Jurnal Hiperglikemia

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Ann N Y Acad Sci. 2010 November ; 1212: 111. doi:10.1111/j.1749-6632.2010.05805.x.
Management of hyperglycemia in hospitalized patients

Dawn Smiley and Guillermo E. Umpierrez
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
Abstract
Hyperglycemia is a common occurrence in hospitalized patients, and several studies have shown a
strong association between hyperglycemia and the risk of complications, prolonged
hospitalization, and death for patients with and without diabetes. Past studies have shown that
glucose management in the intensive care setting improves clinical outcomes by reducing the risk
of multiorgan failure, systemic infection, and mortality, and that the importance of hyperglycemia
also applies to noncritically ill patients. Based on several past observational and interventional
studies, aggressive control of blood glucose had been recommended for most adult patients with
critical illness. Recent randomized controlled trials, however, have shown that aggressive
glycemic control compared to conventional control with higher blood glucose targets is associated
with an increased risk of hypoglycemia and may not result in the improvement in clinical
outcomes. This review aims to give an overview of the evidence for tight glycemic control (blood
glucose targets <140 mg/dL), the evidence against tight glycemic control, and the updated
recommendations for the inpatient management of diabetes in the critical care setting and in the
general wards.
Keywords
inpatient hyperglycemia; guidelines; intensive care unit; general wards; hypoglycemia
Introduction
The prevalence of diabetes mellitus is steadily on the rise, such that nearly 1 in every 13
individuals in the United States is affected.1 In turn, the number of hospital discharges with
diabetes as any listed diagnosis has more than doubled between 1980 and 2006.2 Patients
with diabetes have a threefold greater chance of hospitalization compared to those without
diabetes,3,4 and it is estimated that 20% of all adults discharged have diabetes, with 30% of
them requiring two or more hospitalizations in any given year.3 The exact prevalence of
hospital hyperglycemia is not known, but it varies based on the definition used in previous
reports and the population studied. Observational studies have reported a prevalence of
hyperglycemia ranging from 32% to 38% in community hospitals,5,6 to 70% of diabetic
patients with acute coronary syndrome,7 and 80% of cardiac surgery patients in the
perioperative period.8,9 Although stress hyperglycemia typically resolves as the acute illness
or medico-surgical stress decreases, it is important to identify and track those patients that
are affected, as one small study showed that 60% of patients with admission hyperglycemia
had 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, Grady
Health System, 49 Jesse Hill Jr. Dr. SE, Atlanta, GA 30303. dsmiley@emory.edu.
Conflict of interest
The authors declare no conflicts of interest.
Smiley and Umpierrez
Page 2
There is a strong association between hyperglycemia and complications occurring in

