jurnal hiperglikemia

Management of hyperglycemia in hospitalized patients

Dawn Smiley and Guillermo E. UmpierrezDepartment of Medicine, Emory University School of Medicine, Atlanta, Georgia

AbstractHyperglycemia is a common occurrence in hospitalized patients, and several studies have shown astrong association between hyperglycemia and the risk of complications, prolongedhospitalization, and death for patients with and without diabetes. Past studies have shown thatglucose management in the intensive care setting improves clinical outcomes by reducing the riskof multiorgan failure, systemic infection, and mortality, and that the importance of hyperglycemiaalso applies to noncritically ill patients. Based on several past observational and interventionalstudies, aggressive control of blood glucose had been recommended for most adult patients withcritical illness. Recent randomized controlled trials, however, have shown that aggressiveglycemic control compared to conventional control with higher blood glucose targets is associatedwith an increased risk of hypoglycemia and may not result in the improvement in clinicaloutcomes. This review aims to give an overview of the evidence for tight glycemic control (bloodglucose targets <140 mg/dL), the evidence against tight glycemic control, and the updatedrecommendations for the inpatient management of diabetes in the critical care setting and in thegeneral wards.

Keywordsinpatient hyperglycemia; guidelines; intensive care unit; general wards; hypoglycemia

IntroductionThe prevalence of diabetes mellitus is steadily on the rise, such that nearly 1 in every 13individuals in the United States is affected.1 In turn, the number of hospital discharges withdiabetes as any listed diagnosis has more than doubled between 1980 and 2006.2 Patientswith diabetes have a threefold greater chance of hospitalization compared to those withoutdiabetes,3,4 and it is estimated that 20% of all adults discharged have diabetes, with 30% ofthem requiring two or more hospitalizations in any given year.3 The exact prevalence ofhospital hyperglycemia is not known, but it varies based on the definition used in previousreports and the population studied. Observational studies have reported a prevalence ofhyperglycemia ranging from 32% to 38% in community hospitals,5,6 to ∼70% of diabeticpatients with acute coronary syndrome,7 and ∼80% of cardiac surgery patients in theperioperative period.8,9 Although stress hyperglycemia typically resolves as the acute illnessor medico-surgical stress decreases, it is important to identify and track those patients thatare affected, as one small study showed that 60% of patients with admission hyperglycemiahad confirmed diabetes at 1 year.10

© 2010 New York Academy of Sciences.

Address for correspondence: Dawn Smiley, M.D., Assistant Professor of Medicine, Emory University School of Medicine, GradyHealth System, 49 Jesse Hill Jr. Dr. SE, Atlanta, GA 30303. [email protected].

Conflict of interestThe authors declare no conflicts of interest.

NIH Public AccessAuthor ManuscriptAnn N Y Acad Sci. Author manuscript; available in PMC 2013 August 05.

Published in final edited form as:Ann N Y Acad Sci. 2010 November ; 1212: 1–11. doi:10.1111/j.1749-6632.2010.05805.x.

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There is a strong association between hyperglycemia and complications occurring inhospitalized patients with and without a history of diabetes.5,11–13 This association is welldocumented not only upon admission, but also for the mean glucose level during the hospitalstay.14–16 Cross-sectional studies have shown that the risk of complications and mortalityrelates to the severity of hyperglycemia, with a higher risk observed inpatients without ahistory of diabetes (new onset and stress-induced hyperglycemia) compared to those with aknown diagnosis. Evidence from observational studies indicates that development ofhyperglycemia in critically ill patients is associated with an increased risk of hospitalcomplications, mortality, and a higher total hospitalization cost.9,17,18 The importance ofhyperglycemia also applies to noncritically ill patients admitted to general medicine andsurgery services. In such patients, the presence of hyperglycemia is associated withprolonged hospital stay, infection, disability after hospital discharge, and death.5,19,20 Thisreview aims to present updated recommendations for the in patient management of diabetesin the critical care setting and in the general medicine/surgical wards.

