management of diabetes and hyperglicemia in hospital

Abbreviations: ADA, American Diabetes Association; AMI, acute myocardial infarction; CDE, certified diabetes educator; CHF, congestive heart failure; CK, creatinine kinase; CQI, continuo

Management of Diabetes and

ELIZABETH P SMITH, RN, MS, CANP, CDE 1

REBECCA G SCHAFER, MS, RD, CDE 5 IRL B HIRSCH, MD 6

ON BEHALF OF THE DIABETES IN HOSPITALS WRITING COMMITTEE

Diabetes increases the risk for

disor-ders that predispose individuals to

hospitalization, including coronary

artery, cerebrovascular and peripheral

vascular disease, nephropathy, infection,

and lower-extremity amputations The

management of diabetes in the hospital is

generally considered secondary in

impor-tance compared with the condition that

prompted admission Recent studies (1,2)

have focused attention to the possibility

that hyperglycemia in the hospital is not

necessarily a benign condition and that

aggressive treatment of diabetes and

hy-perglycemia results in reduced mortality

and morbidity The purpose of this

tech-nical review is to evaluate the evidence

relating to the management of

hypergly-cemia in hospitals, with particular focus

on 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 glucoseⱖ126 mg/dl orrandom blood glucose ⱖ200 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: glycemia (fasting blood glucoseⱖ126mg/dl or random blood glucoseⱖ200mg/dl) occurring during the hospital-ization that reverts to normal after hos-pital discharge

hyper-What is the prevalence of diabetes inhospitals?

The prevalence of diabetes in hospitalizedadult patients is not known In the year

2000, 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 having

a medical history of diabetes, patients senting to hospitals may have unrecog-nized diabetes or hospital-relatedhyperglycemia Umpierrez et al (1) re-ported a 26% prevalence of known diabe-

pre-t e s i n h o s p i pre-t a l i z e d p a pre-t i e n pre-t s i n 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-

i n g n e w - o n s e t d i a b e t e s d u r i n ghospitalization Thirty-six percent of thehyperglycemic patients remained unrec-ognized as having diabetes in the dis-charge summary, although diabetes or

“hyperglycemia” was documented in

6

University of Washington, Seattle, Washington.

Address correspondence and reprint requests to Dr Stephen Clement, MD, Georgetown University

Hospital, Department of Endocrinology, Bldg D, Rm 232, 4000 Reservoir Rd., NW, Washington, DC

20007 E-mail: clements@gunet.georgetown.edu

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 from

Aventis, 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 honoraria

from Aventis, Bayer, BMS, GlaxoSmithKline, Johnson & Johnson, Lilly, Novo Nordisk, Pfizer, and Takeda

and 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, certified

diabetes 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, diabetes

self-management education; DSWI, deep sternal wound infection; FFA, free fatty acid; GIK,

glucose-insulin-potassium; ICAM, intercellular adhesion molecule; ICU, intensive care unit; IL, interleukin; IIT, intensive

insulin therapy; JCAHO, Joint Commission of Accredited Hospital Organization; LIMP, lysosomal integral

membrane protein; MCP, monocyte chemoattractant protein; MI, myocardial infarction; MRI, magnetic

resonance imaging; MRS, magnetic resonance spectroscopy; NF, nuclear factor; NPO, nothing by mouth;

PAI, plasminogen activator inhibitor; PCU, patient care unit; PKC, protein kinase C; PBMC, peripheral blood

mononuclear cell; PMN, polymorphonuclear leukocyte; ROS, reactive oxygen species; TNF, tumor necrosis

factor; TPN, total parenteral nutrition; UKPDS, U.K Prospective Diabetes Study.

A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion

factors for many substances.

© 2004 by the American Diabetes Association.

the progress notes for one-third of these

patients

Norhammar et al (7) studied 181

consecutive patients admitted to the

cor-onary care units of two hospitals in

Swe-den with acute myocardial infarction

(AMI), no diagnosis of diabetes, and a

blood glucose ⬍200 mg/dl (⬍11.1

mmol/l) on admission A standard 75-g

glucose tolerance test was done at

dis-charge and again 3 months later The

au-thors found a 31% prevalence of diabetes

at the time of hospital discharge and a

25% 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 valuable

case-finding tool for identifying diabetes

in hospitalized patients Greci et al (8)

reported that an A1C ⬎6% was 100%

specific and 57% sensitive for identifying

persons with diabetes in a small cohort of

patients admitted through the emergency

department of one hospital with a random

blood glucose ⱖ126 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 increased

with age, duration of diabetes, and

num-ber of diabetes complications Persons

with diabetes reported being hospitalized

in the previous year three times more

fre-quently compared with persons without

diabetes In summary, the prevalence of

diabetes in hospitalized adults is

conser-vatively estimated at 12.4 –25%,

depend-ing on the thoroughness used in

identifying patients

WHAT IS THE LINK

BETWEEN HIGH BLOOD

GLUCOSE AND POOR

OUTCOMES? POSSIBLE

MECHANISMS — The mechanism

of harm from hyperglycemia on various

cells and organ systems has been studied

in in vitro systems and animal models

This research has centered on the

im-mune system, mediators of inflammation,

vascular responses, and brain cell

re-sponses

Hyperglycemia and immune function

The association of hyperglycemia and

in-fection has long been recognized,

al-though the overall magnitude of the

problem 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 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)

hyper-Alexiewicz et al (17) demonstratedelevated basal levels of cytosolic calcium

in 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 complications

of 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 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 phospholipase

ac-D 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

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 diassys-tolic blood pressure and

in-creased endothelin levels with acute

hyperglycemia in patients with type 2

di-abetes The same researchers also induced

acute hyperglycemia (270 mg/dl or 15

mmol/l) over 2 h in healthy men This

produced elevated systolic and diastolic

blood pressure, increased pulse, elevation

of catecholamine levels, and QTc

prolon-gation (44) Other investigators have

demonstrated an association between

acute hyperglycemia and increased

vis-cosity, blood pressure (45), and natiuretic

peptide levels (46)