hospitalized patients with and without a history of diabetes.5,1113 This association is well
documented not only upon admission, but also for the mean glucose level during the hospital
stay.1416 Cross-sectional studies have shown that the risk of complications and mortality
relates to the severity of hyperglycemia, with a higher risk observed inpatients without a
history of diabetes (new onset and stress-induced hyperglycemia) compared to those with a
known diagnosis. Evidence from observational studies indicates that development of
hyperglycemia in critically ill patients is associated with an increased risk of hospital
complications, mortality, and a higher total hospitalization cost.9,17,18 The importance of
hyperglycemia also applies to noncritically ill patients admitted to general medicine and
surgery services. In such patients, the presence of hyperglycemia is associated with
prolonged hospital stay, infection, disability after hospital discharge, and death.5,19,20 This
review aims to present updated recommendations for the in patient management of diabetes
in the critical care setting and in the general medicine/surgical wards.
Critical care setting
Several observational and prospective studies in hospitalized patients with and without
diabetes indicate that hyperglycemia is an independent predictor of poor outcome in
critically ill patients.5,16,2124 These studies link hyperglycemia with increased risk of
inpatient complications, prolonged hospitalization, and death. Falciglia and colleagues
dissected the data further in a retrospective cohort study of over 250,000 veterans admitted
to various intensive care units (ICUs) and found that in addition to inpatient hyperglycemia
being an independent risk for mortality, hyperglycemia-related risk varies with the
admission 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-heart
surgery and in the ICU setting with continuous insulin infusion (CII) significantly lowered
the 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 graft
and were treated with either subcutaneous insulin (SCI) or CII for hyperglycemia. Compared
to 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) had
significantly fewer deep sternal wound infections16 and a reduction in risk-adjusted
mortality by 50%.18 A follow-up analysis in a subset of this study population revealed that
patients with blood glucose levels >11.1 mmol/L (>200 mg/dL) had higher mortality than
those 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 decade
ago. 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 maintain
target BG levels 1011.1 mmol/L (180200 mg/dL) or intensive therapy to maintain target
blood glucose (BG) levels 4.46.1 mmol/L (80110 mg/dL). Compared to patients in the
conventional arm that had a daily BG average of 8.5 mmol/L (153 mg/dL), patients in the
intensive arm with a daily, average BG of 5.7 mmol/L (103 mg/dL) had significantly less
bacteremia, fewer antibiotic requirements, lower length of ventilator dependency, and an
overall 34% reduction in in-hospital mortality. When the data were further examined, it was
found that in addition to the above benefits, those patients that had exposure to at least 5
days 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 6.2
mmol/L (111 mg/dL) was just above the targeted range (4.46.1 mmol/L; 80110 mg/dL),
Page 3
these patients experienced less ICU and total hospital mortality after 3 days of treatment
with CII.17 These two studies together, based on the positive outcomes on morbidity and
mortality, suggested a glycemic target in the ICU of 4.46.1 mmol/L (80110 mg/dL).25,26
Recent RCTs and meta-analyses, however, have shown that this low BG target has been
difficult to achieve without increasing the risk for severe hypoglycemia.2730 In addition,
several multicenter trials have failed to show significant improvement in clinical outcome
and have even shown increased mortality risk with intensive glycemic control (Table
2).2731 The Glucontrol trial, a seven-country, multicenter RCT, randomized patients in
medical and surgical ICUs to tight glycemic control (BG 4.46.1 mmol/L; 80110 mg/dL)
versus conventional glycemic control (BG 7.810 mmol/L; 140180 mg/dL). The study was
discontinued prematurely due to protocol violations and safety concerns about
hypoglycemia in the intensive arm (threefold higher) and thus was underpowered. The time
spent at target BG, however, in each group was similar, and the investigators did not find a
significant difference in mortality between the two groups.32 The Efficacy of Volume
Substitution and Insulin Therapy in Sepsis (VISEP) study was another trial that attempted to
reproduce the data from the Leuven trial. The study was a multicenter study in Germany that
randomized patients with sepsis to receive CII therapy to maintain BG levels 1011.1 mmol/
L (180200 mg/dL), versus the intensive arm of 4.46.1 (80110 mg/dL).27 The
investigators evaluated differences between the groups in 28- and 90-day mortality, sepsisrelated 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 the
projected enrollment due to an interim analysis showing no difference in 28- or 90-day
mortality 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 that
patients in the intensive arm experienced a significantly greater amount of severe
hypoglycemia (12.1% vs. 2.1%).
The NICE-SUGAR trial, with over 6,000 subjects from three countries, stands as the largest
trial to determine if there is benefit in treating ICU hyperglycemia aggressively.33 The trial
randomized patients to receive either conventional glycemic control (BG < 10 mmol/L;
<180 mg/dL) or intensive glycemic control (4.56 mmol/L; 81108 mg/dL) and found that
in addition to there being no difference in the primary outcome of 90-day mortality, that
more 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 mortality
was 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 NICESUGAR trial compared to the Leuven trials; different nutritional strategies (more parenteral
nutrition in the Leuven trials); variability in devices, techniques, and frequency for blood
glucose measurements across many institutions; and varying levels of expertise in the
respective 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 glycemic
control recommended different glycemic targets in the ICU setting.25 Current guidelines
suggest targeting a BG level between 7.8 and 10.0 mmol/L (140 and 180 mg/dL) for the
majority of ICU patients and a lower glucose targets between 6.1 and 7.8 mmol/L (110 and
140 mg/dL) in selected ICU patients (i.e., centers with extensive experience and appropriate
nursing support, cardiac surgical patients, patients with stable glycemic control without
hypoglycemia). Glucose targets >10 mmol/L (>180 mg/dL) or <6.1 mmol/L (<110 mg/dL)
are not recommended in ICU patients.
Page 4
Noncritically ill patients