Critical care settingSeveral observational and prospective studies in hospitalized patients with and withoutdiabetes indicate that hyperglycemia is an independent predictor of poor outcome incritically ill patients.5,16,21–24 These studies link hyperglycemia with increased risk ofinpatient complications, prolonged hospitalization, and death. Falciglia and colleaguesdissected the data further in a retrospective cohort study of over 250,000 veterans admittedto various intensive care units (ICUs) and found that in addition to inpatient hyperglycemiabeing an independent risk for mortality, hyperglycemia-related risk varies with theadmission diagnosis such that individuals with cardiac diagnoses, sepsis, respiratory failure,and pulmonary embolism are at increased risk for mortality.14 More importantly, larger,milestone studies showed that aggressively controlling glucose levels after open-heartsurgery and in the ICU setting with continuous insulin infusion (CII) significantly loweredthe risk of these poor outcomes (Table 1).9,16,17 In a nonrandomized prospective study,Furnary followed 3,554 patients with diabetes that underwent coronary artery bypass graftand were treated with either subcutaneous insulin (SCI) or CII for hyperglycemia. Comparedto patients treated with SCI that had an average blood glucose of 11.9 mmol/L (214 mg/dL),patients treated with CII with an average blood glucose of 9.8 mmol/L (177 mg/dL) hadsignificantly fewer deep sternal wound infections16 and a reduction in risk-adjustedmortality by 50%.18 A follow-up analysis in a subset of this study population revealed thatpatients with blood glucose levels >11.1 mmol/L (>200 mg/dL) had higher mortality thanthose with blood glucose levels <11.1 mmol/L (<200 mg/dL) (5.0% vs. 1.8%, P < 0.001).16

The Leuven SICU study could likely be considered the main randomized controlled trial(RCT) that set the stage for aggressive glycemic control in the critical care setting a decadeago. This study randomized 1,548 patients admitted to the surgical ICU (63% cardiac cases,13% with diabetes, early parenteral nutrition use) to either conventional therapy to maintaintarget BG levels 10–11.1 mmol/L (180–200 mg/dL) or intensive therapy to maintain targetblood glucose (BG) levels 4.4–6.1 mmol/L (80–110 mg/dL). Compared to patients in theconventional arm that had a daily BG average of 8.5 mmol/L (153 mg/dL), patients in theintensive arm with a daily, average BG of 5.7 mmol/L (103 mg/dL) had significantly lessbacteremia, fewer antibiotic requirements, lower length of ventilator dependency, and anoverall 34% reduction in in-hospital mortality. When the data were further examined, it wasfound that in addition to the above benefits, those patients that had exposure to at least 5days of treatment with CII also had significantly fewer ICU days and lower ICU mortality.9

A similar study was performed by the same study group in the medical ICU setting (18%with diabetes) and during this trial, although the mean, daily BG in the intensive arm of 6.2mmol/L (111 mg/dL) was just above the targeted range (4.4–6.1 mmol/L; 80–110 mg/dL),

Smiley and Umpierrez

Ann N Y Acad Sci. Author manuscript; available in PMC 2013 August 05.

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these patients experienced less ICU and total hospital mortality after 3 days of treatmentwith CII.17 These two studies together, based on the positive outcomes on morbidity andmortality, suggested a glycemic target in the ICU of 4.4–6.1 mmol/L (80–110 mg/dL).25,26

Recent RCTs and meta-analyses, however, have shown that this low BG target has beendifficult to achieve without increasing the risk for severe hypoglycemia.27–30 In addition,several multicenter trials have failed to show significant improvement in clinical outcomeand have even shown increased mortality risk with intensive glycemic control (Table2).27–31 The Glucontrol trial, a seven-country, multicenter RCT, randomized patients inmedical and surgical ICUs to tight glycemic control (BG 4.4–6.1 mmol/L; 80–110 mg/dL)versus conventional glycemic control (BG 7.8–10 mmol/L; 140–180 mg/dL). The study wasdiscontinued prematurely due to protocol violations and safety concerns abouthypoglycemia in the intensive arm (threefold higher) and thus was underpowered. The timespent at target BG, however, in each group was similar, and the investigators did not find asignificant difference in mortality between the two groups.32 The Efficacy of VolumeSubstitution and Insulin Therapy in Sepsis (VISEP) study was another trial that attempted toreproduce the data from the Leuven trial. The study was a multicenter study in Germany thatrandomized patients with sepsis to receive CII therapy to maintain BG levels 10–11.1 mmol/L (180–200 mg/dL), versus the intensive arm of 4.4–6.1 (80–110 mg/dL).27 Theinvestigators evaluated differences between the groups in 28- and 90-day mortality, sepsis-related organ failure, ICU stay, and frequency of hypoglycemia (BG < 2.2 mmol/L; < 40mg/dL). Like the Glucontrol trial, the study was stopped after reaching only ∼2/3 of theprojected enrollment due to an interim analysis showing no difference in 28- or 90-daymortality between patients treated in the conventional arm versus those in the intensive arm(21.6% vs. 21.9%; 29.5 vs. 32.8%, respectively). The interim analysis also revealed thatpatients in the intensive arm experienced a significantly greater amount of severehypoglycemia (12.1% vs. 2.1%).

