict sucroseand do not reflect the current evidence-based nutrition recommendations (433).

Special nutrition issuesLiquid diets. Sugar-free liquid diets arenot appropriate for patients with diabetes.Calories and carbohydrates are needed toprovide for normal physiologic processes.Patients given clear or full liquid dietsshould receive 200 g carbohydrate,spread equally throughout the day inmeals and snacks (428).Surgery and progression diets. Aftersurgery it is desirable to initiate feeding assoon as possible in order to protect intes-tinal integrity (428). Advancement from



clear liquid to full liquid to solid foodsshould be done as quickly as tolerated.Approximately 200 g carbohydrateshould be provided daily in evenly di-vided doses at meals and snacks. Duringillness and surgery, glucose requirementsincrease. Hypoglycemia can occur with-out sufficient glucose (428).

Catabolic illness and nutritionsupportDuring catabolic illness, nutritional needsare altered. Careful continuous monitor-ing of various nutrition parameters andglycemic status is essential so that nutri-tional needs are met and glycemic controlis maintained. Catabolic illness can alterfluid balance and can lead to shrinkage ofbody fat and body cell mass, making nu-trition assessment difficult. A recentweight loss of 10% indicates a need forthorough nutrition assessment. Moderateprotein-calorie malnutrition can occurwith an unintentional weight loss of 10–20%; if the loss is �20%, severe malnu-trition is likely present (430). The timeperiod over which the weight loss has oc-curred bears investigation, since a morerapid weight loss is more hazardous. Themagnitude of recent weight loss with con-sideration of the presence of excess fluidoften present in critically ill patients, thepresence or absence of clinical markers ofstress, and the amount of time the patientwill be unable to eat should determine theneed for nutrition intervention (429). Aconsultation to the registered dietitian iswarranted in these cases.

Enteral feedings have several advan-tages over parenteral feedings, includinglower costs, avoidance of catheter-relatedcomplications, the trophic effect on gas-trointestinal cells, and the more physio-logic route (429). While parenteralnutrition is necessary in certain situa-tions, it is beneficial to progress to enteraltube feedings or oral intake as soon aspossible. As with solid-food diets, theamount of carbohydrate present will havethe greatest impact on blood glucose re-sponse (428). Medications, particularlyinsulin, can be adjusted to maintain gly-cemic control based on frequent bloodglucose monitoring. The dietitian, in con-sultation with other members of the inter-disciplinary team, determines the bestmethod of feeding, the appropriate en-teral formula, and the amounts of protein,lipid, and carbohydrate in parenteral for-mulations. It is important to not overfeed

patients receiving nutrition support, asoverfeeding can exacerbate hyperglyce-mia, cause abnormal liver function tests,and increase oxygen consumption andcarbon dioxide production (429).

Nutrition guidelines for health careinstitutionsIn 1997 the “Translation of the DiabetesNutrition Recommendations for HealthCare Institutions” technical review (428)and position statement (427) were pub-lished. The position statement has beenrepublished without any substantivemodifications (433). The original paperwas based on the nutrition recommenda-tions current at that time, but both theoriginal and updated position statementsconform to the current evidence-basednutrition recommendations (430).

Discharge planningPatients with newly recognized diabetesrequire DSME during hospitalization andneed detailed discharge planning for dia-betes care. Discharge planning includesassessment of the patient’s ability to payfor diabetes supplies and medications. Ofpatients with no prior history of diabeteswho are found to have hyperglycemia(random blood glucose �125 mg/dl or6.9 mmol/l) during hospitalization, 60%are likely to have diabetes at follow-uptesting (8). For this reason, follow-uptesting for diabetes based on ADA criteria(3) is recommended within 1 month ofhospital discharge.

WHAT IS THE ROLE OFBEDSIDE GLUCOSEMONITORING IN THEHOSPITALIZED PATIENT? —Implementing intensive diabetes therapyin the hospital setting requires frequentand accurate blood glucose data. Thismeasure is analogous to an additional “vi-tal sign” for hospitalized patients with di-abetes. Bedside glucose monitoring usingcapillary blood has advantages over labo-ratory venous glucose testing because theresults can be obtained rapidly at the“point of care,” where therapeutic deci-sions are made. For this reason, the termsbedside and point-of-care glucose moni-toring are used interchangeably.

To date, no study has been conductedtesting the effect of frequency of bedsideglucose testing on the incidence of hyper-glycemia or hypoglycemia in the hospital.Without such data, recommendations are

based only on expert and consensus opin-ion. For patients who are eating, com-monly recommended testing frequenciesare premeal and at bedtime. For patientsnot eating, testing every 4–6 h is usuallysufficient for determining correction in-sulin doses. Patients controlled with con-tinuous intravenous insulin typicallyrequire hourly blood glucose testing untilthe blood glucose levels are stable, thenevery 2 h.