The importance of hyperglycemia also applies to noncritically ill patients admitted to

general medicine and surgery services. In such patients, hyperglycemia is associated with
poor hospital outcomes including prolonged hospital stay, infections, disability after hospital
discharge, and death.5,35 In a retrospective study of 1,886 patients admitted to a community
hospital, mortality in the general floors was significantly higher in patients with newly
diagnosed hyperglycemia and those with known diabetes compared to those who were
normoglycemic. (10% vs. 1.7% vs. 0.8%, respectively; P < 0.01).5 Admission
hyperglycemia has also been linked to worse outcomes in patients with community-acquired
pneumonia (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 of
mortality and complications than those with glucose < 11 mmol/L. The risk of in-hospital
complications 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 and
respiratory tract infection, the relative risk of death was 2.1 in those with a blood glucose of
78.9 mmol/L (126160 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 at
increased risk for adverse outcomes. In a case-control study, elevated preoperative glucose
levels increased the risk of postoperative mortality in patients undergoing elective
noncardiac nonvascular surgery.37 Patients with glucose levels of 5.611.1 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 had
serum glucose levels <12.2 mmol/L. A more recent study38 showed an increase of
postoperative infection rate by 30% for every 2.2 mmol/L (40 mg/dL) rise in postoperative
BG level above 50 mmol/L (110 mg/dL).
Complications due to hyperglycemia
The cause of stress hyperglycemia is multifactorial, likely due to a combination of acute

illness, medical treatments, and patient predilection that in turn leads to a physiologic rise in
counter-regulatory hormones, activation of the inflammatory cascade, and oxidative stress
(Table 3).39,40 Counter-regulatory hormones such as cortisol and epinephrine negatively
impact carbohydrate metabolism by increasing peripheral insulin resistance, increasing
hepatic gluconeogenesis and glycogenolysis, and decreasing insulin production.41,42
Elevations in mediators of inflammation and proinflammatory transcription factors are also
associated with episodes of hyperglycemia. Inflammatory mediators such as tumor necrosis
factor-alpha, and cytokine interleukin 1 inhibit postreceptor insulin signaling.39,43 The
activation of proinflammatory transcription factors intra-nuclear factor kappa B (NFB)
binding and activator protein-1 binding44,45 are linked to increased expression of genes that
produce proteins that mediate inflammation, platelet aggregation, apoptosis, and endothelial
dysfunction.45 Finally, reactive oxygen species from oxidative stress during acute illness
and hyperglycemia further lend to more hyperglycemia via damage to lipids, proteins, and
DNA.42,46 Of importance, investigators have noted that several of the hormonal and
proinflammatory aberrations associated with stress hyperglycemia return to normal after the
treatment with insulin and resolution of hyperglycemia.46 Insulin acts to suppress counterregulatory hormones, pro inflammatory transcription factors, and may even suppress the
formation of reactive oxidation species.47,48 Contrary to early literature suggesting that
insulin directly increases the risk of cardiovascular events,49 subsequent studies have shown
Page 5
more so that hyperinsulinemia is simply a marker of underlying insulin resistance

syndromes (i.e., metabolic syndrome and diabetes) that are associated with increased
cardiovascular morbidity and mortality.50 In fact, insulin can reverse variables such as
vasoconstriction, lipolysis, overproduction of free fatty acids, platelet aggregation, and
inflammation which increase cardiovascular risks.47,51 Thus, guided treatment of significant
hyperglycemia and the use of insulin in the inpatient setting appear to be tools for decreasing
the risks associated with increased morbidity and mortality associated with hyperglycemia.
In addition to avoiding extremes of glucose elevation to improve outcomes, several
investigators have linked extremes of glucose variability (GV) to endothelial dysfunction,
oxidative stress, and mortality.5255 In a retrospective study, Krinsley and colleagues
showed that mortality was threefold higher ICU patients with the lowest GV versus patients
with the highest GV (12.1% vs. 37.8%).56 Goyal and colleagues reported that in 1,469
subjects 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 180day mortality in nondiabetic patients.57 Although the relationship between GV and mortality
is consistent, GV targets have not yet been established and may differ for different patient
populations in the ICU setting.
Inpatient hyperglycemia in the ICU