Hyperglycemia and thrombosis

Multiple studies have identified a variety

of hyperglycemia-related abnormalities in

hemostasis, favoring thrombosis (47–51)

For example, hyperglycemic changes in

rats rapidly reduce plasma fibrinolytic

tivity and tissue plasminogen activator

ac-tivity while increasing plasminogen

activator inhibitor (PAI)-1 activity (52)

Human studies in patients with type 2

di-abetes have shown platelet hyperactivity

indicated by increased thromboxane

bio-synthesis (47) Thromboxane

biosynthe-sis decreases with reduction in blood

glucose Hyperglycemia-induced

eleva-tions of interleukin (IL)-6 levels have

been linked to elevated plasma fibrinogen

concentrations and fibrinogen mRNA

(53,54)

Increased platelet activation as shown

by shear-induced platelet adhesion and

aggregation on extracellular matrix has

been demonstrated in patients with

dia-betes (48) As little as 4 h of acute

hyper-glycemia enhances platelet activation in

patients with type 2 diabetes (51) In this

crossover, 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-induced

platelet activation as well as platelet

P-selectin and lysosomal integral membrane

protein (LIMP) expression

Hyperglyce-mia also caused increased plasma von

Willebrand factor antigen, von

Wille-brand factor activity, and urinary

11-dehydro-thromboxane B2(a measure of

thromboxane A2 production) These

changes were not seen in the euglycemic

state

If hyperglycemia-induced platelet 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

hy-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 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)

pro-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 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 types

demon-to 1– 8 days of hyperglycemia (58,59,68 –71) In patients with type 1 diabetes, ac-tivation of NF-␬B in PBMCs was

positively correlated to HbA1clevel (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 tivation

ac-Hyperglycemia and endothelial celldysfunction

One proposed link between 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 Human

hyperglyce-in vivo studies utilizhyperglyce-ing 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 i o n o f g e n e r a l m e c h a n i s m s o f

hyperglycemic damage has used various

models of ischemia and various measures

of outcomes Models differ according to

transient versus permanent ischemia as

well as global versus localized ischemia

There is some indication from animal

studies that irreversible ischemia or end

arterial ischemia is not affected by

hyper-glycemia (87,99,100) The major portion

of the brain that is sensitive to injury from

hyperglycemia is the ischemic penumbra

This area surrounds the ischemic core

During evolution of the stroke, the

isch-emic penumbra may evolve into infarcted

tissue or may recover as viable tissue

(87,99,101,102) One of the primary

mechanistic links between hyperglycemia

and enhanced cerebral ischemic damage

appears to be increased tissue acidosis

and lactate levels associated with elevated

glucose concentrations This has been

shown in various animal models with rare

exception (94,102–108) Lactate has

been associated with damage to neurons,

astrocytes, and endothelial cells (104) In

humans, Parsons et al (109)

demon-strated that the lactate-to-choline ratio

determined by proton magnetic

reso-nance spectroscopy (MRS) had value in

predicting clinical outcomes and final

in-farct size in acute stroke More recently,

the same investigators used this method

to 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 with

various acute consequences that likely

serve as intermediaries of adverse

out-comes For example, hyperglycemia

causes accumulation of extracellular

glu-tamate in the neocortex Increased

gluta-mate levels predict ensuing neuronal

damage (95) A unique hippocampal cell

culture model of “in vitro ischemia”

dem-onstrated a similar relationship between

hyperglycemia, glutamate activity, and

increased intracellular calcium with

en-hanced cell death (98) Hyperglycemia

has also been associated with DNA

frag-mentation, disruption of the blood-brain

barrier, more rapid repolarization in

se-verely hypoperfused penumbral tissue,

␤-amyloid precursor protein elevation, as

well 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 exposed

to 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 ports scientifically viable mechanisms ofcentral nervous system injury from hy-perglycemia in the acute setting

sup-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 oxide

to 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 independent

of 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 ports a direct effect of the insulin sinceblood glucose control is not the goal of

sup-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 likely

to be major contributors to the 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-

mecha-o r g a n i c p h mecha-o s p h a t e p r mecha-o d u c t i mecha-o n(148,156,159) Adequate glycolytic ATP

is 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 model

of 60-min low-flow ischemia followed by

30 min of reperfusion in rat hearts, 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 function

inves-in 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 improved

myocardial perfusion by 99

m-Tc-tetrofosmin– gated single photon 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

emis-regarding the use of GIK therapy in

strokes or cerebral ischemia Limited

studies have demonstrated safety of GIK

therapy in the acute stroke patient, with a

trend to reduced mortality, and a decrease

in blood pressure (147,150) However,

the data are clearly inadequate to make

any conclusions of benefit

Beyond GIK therapy, one finds

creasing support for a direct effect of

in-sulin on many of the abnormalities that

underlie inpatient complications Insulin

treatment, ranging in duration from brief

euglycemic-hyperinsulinemic clamps to

2 months of ongoing therapy, improves

endothelial cell function (165–171)