Bedside blood glucose testing is usu-ally performed with portable glucose de-vices that are identical or similar todevices for home self-monitoring of bloodglucose. Characteristics unique to thehospitalized patient and common to thenonhospitalized patient can lead to erro-neous bedside blood glucose testing re-sults (Table 9). Most of these errors can beprevented by implementing and main-taining a strong hospital quality-controlprogram (434,435). The impact of spe-cific interfering substances or hematocritare device-specific (436–440). Elevatedlevels of multiple interfering substancesmay alter bedside glucose results, al-though each substance, by itself, may bebelow the interference threshold specifiedby the manufacturer (441).

New bedside glucose devices allowfor identification of both patient and pro-vider by reading a unique barcode. Theglucose results can also be automaticallydownloaded into the hospital’s central labdatabase, allowing for easier access andmonitoring for quality-control purposes.Most currently used bedside glucosemeters, though designed for capillarywhole-blood testing, are calibrated to re-port results compatible to plasma, whichallows for reliable comparison to the lab-oratory glucose test. For critically ill pa-tients, hypotension, dehydration,anemia, and interfering substances in theblood may render capillary blood glucosetesting inaccurate (437). Using arterial orvenous blood with bedside glucosemeters in these situations is likely morereliable, but frequent comparison withthe laboratory glucose test is recom-mended to avoid errors in insulin ther-apy. Arterial concentrations are 5 mg/dl(0.3 mmol) higher than capillary concen-trations and 10 mg/dl (0.5 mmol)higher than venous concentrations. In thestudy by Van den Berghe et al. (2), inwhich very strict glucose targets weremaintained in critically ill patients, allglucose samples were performed with a



glucose analyzer at 1- to 4-h intervals. Theuse of alternate-site glucose testing (i.e.,arm, leg, or palm) in the hospital has notbeen studied. The use of alternate-siteglucose testing may cause erroneous re-sults when the blood glucose level is rap-id ly r i s ing or fa l l ing and whenhypoglycemia occurs (442).

As with any procedure handlingblood, protective glove use is essential forhealth care personnel performing bedsideglucose monitoring. The use of self-retracting lancet devices has the potentialto eliminate the chance of needlestick in-jury and risk for infection. Table 10 out-lines specific elements of a quality-controlprogram deemed to be necessary for ap-propriate use of bedside blood glucosetesting in the hospital (443). Key partici-pants in the program are clinical labora-tory representatives, nurses, physicians,and hospital administrators. Additionalguidelines are published by the NationalCommittee for Clinical Laboratory Stan-dards (444). For patients practicing dia-betes self-management in the hospital, aquality-control program to test the pa-tient’s blood glucose device and the pa-tient’s testing technique is necessary toensure accurate results.

IS IMPROVED DIABETESCARE IN HOSPITALS COSTEFFECTIVE? — Of the $91.8 billionspent annually in the U.S. for direct med-ical expenditures for diabetes, hospitalcare accounts for the single largest com-ponent of expenditures, comprising $40billion, or 43.9%, of the total cost (445).After adjustment for age, sex, and race/ethnicity, annual per capita costs for hos-pital care is $6,309 for persons withdiabetes versus $2,971 for persons with-

out diabetes—a cost ratio of 2.1. Similarincreased hospital-related cost for dia-betic patients is reported in Europe (446).This increased cost for hospital care is dueto increased frequency of hospital admis-sions (447), increased length of stay, andincreased cost per hospital day due tohigher utilization of intensive care andprocedures (448).

Furnary and colleagues (196,290)performed a cost-effectiveness analysisfollowing implementation of a continu-ous intravenous insulin infusion programfor the first 3 days after cardiac surgicalprocedures in diabetic patients. Com-pared with historical control subjects, theincidence of deep sternal wound infec-tions (DSWIs) was reduced from 1.9 to0.8%, and mortality from DSWIs reduceddecreased from 19 to 3.8% after imple-mentation of the protocol. The averageexcess length of stay from DSWI was 16days, generating an average $26,400 inadditional hospital charges. Furnary et al.(449) estimated the additional expense ofinsulin infusion at $125–150 per patient.Of 1,499 patients in the interventiongroup, the number of DWSIs preventedwas 10, resulting in an average cost toprevent one DSWI at approximately$21,000. This estimate does not incorpo-rate the potential effects of the interven-tion on other outcomes, such as areduction in mortality, cost for chroniccare, and lost income from work.

Van den Berghe et al. (2) reported a34% reduction in hospital mortality incritically ill patients treated with intensiveinsulin therapy. Intensive insulin therapyreduced the duration of intensive care butnot the overall length of stay in the hospi-tal. Subsequent comparison of costs be-tween the groups for rehabilitation,

chronic care, home care, or loss of wagesdue to illness or mortality has not as yetbeen reported.