The NICE-SUGAR trial, with over 6,000 subjects from three countries, stands as the largesttrial to determine if there is benefit in treating ICU hyperglycemia aggressively.33 The trialrandomized patients to receive either conventional glycemic control (BG < 10 mmol/L;<180 mg/dL) or intensive glycemic control (4.5–6 mmol/L; 81–108 mg/dL) and found thatin addition to there being no difference in the primary outcome of 90-day mortality, thatmore aggressive glycemic control was associated with increased mortality at 90 days (24.9%vs. 27.5%, P = 0.02). The clinical question then shifted to whether the increased mortalitywas due to the increased frequency of hypoglycemia in the intensive arm (6.8% vs. 0.5%),and why the results of the NICE-SUGAR study were different of those in the Leuven trials.It has been suggested that the study outcomes differed due to a number of possible reasons,including less BG separation between the conventional and intervention groups in the NICE-SUGAR trial compared to the Leuven trials; different nutritional strategies (more parenteralnutrition in the Leuven trials); variability in devices, techniques, and frequency for bloodglucose measurements across many institutions; and varying levels of expertise in therespective units.34

Based on the results of recent trials, the American Association of Clinical Endocrinologist(AACE) and American Diabetes Association (ADA) task force on inpatient glycemiccontrol recommended different glycemic targets in the ICU setting.25 Current guidelinessuggest targeting a BG level between 7.8 and 10.0 mmol/L (140 and 180 mg/dL) for themajority of ICU patients and a lower glucose targets between 6.1 and 7.8 mmol/L (110 and140 mg/dL) in selected ICU patients (i.e., centers with extensive experience and appropriatenursing support, cardiac surgical patients, patients with stable glycemic control withouthypoglycemia). Glucose targets >10 mmol/L (>180 mg/dL) or <6.1 mmol/L (<110 mg/dL)are not recommended in ICU patients.



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Noncritically ill patientsThe importance of hyperglycemia also applies to noncritically ill patients admitted togeneral medicine and surgery services. In such patients, hyperglycemia is associated withpoor hospital outcomes including prolonged hospital stay, infections, disability after hospitaldischarge, and death.5,35 In a retrospective study of 1,886 patients admitted to a communityhospital, mortality in the general floors was significantly higher in patients with newlydiagnosed hyperglycemia and those with known diabetes compared to those who werenormoglycemic. (10% vs. 1.7% vs. 0.8%, respectively; P < 0.01).5 Admissionhyperglycemia has also been linked to worse outcomes in patients with community-acquiredpneumonia (CAP).21 In a prospective cohort multicenter study of 2,471 patients with CAP,those with admission glucose levels of > 11 mmol/L (198 mg/dL) had a greater risk ofmortality and complications than those with glucose < 11 mmol/L. The risk of in-hospitalcomplications increased 3% for each 1 mmol/L (18 mg/dL) increase in admission glucose.In a retrospective study of 348 patients with chronic obstructive pulmonary disease andrespiratory tract infection, the relative risk of death was 2.1 in those with a blood glucose of7–8.9 mmol/L (126–160 mg/dL), and 3.4 for those with a blood glucose of >9.0 mmol/L (>162 mg/dL), compared to patients with a blood glucose of 6.0 mmol/L (108 mg/dL).36

General surgery patients with hyperglycemia during the perioperative period are also atincreased risk for adverse outcomes. In a case-control study, elevated preoperative glucoselevels increased the risk of postoperative mortality in patients undergoing electivenoncardiac nonvascular surgery.37 Patients with glucose levels of 5.6–11.1 mmol/L (110–200 mg/dL) and those with glucose levels of >11.1 mmol/L (>200 mg/dL) had, respectively,1.7-fold and 2.1-fold increased mortality compared to those with glucose levels <5.6 mmol/L (<110 mg/dL). In another study, patients with glucose levels > 12.2 mmol/L (>220 mg/dL) on the first postoperative day had a rate of infection 2.7 times higher than those who hadserum glucose levels <12.2 mmol/L. A more recent study38 showed an increase ofpostoperative infection rate by 30% for every 2.2 mmol/L (40 mg/dL) rise in postoperativeBG level above 50 mmol/L (110 mg/dL).