There are rare exceptions to this finding

(172) Insulin also has vasodilatory

prop-erties in the internal carotid and femoral

arteries (165,167) The vasodilatory

properties of insulin appear to be

medi-ated at least in part by stimulating nitric

oxide release (165,166) Aortic

endothe-lial cell cultures have also demonstrated

insulin-induced nitric oxide synthase

ac-tivity and increased nitric oxide levels

(172,173) In a rat model, insulin inhibits

the upregulation of the endothelial sion molecule P-selectin expression seen

adhe-as a consequence of elevated glucose els (121)

lev-Insulin infusion has 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 addition

anti-inflamma-to 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 inflammatory action of insulin

anti-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 produces

an 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 perglycemia and relative insulin deficiency caused by metabolic stress triggers immune dysfunction, release

Hy-of fuel substrates, and other mediators such as ROS Tissue and organ injury occur via the combined insults of in- fection, direct fuel-mediated injury, and oxidative stress and other down- stream mediators See text for details.

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 a

direct pharmacologic effect of insulin or

represent an indirect effect by improved

glucose control, enhanced glycolysis, or

suppressed lipolysis is more difficult to

determine Studies in cell cultures control

for glucose but have other physiologic

limitations Nevertheless, the data are

provocative and certainly leave the

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 glucose

manipulation in the hospitalized patient

Potential relationships between

metabolic stress, hyperglycemia,

hypoinsulinemia, and poor hospital

outcomes

To explain the dual role of glucose and

insulin on hospital outcomes, Levetan

and Magee (189) proposed the following

relationships Elevations in

counterregu-larory hormones accelerate catabolism,

hepatic gluconeogenesis, and lipolysis

These events elevate blood glucose, FFAs,

ketones, and lactate The rise in glucose

blunts insulin secretion via the

mecha-nism of glucose toxicity (190), resulting

in further hyperglycemia The vicious

cy-cle of stress-induced hyperglycemia and

hypoinsulinemia subsequently causes

maladaptive responses in immune

func-tion, fuel producfunc-tion, and synthesis of

mediators that cause further tissue and

or-gan dysfunction (Fig 1) Thus, the

com-bination of hyperglycemia and relative

hypoinsulinemia is mechanistically

posi-tioned to provide a plausible explanation

for the poor hospital outcomes seen in

observational studies

WHAT ARE THE TARGET

BLOOD GLUCOSE LEVELS

FOR THE HOSPITALIZED

PATIENT?

A rapidly growing body of literature

sup-ports targeted glucose control in the

hos-pital setting with potential for improved

mortality, morbidity, and health care

eco-nomic outcomes The relationship of

hos-pital outcomes to hyperglycemia has been

extensively examined Hyperglycemia in

the hospital may result from stress,

de-compensation of type 1 diabetes, type 2

diabetes, or other forms of diabetes

and/or may be iatrogenic due to tration of pharmacologic agents, includ-ing glucocorticoids, vasopressors, etc

adminis-Distinction between decompensated betes and stress hyperglycemia is oftennot made or alternatively is not clear at thetime of presentation with an acute illness

dia-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, terventional studies that report improvedoutcomes with targeted glucose control—

in-though few in number—are now ning to provide a source of evidence in theliterature

begin-To make the case for defining targetsfor glucose control in hospital settings, it

is 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 Pomposelli

et al (191) studied 97 patients with 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 was

dia-a sensitive (85%), but reldia-atively 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)

nonspe-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 glucoseⱖ126 mg/dl

or random blood glucoseⱖ200 mg/dl ontwo or more occasions) Care was pro-vided on general medicine and surgeryunits Among these subjects, there were

223 patients (12%) with new 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 ⫾ 0.2

hyperglyce-days, 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 14

vs 9%, respectively, P⬍ 0.01) and weremore likely to require transitional or nurs-ing home care There was a trend toward

a 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 level

of 220 mg/dl (12.2mmol/l) separated tients for risk of infection Data from the

Umpierrez study (1) and most of the

litera-ture from other disciplines, as outlined

else-where in this review, would suggest a lower

threshold for optimal hospital outcomes

Evidence for a blood glucose threshold.

The Umpierrez study demonstrated

bet-ter outcomes for patients with fasting and

admission blood glucose⬍126 mg/dl (7

mmol/l) and all random blood glucose

levels ⬍200 mg/dl (11.1 mmol/l)