In the critical care setting, a variety of intravenous infusion protocols have been shown to be
effective in achieving glycemic control with low rate of hypoglycemic event and in
improving hospital out-come.9,16,18,5861 Formal recommendations for the management of
inpatient 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 Diabetes
Association, and were published online in the June issues of Endocrine Practice and
Diabetes Care (Figure 1).25,26 The guidelines outline that insulin therapy, preferably with
validated intravenous CII protocols, should be initiated for treatment of persistent
hyperglycemia starting at a threshold of no greater than 10 mmol/L (180 mg/dL). Once
insulin therapy has been started, a glucose range of 7.8 81 mmol/L (140180 mg/dL) is
recommended for the majority of critically ill patients; however, more stringent targets may
be appropriate based on the clinical scenario and expertise of the medical staff. The
consensus panel stresses that patients should be monitored closely for hypoglycemia and
that the CII protocol should undergo modification as necessary for unexplained
hypoglycemia (<3.9 mmol/L; <70 mg/dL). Finally, the panel suggests less aggressive
therapy for patients that are terminally ill or have severe comorbidities.
Although hypoglycemia should be avoided and appears to be, just as hyperglycemia, a

marker of poor outcome, there has been no evidence indicating that ICU hypoglycemia
directly causes increased mortality.7,62 With a well-equipped and staffed medical team, the
consensus is that intensive insulin therapy via a CII protocol can be used effectively and
safely, and it is the opinion of the authors that the benefits of tight control (defined as blood
glucose <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 cardiovascular
insult, receive parenteral nutrition, or have hyperglycemia during the first 24 h of admission.
Recent meta-analyses of hyperglycemia studies suggest that patients with cardiovascular and
cardiac surgery may benefit more from tight glycemic control than conventional control in
the ICU. Two recent studies reporting on the impact of intensive glycemic control in the
outpatient setting and cardiovascular outcome were published in September 2009.63,64
These studies found that compared with conventional control, intensive glucose control
reduces the risk of nonfatal myocardial infarction but not cardiovascular death or all-cause
Page 6
mortality. The Griesdale meta-analysis of 26 studies with 13,567 patients (including the
NICE-SUGAR trial) showed that although associated with a significantly higher risk of
hypoglycemia, patients admitted to the surgical ICU had a mortality reduction of 40% with
intensive glycemic control (RR 0.63, CI 0.440.91).29 Thus, patientswith surgical
procedures, particularly open-heart surgeries, may be prime candidates for setting a target
BG goal of 5.67.8 mmol/L (100 140 mg/dL).
Treatment in the noncritical care setting
The use of insulin is the preferred therapeutic agent for blood glucose control in the hospital
setting. Of the three primary categories of oral agentssecretagogues (sulfonylureas and
meglitinides), biguanides,and thiazolidinediones none have been systematically studied
for inpatient use.20,65 The major limitation to the use of these oral antidiabetic agents for
hospital use is their slow onset of action that does not allow rapid glycemic control and/or
dose adjustment to meet the changing needs of the acutely ill patient. In addition, all three
groups have additional limitations that may limit their use for inpatient glucose control. A
long-standing controversy exists regarding the vascular effects of sulfonylureas in patients
with cardiac and cerebral ischemia.6669 Sulfonylureas inhibit adenosine triphosphate
(ATP)-sensitive potassium channels, resulting in cell membrane depolarization and
increased intracellular calcium concentration.70,71 This mechanism may inhibit ischemic
preconditioning and may lead to increased risk of vascular events. Sulfonylureas may also
increase the risk of hypoglycemia in the hospitalized patient with poor appetite or ordered
dietary restrictions. A large number of patients have one or more contraindications to the use
of metformin upon admission,72,73 including acute congestive heart failure, renal or liver
dysfunction, hypoperfusion, and chronic pulmonary disease. Finally, the use of
thiazolidinediones is limited as they can increase intravascular volume and may precipitate
or worsen congestive heart failure and peripheral edema.7376
No single insulin regimen meets the needs for all subjects with type 2 diabetes. Continuous
intravenous insulin therapy is effective at achieving and maintaining desired levels of
glycemic 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 compared
with historic controls. Patients treated with IV insulin experienced a shorter duration of
hyperglycemia without an increase in frequency of hyperglycemia.77 More recently, the
efficacy of CII was noted in 200 patients admitted to a general medicine or surgical service
that received CII for a target BG of 8.3 mmol/L (150 mg/dL). The glycemic goal was
achieved 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; < 40