Complications due to hyperglycemiaThe cause of stress hyperglycemia is multifactorial, likely due to a combination of acuteillness, medical treatments, and patient predilection that in turn leads to a physiologic rise incounter-regulatory hormones, activation of the inflammatory cascade, and oxidative stress(Table 3).39,40 Counter-regulatory hormones such as cortisol and epinephrine negativelyimpact carbohydrate metabolism by increasing peripheral insulin resistance, increasinghepatic gluconeogenesis and glycogenolysis, and decreasing insulin production.41,42

Elevations in mediators of inflammation and proinflammatory transcription factors are alsoassociated with episodes of hyperglycemia. Inflammatory mediators such as tumor necrosisfactor-alpha, and cytokine interleukin 1 inhibit postreceptor insulin signaling.39,43 Theactivation of proinflammatory transcription factors intra-nuclear factor kappa B (NFΚB)binding and activator protein-1 binding44,45 are linked to increased expression of genes thatproduce proteins that mediate inflammation, platelet aggregation, apoptosis, and endothelialdysfunction.45 Finally, reactive oxygen species from oxidative stress during acute illnessand hyperglycemia further lend to more hyperglycemia via damage to lipids, proteins, andDNA.42,46 Of importance, investigators have noted that several of the hormonal andproinflammatory aberrations associated with stress hyperglycemia return to normal after thetreatment with insulin and resolution of hyperglycemia.46 Insulin acts to suppress counter-regulatory hormones, pro inflammatory transcription factors, and may even suppress theformation of reactive oxidation species.47,48 Contrary to early literature suggesting thatinsulin directly increases the risk of cardiovascular events,49 subsequent studies have shown



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more so that hyperinsulinemia is simply a marker of underlying insulin resistancesyndromes (i.e., metabolic syndrome and diabetes) that are associated with increasedcardiovascular morbidity and mortality.50 In fact, insulin can reverse variables such asvasoconstriction, lipolysis, overproduction of free fatty acids, platelet aggregation, andinflammation which increase cardiovascular risks.47,51 Thus, guided treatment of significanthyperglycemia and the use of insulin in the inpatient setting appear to be tools for decreasingthe risks associated with increased morbidity and mortality associated with hyperglycemia.

In addition to avoiding extremes of glucose elevation to improve outcomes, severalinvestigators have linked extremes of glucose variability (GV) to endothelial dysfunction,oxidative stress, and mortality.52–55 In a retrospective study, Krinsley and colleaguesshowed that mortality was threefold higher ICU patients with the lowest GV versus patientswith the highest GV (12.1% vs. 37.8%).56 Goyal and colleagues reported that in 1,469subjects with acute myocardial infarction the baseline glucose and the 24-hour change,particularly a BG change of > 1.7 mmol/L (>30 mg/dL), were significant predictors of 180-day mortality in nondiabetic patients.57 Although the relationship between GV and mortalityis consistent, GV targets have not yet been established and may differ for different patientpopulations in the ICU setting.

Inpatient hyperglycemia in the ICUIn the critical care setting, a variety of intravenous infusion protocols have been shown to beeffective in achieving glycemic control with low rate of hypoglycemic event and inimproving hospital out-come.9,16,18,58–61 Formal recommendations for the management ofinpatient hyperglycemia in critically ill patients in the ICU setting were released on May 8,2009 by the American Association of Clinical Endocrinologists and the American DiabetesAssociation, and were published online in the June issues of Endocrine Practice andDiabetes Care (Figure 1).25,26 The guidelines outline that insulin therapy, preferably withvalidated intravenous CII protocols, should be initiated for treatment of persistenthyperglycemia starting at a threshold of no greater than 10 mmol/L (180 mg/dL). Onceinsulin therapy has been started, a glucose range of 7.8– 81 mmol/L (140–180 mg/dL) isrecommended for the majority of critically ill patients; however, more stringent targets maybe appropriate based on the clinical scenario and expertise of the medical staff. Theconsensus panel stresses that patients should be monitored closely for hypoglycemia andthat the CII protocol should undergo modification as necessary for unexplainedhypoglycemia (<3.9 mmol/L; <70 mg/dL). Finally, the panel suggests less aggressivetherapy for patients that are terminally ill or have severe comorbidities.