Be-cause the Pomposelli and Umpierrez

studies are observational, a causal link

be-tween hyperglycemia and poor outcomes

cannot be established

CVD and critical care

Numerous articles contain data linking

blood glucose level to outcomes in AMI

and cardiac surgery, for which patients

receive care predominantly in the ICU

setting The majority of these trials are

ob-servational, but the literature also

in-c l u d e s s e v e r a l l a r g e , l a n d m a r k

interventional studies that have markedly

increased 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 mortality

in the setting of AMI from 15 previously

published studies and performed a

meta-analysis of the results to compare the RR

of in-hospital mortality and CHF in both

hyper- and normoglycemic patients with

and without diabetes In subjects without

known diabetes whose admission blood

glucose wasⱖ109.8 mg/dl (6.1 mmol/l),

the RR for hospital mortality was

in-creased significantly (RR 3.9, 95% CI

2.9 –5.4) When diabetes was present and

admission glucose wasⱖ180 mg/dl (10

mmol/l), risk of death was moderately

in-creased (1.7, 1.2–2.4) compared with

pa-t i e n pa-t s w h o h a d d i a b e pa-t e s b u pa-t n o

hyperglycemia on admission

Bolk et al (193) analyzed admission

blood glucose values in 336 prospective,

consecutive patients with AMI with

aver-age follow-up to 14.2 months Twelve

percent of this cohort had previously

di-agnosed diabetes Multivariate analysis

revealed an independent association of

admission blood glucose and mortality

The 1-year mortality rate was 19.3% in

subjects with admission plasma glucose

⬍100.8 mg/dl (5.6 mmol/l) and rose to

44% with plasma glucoseⱖ199.8 mg/dl

(11 mmol/l) Mortality was higher in

pa-tients with known diabetes than in those

without 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 group

it 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, ity was 33% in the intensive treatmentgroup and 44% in the conventional treat-ment group (RR 0.72, 95% CI 0.55– 0.92;

mortal-P⫽ 0.011), consistent with persistent 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,

re-0.30 – 0.80; P⫽ 0.004)

In the DIGAMI study, insulin 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

infu-outcomes In addition, it is of interest that

in spite of the observation that blood cose levels between the intensive and con-ventional treatment groups were similar,

glu-a significglu-ant difference in mortglu-ality tween these groups was found A rela-tively modest reduction in blood glucose

be-in the be-intensive treatment group 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

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

● The metaanalysis of Capes et al (192)reported a blood glucose threshold of

⬎109.8 mg/dl (6.1 mmol/l) for 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 progressively

to 44% for blood glucose ⬎199.8mg/dl (11 mmol/l)

● In the DIGAMI study, mean blood 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 range

glu-of blood glucose levels within each armlimits the ability to define specific bloodglucose target thresholds

Cardiac surgery Attainment of targeted

glucose control in the setting of cardiacsurgery is associated with reduced mor-tality and risk of deep sternal wound in-fections Furnary and colleagues(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 1999

it 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 level

for the first 2 days after surgery and a

con-comitant decrease in the proportion of

pa-tients with deep wound infections, from

2.4% (24 of 990) to 1.5% (5 of 595) (P⬍

0.02) (198) A recent analysis or the

co-hort found a positive correlation between

the average postoperative glucose level

and mortality, with the lowest mortality

in patients with average postoperative

blood glucose⬍150 mg/dl (8.3 mmol/l)

(197)

Golden et al (199) performed a

non-concurrent prospective cohort chart

re-view study in cardiac surgery patients

with diabetes (n ⫽ 411) Perioperative

glucose control was assessed by the mean

of six capillary blood glucose measures

performed during the first 36 h following

surgery The overall infectious

complica-tion rate was 24.3% After adjustment for

variables, patients with higher mean

cap-illary glucose readings were at increased

risk of developing infections Compared

with subjects in the lowest quartile for

blood glucose, those in quartiles 2– 4

were at progressively increased risk for

infection (RR 1.17, 1.86, and 1.78 for

quartiles 2, 3, and 4, respectively, P ⫽

0.05 for trend) These data support the

concept that perioperative hyperglycemia

is an independent predictor of infection in

patients with diabetes

Critical care Van den Berghe et al (200)

performed a prospective, randomized

controlled study of 1,548 adults who

were admitted to a surgical intensive care

unit and were receiving mechanical

ven-tilation Reasons for ICU admission were

cardiac surgery (⬃60%) and noncardiac

indications, including neurologic disease

(cerebral trauma or brain surgery), other

thoracic surgery, abdominal surgery or

peritonitis, vascular surgery, multiple

trauma, or burns and transplant (4 –9%

each group) Patients were randomized to

receive intensive insulin therapy (IIT) to

maintain target blood glucose in the 80 –

110 mg/dl (4.4 – 6.1) range or

conven-tional therapy to maintain target blood

glucose between 180 and 200 mg/dl (10 –

11.1 mmol/l) Insulin infusion was

initi-ated in the conventional treatment group

only if blood glucose exceeded 215 mg/dl

(11.9 mmol/l), and the infusion was

ad-justed to maintain the blood glucose level

between 180 and 200 mg/dl (10.0 and

11.1 mmol/l) After the patients left the

ICU they received standard care in the

hospital with a target blood glucose of

180 and 200 mg/dl (10.0 and 11.1 mmol/

l)

Ninety-nine percent of patients in 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 conventional

treatment to 4.6% (P⬍ 0.04) The benefit

of IIT was attributable to its effect on tality among patients who remained in theunit for more than 5 days (20.2% withconventional treatment vs 10.6% with

mor-IIT, 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 ICU

death 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 had

no history of diabetes

Evidence for a blood glucose threshold

in cardiac surgery and critical care.