Levetan et al. (379) reported the im-pact of obtaining an endocrinology con-sultation, either alone or as part ofmultidisciplinary diabetes team (endocri-nologist, diabetes nurse educator, and aregistered dietitian), on hospital length ofstay in patients admitted with the princi-pal diagnosis of diabetes, including hy-perosmolar state, diabetic ketoacidosis,and uncontrolled diabetes. In this non-randomized observational study, the av-erage length of stay of the diabetes teampatients was 3.6 � 1.7 days as comparedwith 8.2 � 6.2 days for patients in theno-consultation group and 5.5 � 3.4 daysfor the patients who received a traditionalindividual endocrine consultation. Possi-ble reasons for shortened length of staywere more rapid normalization of glucoselevels, more efficient transition from in-travenous to subcutaneous insulin, fastertransition to a definitive insulin or oralmedication regimen, and more effectiveteaching of diabetes survival skills. Esti-mated cost savings from reduction inlength of stay for the 34 patients seen bythe diabetes team was $120,000 com-pared with the cost in salaries of $40,000.

In summary, the potential opportu-nity for cost savings from improved hos-pital outcomes, reduced mortality, andshortened length of stay for patients withdiabetes and hospital-related hyperglyce-mia is substantial. Future studies usingrandomized prospective design areneeded to verify these results.

SUGGESTIONS FOR FUTURERESEARCH — While outcomes stud-ies that provide evidence for a clear role

Table 9—Conditions causing erroneous bedside blood glucose results

Sources of analytical error Sources of user error

Low hematocrit* Inadequate meter calibrationHigh hematocrit† Using a test strip that does not match the meter code or that has

passed the expiration dateShock and dehydration‡ Inadequate quality-control testingHypoxia‡ Poor meter maintenanceHyperbilirubinemia, severe lipemia* Poor technique in performing fingerprickSpecimen additives: sodium flouride† Poor technique of applying drop of blood to the test stripDrugs—acetaminophen overdose, ascorbic acid,

dopamine, fluorescein, mannitol, salicylate‡Failure to record results in patient’s chart or to take action if

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.



for targeted glucose control in the hospi-tal management of diabetes are beginningto accumulate in the scientific literature,numerous questions related to how tobest manage diabetes in this hospital set-ting remain to be addressed. These ques-tions may be grouped into three mainareas: health care outcomes attributableto glycemic control, specific strategies forinsulin delivery, and processes for opti-mizing diabetes care and education in thehospital setting.

Health care outcomes related toglycemic controlFew studies in the literature contain ran-domized, controlled evidence to supportspecific interventions that target glucosecontrol in various clinical settings. Workis clearly needed to provide rigorous evi-dence in the hospital management of dia-betes in order to:

● Further define the role of targeted glu-cose control and the threshold for im-pact of blood glucose level on healthcare outcomes in diverse clinical set-tings, such as general medicine and sur-gery pa t i en t s , and in spec ificcircumstances, such as stroke, neuro-surgery, and CVDs

● Examine clinical outcomes● Examine health care economic out-

comes such as length of stay and costeffectiveness

● Further examine the impact of special-ist care and diabetes team management

● Define the impact of diabetes educa-tion.

Specific strategies for insulindeliveryDevelopment and implementation of spe-cific strategies for insulin delivery, basedon knowledge of the pharmacokinetics ofthe currently available insulins, will allowphysicians and nurses to overcome barri-ers to its effective use in managing bloodglucose. Such strategies will need to dem-onstrate safety and efficacy of specific ap-plications of insulin therapies thataddress known areas of need, including:

● Optimum methods for delivering basalinsulin under various clinical condi-tions

● Feasibility of using subcutaneousglargine or detemir insulin to meetbasal insulin requirements (e.g., formedicine services) in the operating

Table 10—Characteristics of an effectivebedside glucose monitoring (BGM) quality-control program

Characteristic

● A specifically designated responsibleindividual, preferably a laboratoryprofessional, is involved in theadministration and quality assurance ofthe BGM program.

● A written procedure for the BGMprogram.

● An organized training program thatinvolves laboratory personnel andnursing staff.

● Defined frequencies and requirements formaintenance and cleaning of BGMinstruments.

● Regular performance of quality controltesting on each instrument (daily or byshift), depending on the frequency ofpatient testing.

● A policy to regularly compare the BGMresults from each operator andinstrument with results from acorresponding sample tested in theclinical laboratory. Suggest that all BGMresults are, at least, within �15%variation from the clinical laboratoryresults.

● Participation in an external proficiencytesting program.

● Acknowledgment of the limitations ofBGM and requirement of a clinicallaboratory glucose determination when aBGM result is outside a defined range.