mg/dL) occurred in 5% of patients, which is similar to hypoglycemia rates reported in CII
trials in critically ill patient populations.78
Scheduled SCI therapy with basal or intermediate acting insulin given once or twice a day in
combination with short or rapid acting insulin administered prior to meals is preferred as an
effective and safe strategy for glycemic management in noncritically ill patients. The
practice of discontinuing oral diabetes medications and/or insulin therapy and starting
sliding scale insulin (SSI) results in undesirable levels of hypoglycemia and
hyperglycemia.79,80 The SSI regimen, although straightforward and easy to use, is faced
with several challenges that include inadequate coverage of glycemic excursions and insulin
stacking.81 The safety of scheduled subcuntaneous (SC) basal bolus insulin has been
demonstrated in different studies in hospitalized patients with type 2 diabetes.82,83 In one
study that included insulin naive patients with type 2 diabetes, glycemic control was
achieved 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
Page 7
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 in
this study. Among patients randomized to SSI alone, 14% required rescue therapy with basal
bolus insulin due to persistent BG > 13.3 mmol/L (>240 mg/dL). A second study compared
two 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 therapy
prior to hospitalization. There were no significant differences in the levels of glycemic
control or in the frequency of hypoglycemia.
The recent Rabbit Surgery trial, a randomized multicenter study, compared the efficacy and
safety of improving glycemic control with a basal bolus regimen compared to sliding scale
regular 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 postoperative
complications including wound infection, pneumonia, respiratory failure, acute renal failure,
and bacteremia. Patients were randomized to receive basal bolus regimen with glargine and
glulisine at a starting dose of 0.5 unit/kg/day or SSI given 4 times/day. The basal bolus
regimen resulted in significant improvement in glycemic control and reduced the frequency
of the composite outcome. The results of the Rabbit Surgery trial indicate that treatment
with glargine once daily plus rapid-acting insulin before meals improves glycemic control
and reduces hospital complications compared to SSI in general surgery patients with type 2
diabetes.
Using these studies as a guide, the AACE/ADA outlines that insulin can be used to maintain
random BG levels <180 mg/dL for the majority of noncritically-ill patients. In conjunction
with this, premeal BG targets should generally be <140 mg/dL as long as they can be
achieved safely (Figure 2). A suggested method for determining starting doses of scheduled
insulin therapy in the non-critical care setting can be based on a patients body weight and
administered 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 nutritional
insulin in divided doses. Adjustments of insulin doses are based on results of bedside
glucose monitoring to achieve glycemic targets and minimize risks for hypoglycemia. An
alternative method for calculating the total daily insulin dose is based on the amount of
correction insulin administered over the preceding 24 h and distributing this into basal and
nutritional components.
Summary
Studies have clearly found that inpatient hyperglycemia is associated with poor outcomes
and that improved glycemic control can result in better clinical outcomes and reduce
mortality in certain clinical scenarios. What is not quite clear, however, is what the glucose
target cutoffs are for lack or gain of benefit. Intravenous insulin infusion is the preferred
regimen for critically ill patients in the ICU. Scheduled subcutaneous administration of
basal, nutritional, and correction components rather than the sole use of SSI is the preferred
method for achieving and maintaining glucose control in non-ICU setting. Oral antidiabetic
agents 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), and
potential reactions/toxicities associated with oral agents (i.e., metformin and IV contrast).
Several guidelines and position statements offer medical institutions evidence-based
guidelines for the management of inpatient hyperglycemia in both the ICU and non-ICU
settings; however, more research is needed to further delineate the patient populations that
would benefit most from tighter glycemic control and which insulin regimens are the safest
and most effective.
Page 8
Acknowledgments
Dr. Smiley receives research support from the National Institute of Health (K08 DK083036) and Clinical
Translational Science Award (M01 RR-00039). Dr. Umpierrez is supported by research grants from the American
Diabetes Association (7-07-CR-56), NIH/NCRR Clinical Translational Science Award (M01 RR-00039), and has
received research funding from Sanofi-Aventis.
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Page 13

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

Page 14

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


Med-surgical
ICU
Med-surgical
ICU
Med-surgical
ICU
De La Rosa, 2008
Glucontrol,
2009
NICE-SUGAR,
2009
Mixed
Mixed
Mixed
Mixed w/sepsis
Mixed, cardiac
surgery
Population
IT = intensive therapy; CT = conventional therapy.