● Furnary et al (196) and Zerr et al (198)identified a reduction in 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 sive intravenous insulin therapy, re-ported a 45% reduction in ICUmortality with a mean blood glucose of

inten-103 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 In

the 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 from

26 studies, published between 1996 and

2000, where RRs for prespecified 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

out-⬎121–144 mg/dl (6.7–8 mmol/l) had an

RR of 1.41 (1.16 –1.73) for poor tional recovery After hemorrhagic stroke,admission hyperglycemia was not associ-ated with higher mortality in either thediabetes or nondiabetes groups

func-Several of the studies that were 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 acute

in-ischemic 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 admission

glucose (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 fect of admission glucose level and risk forintracerebral hemorrhage into an infarct

ef-when treatment with recombinant tissue

plasminogen activator was given to 138

patients presenting with stroke

Twenty-three percent of the cohort had known

diabetes The authors reported admission

blood glucose and/or history of diabetes

as the only independent predictors of

hemorrhage Kiers et al (204)

prospec-tively studied 176 sequential acute stroke

patients and grouped them by admission

blood glucose level, HbA1clevel, and

his-tory of diabetes Threshold blood glucose

for euglycemia was defined as fasting

blood glucose⬍140 mg/dl (7.8 mmol/l)

The authors divided patients into one of

four groups: euglycemia with no history

of diabetes, patients with “stress

hyper-glycemia” (blood glucose ⬎140 mg/dl,

7.8 mmol/l, and HbA1c⬍8%), newly

di-agnosed diabetes (blood glucose ⬎140

mg/dl, 7.8 mmol/l, and HbA1c⬎8%), and

known diabetes No difference was found

in the type or site of stroke among the four

groups Compared with the euglycemic,

nondiabetic patients, mortality was

in-creased in all three groups of

hyperglyce-mic patients

Williams et al (205) reported on the

association of hyperglycemia and

out-comes in a group of 656 acute stroke

pa-tients Fifty-two percent of the cohort had

a known history of diabetes

Hyperglyce-mia, defined as a random blood glucose

ⱖ130 mg/dl (7.22 mmol/l), was present

in 40% of patients at the time of

admis-sion Hyperglycemia was an independent

predictor of death at 30 days (RR 1.87)

and at 1 year (RR 1.75) (both Pⱕ 0.01)

Other outcomes that were significantly

correlated with hyperglycemia, when

compared with normal blood glucose,

were length of stay (7 vs 6 days, P ⫽

0.015) and charges ($6,611 vs $5,262,

P⬍ 0.001)

Recently, Parsons et al (110)

re-ported a study of magnetic resonance

im-aging (MRI) and MRS in acute stroke

Sixty-three acute stroke patients were

prospectively evaluated with serial

diffu-sion-weighted and perfudiffu-sion-weighted

MRI and acute blood glucose

measure-ments Median acute blood glucose was

133.2 mg/dl (7.4 mmol/l), range 104.4 –

172.8 mg/dl (5.8 –9.6 mmol/l) A

dou-bling of blood glucose from 90 to 180

mg/dl (5⫺10 mmol/l) led to a 60%

reduc-tion in penumbral salvage and a 56 cm3

increase in final infarct size For patients

with acute perfusion-diffusion mismatch,

acute hyperglycemia was correlated with

reduced salvage of mismatch tissue frominfarction, greater final infarct size, andworse functional outcome, independent

of 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 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 mortality

stud-in patients with acute stroke and moderate hyperglycemia (206) No data

mild-to-on functimild-to-onal recovery were reported

While it is promising that these tors were able to lower plasma glucosewithout increasing risk of hypoglycemia

investiga-or minvestiga-ortality finvestiga-or stroke patients, until ther studies test the effectiveness of thisapproach and possible impact on out-comes, it cannot be considered standardpractice

fur-Hyperglycemia is associated withworsened outcomes in patients with acutestroke and head injury, as evidenced bythe large number of observational studies

in 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 marker

of the level of stress the patient is 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

experi-Evidence for a blood glucose threshold

in acute neurologic disorders

Obser-vational studies suggest a correlation tween blood glucose level, mortality,morbidity, and health outcomes in pa-tients with stroke

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

identi-● 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), and

144 mg/dl (8 mmol/l), respectively, forincreased severity ad mortality for acutestroke

● Williams et al (205) reported a old admission blood glucose ⱖ130mg/dl (7.2 mmol/l) for increased mor-tality, length of stay, and charges inacute stroke

thresh-● Scott et al (206) demonstrated 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

accept-● Parsons et al (110) reported that a bling of blood glucose from 90 to 180mg/dl (5–10 mmol/l) was associatedwith 60% worsening of penumbral sal-vage and a 56-cm3increase in infarctsize

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

Role of oral diabetes agents

No large studies have investigated the 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