● Acknowledgment of the effect ofhematocrit value variation on BGMresults and establishment of hematocritvalue limitations for the instrument inuse.

● Determination of the bias of theinstrument in use and communication ofthis information to the physicians and theinstitutional quality assurance program.

Adapted from Jones et al. (443).

Table 11—Summary of major recommendations for hospital management of hyperglycemia

RecommendationLevel of

evidence

● Good metabolic control is associated with improved hospital outcomes. Targetplasma glucose levels are:

B

•�110 mg/dl preprandial and �180 mg/dl peak postprandial.● Intensive insulin therapy with intravenous insulin, with the goal of

maintaining blood glucose 80–110 mg/dl, reduces morbidity and mortalityamong critically ill patients in the surgical ICU.

A

● Intravenous insulin infusion is safe and effective for achieving metaboliccontrol during major surgery, hemodynamic instability, and NPO status.

B

● Intravenous insulin infusion is safe and effective for patients who have poorlycontrolled diabetes and widely fluctuating blood glucose levels or who areinsulin deficient or severely insulin resistant.

B

● Intravenous insulin infusion, followed by multidose subcutaneous insulintherapy, improves survival in diabetic patients after myocardial infarction.

A

● For insulin-deficient patients, despite reductions or the absence of caloricintake, basal insulin must be provided to prevent diabetic ketoacidosis.

B

● Use of scheduled insulin improves blood glucose control compared withorders based on sliding scale insulin coverage alone.

B

● For patients who are alert and demonstrate accurate insulin self-administrationand glucose monitoring, insulin self-management should be allowed as anadjunct to standard nurse-delivered diabetes management.

E

● Patients with no prior history of diabetes who are found to have hyperglycemia(random blood glucose �125 mg/dl or 6.9 mmol/l) during hospitalizationshould have follow-up testing for diabetes within 1 month of hospitaldischarge.

E

● Establishing a multidisciplinary team that sets and implements institutionalguidelines, protocols, and standardized order sets for the hospital results inreduced hypoglycemic and hyperglycemic events.

B

● Diabetes education, medical nutrition therapy, and timely diabetes-specificdischarge planning are essential components of hospital-based diabetes care.

C



room and for periprocedural manage-ment

● The role of standardization of diabetesmanagement and algorithmic care andvalidation of such pathways and tools

● Safety and practicality of delivering in-sulin infusion therapy outside the in-tensive care unit

● Simple algorithms for subcutaneousdelivery of programmed basal, prandi-al/nutritional, and correction doses ofinsulin and insulin infusion algorithms.

Improved methods for glucosemonitoringCurrent methods for blood glucose mon-itoring are painful and time consuming.Improved methods for frequent and accu-rate blood glucose monitoring would en-hance the ability to reach target bloodglucose levels safely. Development of con-tinuous glucose monitoring systems thatare safe and accurate is encouraged.

Processes for optimizing diabetescare and education in the hospitalsettingBecause diabetes is seen in a broad spec-trum of inpatients, processes need to bedefined and tested to enable safe and ef-fective patient management and optimi-zation of outcomes. Areas of interestinclude:

● Strategies adopted by institutions to re-duce errors, enhance safety, and im-prove quality of care

● Development and implementation ofnursing policies effective for hypogly-cemia prevention

● Impact of institutional hypoglycemiaprograms on willingness of physiciansto prescribe insulin to adequately con-trol hyperglycemia

● Whether correlation exists between in-stitutional adherence to clinical path-ways and algorithms and outcomes

● Most appropriate CQI measures forevaluation of performance in achievingglycemic control

● Most appropriate focus for regulatoryorganizations such as JCAHO.

CONCLUSIONS — Hyperglycemiais associated with poor hospital out-comes. The key question for guiding ther-apy is whether hyperglycemia observed inthe hospital is a simple marker for theunderlying disease state (i.e., diabetes) or

the severity of illness or if hyperglycemiaitself, in conjunction with relative hypo-insulinemia, is pathogenic for tissue in-jury and poor hospital outcomes. Basedon limited interventional studies in se-lected settings, aggressive control ofblood glucose in the hospital may providean opportunity to improve patient out-comes. Clinical trials are needed to an-swer these questions. The target bloodglucose threshold to optimize outcomesin the hospital is not clearly defined butmay be lower than previously thought.From a cost perspective, research andstrategies targeting glucose control anddiabetes care in the hospital have thepotential to translate to substantial costsavings.

Acknowledgments— Support for this Tech-nical Review was provided by an unrestrictededucational grant from Novo Nordisk.

The authors thank the members of the ADAProfessional Practice Committee for theirthoughtful review of the manuscript. The au-thors also thank Drs. James Lenhard and Ste-phen Hodak for their helpful comments.

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