Although hypoglycemia should be avoided and appears to be, just as hyperglycemia, amarker of poor outcome, there has been no evidence indicating that ICU hypoglycemiadirectly causes increased mortality.7,62 With a well-equipped and staffed medical team, theconsensus is that intensive insulin therapy via a CII protocol can be used effectively andsafely, and it is the opinion of the authors that the benefits of tight control (defined as bloodglucose <140 mg/dL) may outweigh the deleterious effects in individuals that are healthier,are in the SICU, do not have severe renal failure or sepsis, have had an acute cardiovascularinsult, receive parenteral nutrition, or have hyperglycemia during the first 24 h of admission.

Recent meta-analyses of hyperglycemia studies suggest that patients with cardiovascular andcardiac surgery may benefit more from tight glycemic control than conventional control inthe ICU. Two recent studies reporting on the impact of intensive glycemic control in theoutpatient setting and cardiovascular outcome were published in September 2009.63,64

These studies found that compared with conventional control, intensive glucose controlreduces the risk of nonfatal myocardial infarction but not cardiovascular death or all-cause



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mortality. The Griesdale meta-analysis of 26 studies with 13,567 patients (including theNICE-SUGAR trial) showed that although associated with a significantly higher risk ofhypoglycemia, patients admitted to the surgical ICU had a mortality reduction of ∼40% withintensive glycemic control (RR 0.63, CI 0.44–0.91).29 Thus, patientswith surgicalprocedures, particularly open-heart surgeries, may be prime candidates for setting a targetBG goal of 5.6–7.8 mmol/L (100– 140 mg/dL).

Treatment in the noncritical care settingThe use of insulin is the preferred therapeutic agent for blood glucose control in the hospitalsetting. Of the three primary categories of oral agents—secretagogues (sulfonylureas andmeglitinides), biguanides,and thiazolidinediones— none have been systematically studiedfor inpatient use.20,65 The major limitation to the use of these oral antidiabetic agents forhospital use is their slow onset of action that does not allow rapid glycemic control and/ordose adjustment to meet the changing needs of the acutely ill patient. In addition, all threegroups have additional limitations that may limit their use for inpatient glucose control. Along-standing controversy exists regarding the vascular effects of sulfonylureas in patientswith cardiac and cerebral ischemia.66–69 Sulfonylureas inhibit adenosine triphosphate(ATP)-sensitive potassium channels, resulting in cell membrane depolarization andincreased intracellular calcium concentration.70,71 This mechanism may inhibit ischemicpreconditioning and may lead to increased risk of vascular events. Sulfonylureas may alsoincrease the risk of hypoglycemia in the hospitalized patient with poor appetite or ordereddietary restrictions. A large number of patients have one or more contraindications to the useof metformin upon admission,72,73 including acute congestive heart failure, renal or liverdysfunction, hypoperfusion, and chronic pulmonary disease. Finally, the use ofthiazolidinediones is limited as they can increase intravascular volume and may precipitateor worsen congestive heart failure and peripheral edema.73–76

No single insulin regimen meets the needs for all subjects with type 2 diabetes. Continuousintravenous insulin therapy is effective at achieving and maintaining desired levels ofglycemic control in noncritically ill patients outside of a critical care area.77,78 In one study,glycemic parameters in 156 noncritically ill patients treated with IV insulin were comparedwith historic controls. Patients treated with IV insulin experienced a shorter duration ofhyperglycemia without an increase in frequency of hyperglycemia.77 More recently, theefficacy of CII was noted in 200 patients admitted to a general medicine or surgical servicethat received CII for a target BG of 8.3 mmol/L (150 mg/dL). The glycemic goal wasachieved in 85% of patients; however, hypoglycemia (BG < 3.3 mmol/L; < 60 mg/dL)occurred at least once in 22% of patients, and severe hypoglycemia (BG < 2.2 mmol/L; < 40mg/dL) occurred in 5% of patients, which is similar to hypoglycemia rates reported in CIItrials in critically ill patient populations.78