Concern about inpatient use of

sulfonyl-ureas centers on vascular effects

(207,208) Over 30 years ago the report of

the University Group Diabetes Program

proposed increased cardiovascular events

in patients treated with sulfonylureas

(209) This report resulted in an ongoing

labeling caution for sulfonylureas and

heart disease, although the findings have

been questioned and have had very

lim-ited influence on prescribing habits

Re-sidual fears seemingly were allayed with

the findings of the U.K Prospective

Dia-betes Study (UKPDS) (210) This large

prospective trial did not find any evidence

of increased frequency of MI among

indi-viduals treated with sulfonylureas

Rather, the trend was in the direction of

reduced events However, questions

re-main For instance, it is possible that

con-trol of hyperglycemia by any means

reduces the frequency of vascular events

to a greater extent than any effect

sulfo-nylureas may have to increase vascular

events A variety of studies have served to

fuel continued controversy

Ischemic preconditioning appears to

be an adaptive, protective mechanism

serving to reduce ischemic injury in

hu-mans (211,212) Sulfonylureas inhibit

ATP-sensitive potassium channels,

result-ing in cell membrane depolarization,

ele-vation of intracellular calcium, and

cellular response (213,214) This

mecha-nism may inhibit ischemic

precondition-ing (215–217) Various methods

evaluating cardiac ischemic

precondi-tioning have been used to compare

cer-tain of the available sulfonylureas For

example, using isolated rabbit hearts,

re-searchers found that glyburide but not

glimepiride reversed the beneficial effects

of ischemic preconditioning and

diazox-ide in reducing infarct size (218) Other

studies using similar animal heart models

or cell cultures have found differences

among the sulfonylureas, usually

show-ing glyburide to be potentially more

harmful than other agents studied (219 –

222) A unique, double-blind,

placebo-controlled study using acute balloon

occlusion of high-grade coronary

steno-ses in humans looked at the relative

ef-fects of intravenously administered

placebo, glimepiride, or glyburide (223)

The researchers measured mean ST

seg-ment shifts and time to angina The

re-sults again demonstrated suppression of

the myocardial preconditioning by

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

per-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 ated the relative functional cardiac effects

evalu-of 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 effects

of 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 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 previous

inde-MI The researchers looked for 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 on

subse-a compsubse-arison with sulfonyluresubse-as.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 type

2 diabetes treated with sulfonylureas sus other therapies (237)

ver-None of the studies looking at 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 presentation

sulfo-to 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 the

inpatient setting Their long action and

predisposition to hypoglycemia in

pa-tients not consuming their normal

nutri-tion serve as relative contraindicanutri-tions to

routine use in the hospital for many

pa-tients (239) Sulfonylureas do not

gener-ally allow rapid dose adjustment to meet

the changing inpatient needs

Sulfonyl-ureas also vary in duration of action

be-tween individuals and likely vary in the

frequency with which they induce

hypo-glycemia (240)

Metformin

Metformin represents a second agent that

individuals are likely to be using as an

outpatient, with potential for

continua-tion as an inpatient There is a suggescontinua-tion

from the UKPDS that metformin may

have cardioprotective effects, although

the study was not powered to allow for a

comparison with sulfonylureas (241)

The major limitation to metformin

use in the hospital is a number of specific

contraindications to its use, many of

which occur in the hospital All of these

contraindications relate to a potentially

fatal complication of metformin therapy,

lactic acidosis The most common risk

factors for lactic acidosis in

metformtreated patients are cardiac disease,

in-cluding CHF, hypoperfusion, renal

insufficiency, old age, and chronic

pul-monary disease (242) In an outpatient

setting, using slightly variable criteria,

22–54% of patients treated with

met-formin have absolute or relative

contrain-dications to its use (242–245) One recent

report noted that 27% of patients on

met-formin in the hospital had at least one

contraindication to its use (246) In 41%

of these cases, metformin was continued

despite the contraindication This study

seemingly underestimates the usual

fre-quency of contraindications since it

iden-tified no individuals with CHF, a risk

factor that has been frequently noted in

many of the outpatient studies Not

sur-prisingly, a recent review of hospital

Medicare data found that 11.2% of

pa-tients with concomitant diagnoses of

dia-betes and CHF were discharged with a

prescription of metformin (247)

Recent evidence continues to indicate

lactic acidosis is a rare complication,

de-spite the relative frequency of risk factors

(248) However, in the hospital,where the

risk for hypoxia, hypoperfusion, and

re-nal insufficiency is much higher, it still

seems prudent to avoid the use of 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

met-ThiazolidinedionesAlthough thiazolidinediones have veryfew acute adverse effects (249,250), they

do increase intravascular volume, a ticular problem in those predisposed toCHF and potentially a problem for pa-tients with hemodynamic changes related

par-to admission diagnoses (e.g., acute nary ischemia) or interventions common

coro-in hospitalized patients The same study

of 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 strated that when exposed to high con-centrations of rosiglitazone, a monolayer

demon-of 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 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

signifi-In summary, each of the major classes

of 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

pharmacoki-Components of the insulin dose quirement defined physiologically In

re-the 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 provided

as discrete meals The insulin dose 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 fer to the amount of exogenous insulinper unit of time necessary to prevent un-checked gluconeogenesis and ketogenesis

re-An additional variable that mines total insulin needs in the hospital is

deter-an 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 factors

is 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 tween individuals (Fig 2)

be-Is the patient insulin deficient or non– insulin deficient? As in the outpatient

setting, a key component to providing 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

ef-Subcutaneous insulin therapy

Subcu-taneous insulin therapy may be used to

attain glucose control in most

hospital-ized patients with diabetes The

compo-n e compo-n t s o f t h e d a i l y i compo-n s u l i compo-n d o s e

requirement can be met by a variety of

insulins, depending on the particular

hos-pital situation Subcutaneous insulin

therapy is subdivided into programmed

or scheduled insulin and supplemental or

correction insulin (Table 3)

Scheduled insulin therapy This review

will use the term “programmed” or

“scheduled insulin requirement” to refer

to the dose requirement in the hospital

necessary to cover the both basal and

nu-tritional needs For patients who are

eat-ing discrete meals, it is appropriate to

consider the basal and prandial

compo-nents of the insulin requirement separately

Basal insulin therapy for patients who

are eating Subcutaneous basal insulin

can be provided by any one of several

strategies These include continuous

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 return

to 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 used

in very low doses, it can also be tered four times daily as an alternate way

adminis-to provide basal insulin action (253)