Mixed = nondiabetics and diabetics.
Study underpowered due to premature discontinuation.
Medical ICU
Operating
room
Ghandi, 2007
VISEP, 2008
Setting
Study
4.56 mmol/L
versus 10
mmol/L
4.4 5.6 mmol/L

versus
1407.810
mmol/L
4.45.6 mmol/L
versus 1011.1
mmol/L
4.45.6 mmol/L
versus 1011.1
mmol/L
4.45.6 mmol/L
versus
< 11.1 mmol/L
Target BG
(IT vs. CT arm)
115 mg/dL versus

144 mg/dL
117 mg/dL versus

144 mg/dL
117 mg/dL versus

148 mg/dL
112 mg/dL versus

151 mg/dL
114 mg/dL versus

157 mg/dL
Mean BG achieved
(IT vs. CT arm)
Randomized control trials showing no benefit for tight glycemic control
No difference in
90-day mortality
No difference in
28-day
mortalitya
No difference in
28-day mortality or
infection rate
No difference in
28-day or 90-day
mortality,
end-organ
failure, LOSa
No difference in
mortality; in
stroke rate in IT
arm
Clinical outcome
Table 1
Page 15
Page 16
Table 2
Randomized control trials showing benefit of tight glycemic control85

Study
Setting
Population
Clinical outcome
Malmberg, 1995
CCU
Mixed
28% mortality
after 1 year
Furnary, 1999
CCU
DM undergoing CABG
65% reduction in deep sterna

wound infection rate
Van den Berghe, 2001
Surgical ICU
Mixed, with CABG
34% mortalitya
Furnary, 2003
CCU
DM undergoing CABG
50% reduction in adjusted

mortality rate
Krinsley, 2004
Med-surgical ICU
Mixed, noncardiac
29% reduction in mortality
Lazar, 2004
OR and ICU
DM with CABG
60% reduction of postoperative

atrial fibrillation
Van den Berghe, 2006
Medical ICU
Mixed
18% mortalitya
Intention-to-treat analysis
Mixed = nondiabetics and diabetics

Page 17
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 and

glycogenolysis,
lipolysis, insulin
secretion
Norepinephrine
gluconeogenesis (at high levels), lipolysis
Glucagon
gluconeogenesis and
glycogenolysis
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 in hospitalized patients

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2010 New York Academy of Sciences.

Smiley and Umpierrez

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There is a strong association between hyperglycemia and complications occurring in

Critical care setting

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Smiley and Umpierrez

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Smiley and Umpierrez

Noncritically ill patients

The importance of hyperglycemia also applies to noncritically ill patients admitted to

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Complications due to hyperglycemia

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The cause of stress hyperglycemia is multifactorial, likely due to a combination of acute

Smiley and Umpierrez

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more so that hyperinsulinemia is simply a marker of underlying insulin resistance

Inpatient hyperglycemia in the ICU

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Although hypoglycemia should be avoided and appears to be, just as hyperglycemia, a

Smiley and Umpierrez

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Treatment in the noncritical care setting

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Smiley and Umpierrez

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Smiley and Umpierrez

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Smiley and Umpierrez

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Smiley and Umpierrez

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38. Ramos M, Khalpey Z, Lipsitz S, et al. Relationship of perioperative hyperglycemia and

Smiley and Umpierrez

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Smiley and Umpierrez

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NIH-PA Author Manuscript

Smiley and Umpierrez

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

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Smiley and Umpierrez

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

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NIH-PA Author Manuscript

IT = intensive therapy; CT = conventional therapy.

Study underpowered due to premature discontinuation.