Scheduled SCI therapy with basal or intermediate acting insulin given once or twice a day incombination with short or rapid acting insulin administered prior to meals is preferred as aneffective and safe strategy for glycemic management in noncritically ill patients. Thepractice of discontinuing oral diabetes medications and/or insulin therapy and startingsliding scale insulin (SSI) results in undesirable levels of hypoglycemia andhyperglycemia.79,80 The SSI regimen, although straightforward and easy to use, is facedwith several challenges that include inadequate coverage of glycemic excursions and insulinstacking.81 The safety of scheduled subcuntaneous (SC) basal bolus insulin has beendemonstrated in different studies in hospitalized patients with type 2 diabetes.82,83 In onestudy that included insulin naive patients with type 2 diabetes, glycemic control wasachieved more effectively with basal bolus insulin than with SSI.83 Mean glucose levels of <10 mmol/L (< 180 mg/dL) were achieved by the second day of hospitalization without an



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increase in the frequency of hypoglycemia in those randomized to the basal bolus regimen.The incidence of hypoglycemia, defined as a BG < 3.3 mmol/L (<60 mg/dL), was low inthis study. Among patients randomized to SSI alone, 14% required rescue therapy with basalbolus insulin due to persistent BG > 13.3 mmol/L (>240 mg/dL). A second study comparedtwo different basal bolus insulin regimens (detemir plus aspart vs. NPH plus regular insulin)in hospitalized patients with type 2 diabetes, some of whom were receiving insulin therapyprior to hospitalization. There were no significant differences in the levels of glycemiccontrol or in the frequency of hypoglycemia.

The recent Rabbit Surgery trial, a randomized multicenter study, compared the efficacy andsafety of improving glycemic control with a basal bolus regimen compared to sliding scaleregular insulin (SSI) in 211 patients with type 2 diabetes undergoing general surgery.84

Study outcomes included differences in daily BG levels and a composite of postoperativecomplications including wound infection, pneumonia, respiratory failure, acute renal failure,and bacteremia. Patients were randomized to receive basal bolus regimen with glargine andglulisine at a starting dose of 0.5 unit/kg/day or SSI given 4 times/day. The basal bolusregimen resulted in significant improvement in glycemic control and reduced the frequencyof the composite outcome. The results of the Rabbit Surgery trial indicate that treatmentwith glargine once daily plus rapid-acting insulin before meals improves glycemic controland reduces hospital complications compared to SSI in general surgery patients with type 2diabetes.

Using these studies as a guide, the AACE/ADA outlines that insulin can be used to maintainrandom BG levels <180 mg/dL for the majority of noncritically-ill patients. In conjunctionwith this, premeal BG targets should generally be <140 mg/dL as long as they can beachieved safely (Figure 2). A suggested method for determining starting doses of scheduledinsulin therapy in the non-critical care setting can be based on a patient’s body weight andadministered as a range of 0.3 to 0.5 units per kg as the total daily dose. Approximately 50%of the calculated dose can be administered as basal insulin and 50% as prandial or nutritionalinsulin in divided doses. Adjustments of insulin doses are based on results of bedsideglucose monitoring to achieve glycemic targets and minimize risks for hypoglycemia. Analternative method for calculating the total daily insulin dose is based on the amount ofcorrection insulin administered over the preceding 24 h and distributing this into basal andnutritional components.

SummaryStudies have clearly found that inpatient hyperglycemia is associated with poor outcomesand that improved glycemic control can result in better clinical outcomes and reducemortality in certain clinical scenarios. What is not quite clear, however, is what the glucosetarget cutoffs are for lack or gain of benefit. Intravenous insulin infusion is the preferredregimen for critically ill patients in the ICU. Scheduled subcutaneous administration ofbasal, nutritional, and correction components rather than the sole use of SSI is the preferredmethod for achieving and maintaining glucose control in non-ICU setting. Oral antidiabeticagents are typically not appropriate for most hospitalized patients due to potential nausea/appetite changes, unpredictable timing of meal delivery, variable diet status (i.e., NPO), andpotential reactions/toxicities associated with oral agents (i.e., metformin and IV contrast).Several guidelines and position statements offer medical institutions evidence-basedguidelines for the management of inpatient hyperglycemia in both the ICU and non-ICUsettings; however, more research is needed to further delineate the patient populations thatwould benefit most from tighter glycemic control and which insulin regimens are the safestand most effective.



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AcknowledgmentsDr. Smiley receives research support from the National Institute of Health (K08 DK083036) and ClinicalTranslational Science Award (M01 RR-00039). Dr. Umpierrez is supported by research grants from the AmericanDiabetes Association (7-07-CR-56), NIH/NCRR Clinical Translational Science Award (M01 RR-00039), and hasreceived research funding from Sanofi-Aventis.