Prandial insulin therapy for patients who are eating Prandial insulin re-

placement has its main effect on 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 and

periph-an 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 insulin

is more accurately considered to haveboth basal and prandial components due

to 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 can

be a disadvantage since the timing ofmeals and the quantity of food is ofteninconsistent

Basal insulin therapy for patients who are not eating While not eating, pa-

tients who are not insulin deficient maynot require basal insulin Since reduction

of caloric intake may alter insulin 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 therapy

resis-is 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 intermittent nutritional intake Hospitalized pa-

tients may receive nutrition 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 timed

intermit-to match the intermittent nutritional intake

Illness-related or stress dose insulin therapy The illness-related insulin can

be 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, and

to later return to lower doses, it is 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

impor-Figure 2—Insulin requirements

in health and illness Components

of insulin requirement are divided into basal, prandial or nutritional, and correction insulin When writ- ing insulin orders, the basal and prandial/nutritional insulin doses are written as programmed (scheduled) insulin, and correc- tion-dose insulin is written as an algorithm to supplement the scheduled insulin (see online ap- pendix 2) Programmed and cor- rection insulin are increased to meet the higher daily basal and prandial or nutritional require- ments Total insulin requirements may 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) and

consensus from the authors.

changes in the scheduled insulin doses, asthe blood glucose levels dictate.

Correction-dose insulin therapy Also

called “supplemental” insulin, this 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-tient 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 timing

usu-of the food, the presence or absence usu-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 sulin doses be increased the following day

in-to accommodate the increased insulinneeds

Writing insulin orders An example of

an insulin order form that prompts thephysician to address all three components

of insulin therapy (i.e., basal, prandial,and correction dose) is provided (see on-line appendix 1 [available at http://care.diabetesjournals.org]) The formscan be incorporated into computerizedorder sets and other prompting methods

to reduce errors Practice guidelines for

using insulin under various clinical

cir-cumstances are summarized in Table 3

Intravenous insulin infusion The only

method of insulin delivery specifically

de-veloped for use in the hospital is

contin-uous intravenous infusion, using regular

crystalline insulin There is no advantage

to using insulin lispro or aspart in an

in-travenous insulin infusion The medical

literature supports the use of intravenous

insulin infusion in preference to the

sub-cutaneous route of insulin administration

for several clinical indications among

nonpregnant adults, including diabetic

ketoacidosis and nonketotic

hyperosmo-lar state (258 –275); general preoperative,

intraoperative, and postoperative care

(257,276 –290); the postoperative period

following heart surgery (142,196,198,

290,291); organ transplantation (297); or

cardiogenic shock (128,194,292–296)

and possibly stroke (147); exacerbated

hyperglycemia 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 2

diabetes (Table 4) (302–304) Some of

these settings may be characterized by, or

associated with, severe or rapidly

chang-ing insulin requirements, generalized

pa-tient edema, impaired perfusion of

subcutaneous sites, requirement for

pres-sor support, and/or use of total parenteral

nutrition In these settings the

intrave-nous route for insulin administration

sur-passes the subcutaneous route with

respect to rapidity of onset of effect in

controlling hyperglycemia, overall ability

to achieve glycemic control, and most portantly, nonglycemic patient outcomes

im-During intravenous insulin infusion used

to control hyperglycemic crises, cemia (if it occurs) is short-lived, whereas

hypogly-in the same clhypogly-inical setthypogly-ings repeated 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)

ad-Depending on the indication for 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 fusing dextrose simultaneously depends

in-on the blood glucose cin-oncentratiin-on 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, solutions

as dilute as 1 unit insulin per 10 ml mal saline may be used (306,307) Whenthe more dilute solutions are used, at least

nor-50 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 ate intravenous insulin infusion is contro-versial (265) The half-life 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 action

initi-of insulin, the initial priming bolus initi-of travenous insulin, if used, must be fol-lowed by maintenance insulin infusiontherapy (310,311)

in-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 䡠 kg⫺1䡠 h⫺1as 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