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Figure 1.AACE/ADA target glucose level recommendations in the intensive care setting.26



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Figure 2.AACE/ADA target glucose level recommendations in the non-ICU setting.26



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Tabl

e 1

Ran

dom

ized

con

trol

tria

ls s

how

ing

no b

enef

it fo

r tig

ht g

lyce

mic

con

trol

Stud

ySe

ttin

gP

opul

atio

nT

arge

t B

G(I

T v

s. C

T a

rm)

Mea

n B

G a

chie

ved

(IT

vs.

CT

arm

)C

linic

al o

utco

me

Gha

ndi,

2007

Ope

ratin

gro

omM

ixed

, car

diac

surg

ery

4.4–

5.6

mm

ol/L

vers

us<

11.

1 m

mol

/L

114

mg/

dL v

ersu

s15

7 m

g/dL

No

diff

eren

ce in

mor

talit

y; ↑

inst

roke

rat

e in

IT

arm

VIS

EP,

200

8M

edic

al I

CU

Mix

ed w

/sep

sis

4.4–

5.6

mm

ol/L

vers

us 1

0–11

.1m

mol

/L

112

mg/

dL v

ersu

s15

1 m

g/dL

No

diff

eren

ce in

28-d

ay o

r 90

-day

mor

talit

y,en

d-or

gan

failu

re, L

OSa

De

La

Ros

a, 2

008

Med

-sur

gica

lIC

UM

ixed

4.4–

5.6

mm

ol/L

vers

us 1

0–11

.1m

mol

/L

117

mg/

dL v

ersu

s14

8 m

g/dL

No

diff

eren

ce in

28-d

ay m

orta

lity

orin

fect

ion

rate

Glu

cont

rol,

200

9M

ed-s

urgi

cal

ICU

Mix

ed4.

4 –5

.6 m

mol

/Lve

rsus

140−

7.8–

10m

mol

/L

117

mg/

dL v

ersu

s14

4 m

g/dL

No

diff

eren

ce in

28-d

ay

mor

talit

ya

NIC

E-S

UG

AR

, 2

009

Med

-sur

gica

lIC

UM

ixed

4.5–

6 m

mol

/Lve

rsus

≤ 1

0m

mol

/L

115

mg/

dL v

ersu

s14

4 m

g/dL

No

diff

eren

ce in

90-d

ay m

orta

lity

a Stud

y un

derp

ower

ed d

ue to

pre

mat

ure

disc

ontin

uatio

n.

IT =

inte

nsiv

e th

erap

y; C

T =

con

vent

iona

l the

rapy

.M

ixed

= n

ondi

abet

ics

and

diab

etic

s.


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Table 2

Randomized control trials showing benefit of tight glycemic control85

Study Setting Population Clinical outcome

Malmberg, 1995 CCU Mixed 28% ↓ mortalityafter 1 year

Furnary, 1999 CCU DM undergoing CABG 65% reduction in deep sternawound infection rate

Van den Berghe, 2001 Surgical ICU Mixed, with CABG 34% ↓ mortalitya

Furnary, 2003 CCU DM undergoing CABG 50% reduction in adjustedmortality rate

Krinsley, 2004 Med-surgical ICU Mixed, noncardiac 29% reduction in mortality

Lazar, 2004 OR and ICU DM with CABG 60% reduction of postoperativeatrial fibrillation

Van den Berghe, 2006 Medical ICU Mixed 18% ↓ mortalitya

aIntention-to-treat analysis

Mixed = nondiabetics and diabetics


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Table 3

Counter-regulatory hormones and mediators of inflammation associated with stress hyperglycemia41

Hormone Effect

Cortisol ↑ skeletal muscle IR, ↑lipolysis → substrate for ↑gluconeogenesis

Epinephrine ↑ skeletal muscle IR, ↑ gluconeogenesis andglycogenolysis,↑ lipolysis, ↓ insulinsecretion

Norepinephrine ↑ gluconeogenesis (at high levels), ↑ lipolysis

Glucagon ↑ gluconeogenesis andglycogenolysis

Growth hormone ↑ skeletal muscle IR, ↑gluconeogenesis, ↑ lipolysis

Inflammation mediators

Effect

Tumor necrosis factor

↑ skeletal and hepatic IR

Interleukin-1

Interleukin-6

IR = insulin resistance; TNF = tumor necrosis factor.


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management of hyperglycemia

hyperglycemiarelated

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