Indication

Strength of Evidence

Exacerbated hyperglycemia during high-dose glucocorticoid therapy E

Critically ill surgical patient requiring mechanical ventilation A

Dose-finding strategy, anticipatory to initiation or reinitiating of

subcutaneous insulin therapy in type 1 or type 2 diabetes

C

such as ⱖ2 units/h may be used when

hyperglycemia is present, when

pread-mission insulin requirements are high, or

if the patient has conditions predicting

the presence of insulin resistance Among

hyperglycemic type 1 and type 2 diabetic

patients who were otherwise well and

re-ceiving no concomitant intravenous

dex-trose, the prime determinants of the initial

hourly intravenous insulin requirement

are the initial plasma glucose and BMI

After attainment of normoglycemia, only

the BMI correlates with the hourly insulin

infusion requirement (313) It has been

argued that the maximum biologic effect

of insulin might be expected at infusion

rates of 10 units/h or less However, some

patients benefit from higher infusion rates

according to setting, and use of hourly

insulin infusion rates as high as 50 units/h

has 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 on

knowledge of the condition of the patient,

the blood glucose level, and the response

to previous therapy Blood glucose

deter-minations should be performed hourly

until stability of blood glucose level has

been demonstrated for 6 – 8 h; then, the

frequency of blood glucose testing can be

reduced to every 2–3 h To avoid

un-wanted excursions of blood glucose,

es-pecially when making corrective changes

in the insulin infusion rate, the

pharmaco-dynamics of intravenous insulin

adminis-tration and delay of tissue responsiveness

following attainment of a given blood

level of insulin must be considered If

concomitant infusion of dextrose is used,

caregivers must be alert to the effects of

abrupt changes of dextrose infusion rate

Well-conducted insulin infusion therapy

should demonstrate progressively smaller

oscillations of the hourly insulin infusion

rate and narrower excursions of blood

glucose, as the caregiver discovers the

hourly rate that will maintain

normogly-cemia for a given patient

Many institutions use insulin infusion

algorithms that can be implemented by

nursing staff (2,189,194,197,200,280,

298,301,304,307,314) Algorithms

should incorporate the concept that

maintenance requirements differ between

patients and change over the course of

treatment The algorithm should facilitate

communication between physicians and

nurses, achieve correction of

hyperglyce-mia in a timely manner, provide a method

to determine the insulin infusion rate quired to maintain blood sugars within adefined the target range, include a rule formaking temporary corrective increments

re-or 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 difficult

to 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, accompanied

by 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 taneous insulin therapy To maintain

subcu-effective blood levels of insulin, it is 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

nec-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 sions, and correction-dose calcula-

deci-tions The initial doses of scheduled

subcutaneous insulin are based on 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 stability

previ-or 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 duction of the correction dose at bedtime

re-is appropriate to reduce the rre-isk of turnal hypoglycemia For patients whoseinsulin requirements are unknown andwhose nutritional intake will be adequate,

noc-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/kg

or more for patients having type 2 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 calculated

diabe-by body weight should be reduced diabe-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 In

the perioperative period for all type 1 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

di-applied on the morning of surgery if the

morning glucose concentration exceeds

180 mg/dl

Appropriate use of insulin

self-management Recognition of the patient

rights, patient responsibilities, and the

importance of patient-oriented care are

critical to the care of diabetes (321–323)

In the ambulatory setting, patient

self-management has a favorable impact on

glycemic control and quality of life

(324,325) Using the tools of multiple

daily injections of insulin or CSII, patient

self-management has been shown to be

capable of improving glycemic control

and microvascular outcomes (326 –328)

In multiple-dose insulin therapy,

meal-time treatment with rapid-acting insulin

analog improves hypoglycemia and

post-prandial hyperglycemia in comparison

with conventional therapy in both type 2

(329) and type 1 diabetes (253,330 –

332) In comparison with conventional

management using intermediate-acting

insulin for basal effect, patients using

long-acting insulin analog for basal

insu-lin effect experience less overall or

noctur-nal hypoglycemia (333–336), better

control of fasting plasma glucose levels

(333,337), and lower HbA1clevels (333)

In CSII therapy, rapid-acting analogs

im-prove control for most patients (338 –

340) Use of advanced carbohydrate

counting and an insulin-to-carbohydrate

ratio have markedly enhanced the success

of patients to implement intensive

self-management (341) Patients familiar with

their own needs sometimes have

experi-enced adverse events or, perceiving threat

of adverse events, express frustration with

rigidity of hospital routine and delegation

of decision making to providers who are

less likely to understand their immediate

needs

Self-management in the hospital may

be appropriate for competent adult

pa-tients who have stable level of

conscious-ness and reasonably stable known daily

insulin requirements and successfully

conduct self-management of diabetes at

home, have physical skills appropriate to

successfully self-administer insulin,

per-form self-monitoring of blood glucose,

and have adequate oral intake

Appropri-ate patients are those already proficient in

carbohydrate counting, use of multiple

daily injections of insulin or insulin pump

therapy, and sick-day management The

patient and physician in consultation

with 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 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 Orders

de-to replace self-management with 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

provid-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 therapy

is 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 measured capillary or venous blood test and patient-performed capillary blood glucose test The capillary blood glucose test should be ⫾15% of the laboratory test.

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

self-● Patient is alert and is able to make appropriate decisions on insulin dose.

● All insulin administered by the patient and nurse is recorded in the medication record.

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

preventive strategies could potentially

include a provision, under protocol or by

physician order, to perform blood glucose

testing more frequently and, for falling

levels, to take preventive action

Special situations: TPN

Hyperglycemia 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 preexisting

type 2 diabetes not previously receiving

insulin therapy, 77% of patients required

insulin 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 of

insulin to the TPN is one option, but this

may require days to determine the correct

insulin dose (306) The use of a separate

intravenous insulin infusion brings most

patients within target within 24 h (364)

Two-thirds to 100% of the total number

of units of insulin used in the variable rate

infusion over the previous 24-h period

can subsequently be added to the

subse-quent TPN bag(s) (306,365)

Special situations: glucocorticoid

therapy

Glucocorticoids are well known to affect

carbohydrate metabolism They increase

hepatic 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 early

defect (369,370), and thus it is not

sur-prising that for hospitalized patients with

well-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 how

to best treat glucocorticoid-induced 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 will

hy-be a greater increase in prandial pared with basal insulin doses There are

com-no trials comparing the use of insulin pro or insulin aspart to regular insulin forthis situation

lis-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 should

be 1.2–1.5 g䡠 kg⫺1䡠 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 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, HbA1clevels 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

gly-There are no clinical trial data 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 planned

exam-or not, the subcutaneous insulin depot

Table 6—Conditions creating high risk for

hypoglycemia in patients receiving scheduled

● Unexpected transport from nursing unit

after rapid-action insulin given

● Reduction in corticosteroid dose