Journal of Critical Care (2010) 25, 84–89

A carbohydrate-restrictive strategy is safer and as efficient

as intensive insulin therapy in critically ill patients
José Raimundo A. de Azevedo MD ⁎, Leonardo Oliveira de Araujo RN,
Widlani Sousa da Silva RN, Renato Palácio de Azevedo
Intensive Care Units of Hospital São Domingos and Hospital Dr Clementino Moura, São Luis, Maranhão, Brazil

Keywords:
Abstract
Critical illness;
Purpose: The aim of this study is to compare the safety and efficacy of 2 different strategies for
Insulin;
glycemic control in critically ill adult patients.
Hypoglycemia;
Materials and Methods: A total of 337 patients were randomly assigned to a carbohydrate-restrictive
Intensive care;
strategy (group 1) through glucose-free venous hydration, hypoglycidic nutritional formula, and
Mortality
subcutaneous insulin if blood glucose level was higher than 180 mg/dL or to strict normalization of
blood glucose levels (80-120 mg/dL) with the use of insulin infusion (group 2).
Results: Patients in group 1 (n = 169) received 2 (0-6.5) units of regular insulin per day, whereas
patients in group 2 (n = 168) received 52 (35-74.5) units per day (P b .001). The median blood glucose
level was 144 mg/dL in group 1 and 133.6 mg/dL in group 2 (P = .003). Hypoglycemia occurred in 6
(3.5%) patients in group 1 and 27 (16%) in group 2 (P b .001) and was an independent risk factor for
neurological dysfunction and mortality.
Conclusions: A carbohydrate-restrictive strategy reduced significantly the incidence of hypoglycemia in
critically ill patients compared to intensive insulin therapy. Mortality and morbidity were comparable
between the 2 groups.
© 2010 Elsevier Inc. All rights reserved.

1. Introduction
Until recently, hyperglycemia was accepted and even
considered a beneficial adaptive response to critical illness.
Studies published in the 1980s had already shown the
correlation between hyperglycemia, morbidity, and mortality
in patients with acute brain injury [1], postoperative of
cardiac surgery [2], and acute myocardial infarction [3], A
meta-analysis of 32 studies relating acute post stroke blood
⁎ Corresponding author. Tel.: +55 98 32275735; fax: +55 98 32276798.
E-mail address: jrazevedo@elo.com.br (J.R.A. de Azevedo).
glucose levels to the outcome showed that the risk of death
during hospital stay was 3 times greater in patients with
hyperglycemia on admission [4].
In 2001, Van den Berghe et al [5] published a study that
radically modified the conventional approach of tolerating
high blood glucose levels in the critically ill patient.
Analyzing 1548 patients admitted to a surgical intensive
care unit (ICU) randomized to intensive insulin therapy (IIT),
with the aim of maintaining blood glucose levels between 80
and 110 mg/dL, or conventional glycemic control, the
authors have shown that the group submitted to IIT presented
expressive reduction in morbidity and mortality. Despite the

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Carbohydrate-restrictive strategy in critically ill patients
unquestionable results, the study analyzed patients admitted
to just 1 hospital and a population of surgical patients, most
of them postoperative of cardiac surgery. In spite of these
limitations, many entities started to recommend the use of IIT
in ICU patients [6,7].
In an observational study published in 2004, Krisley [8]
suggested that IIT improved the morbidity and mortality in
patients admitted to a general ICU.
Van den Berghe et al [9], in a study published in 2006
with 1200 patients admitted to a medical ICU using the same
protocol from 2001, showed much less expressive results.
Hospital mortality was not reduced by IIT, although the
analysis of a subgroup of patients that stayed for 3 days or
more in the ICU has shown a reduction in morbidity and
mortality. In this study, the occurrence of severe hypogly-
cemia was significantly high. In the group that stayed in the
ICU for more than 3 days and that received IIT,
hypoglycemia incidence reached 25%.
The VISEP (Efficacy of Volume Substitution and Insulin
Therapy in Severe Sepsis) study [10], designed to randomize
600 patients for IIT or standard glycemic control, was
interrupted after the enrolment of 488 patients. The reasons
were that no difference was seen in mortality and that there
was a significantly higher incidence of hypoglycemia in the
group that received IIT (17.0% vs 4.1%). Following this
same reasoning, the multicenter study GLUCONTROL [11],
designed to include 3500 patients, was interrupted when
1109 patients had been included. The reasons were the high
incidence of hypoglycemia and also the expressively higher
mortality in patients that presented with this complication.
Nowadays, the risk of hypoglycemia represents the major
limitation for the use of IIT in a higher-scale pattern in
critically ill patients. Strategies for glycemic control in ICU
involving the use of lower doses of insulin would represent
viable alternatives to benefit critically ill patients while
avoiding or minimizing the harmful effects of hypoglycemia
due to the use of high doses of insulin.
The objective of this study was to evaluate the safety and
efficacy of a carbohydrate-restrictive strategy (CRS) as
compared to IIT for glycemic control in critically ill patients,
assessing primarily the occurrence of hypoglycemia and
secondarily the mortality, incidence of infectious complica-
tions, and organ dysfunctions.
2. Materials and methods
Included in this study were all adult, nonpregnant,
patients admitted from July 1, 2004, to December 31,
2006, to a 20-bed multidisciplinary ICU of a general hospital
and to an 11-bed trauma center ICU, who had at least 2 blood
glucose levels above 150 mg/dL from 3 measurements
obtained in the first 12 hours after admission. Written
informed consent was obtained from the patient or a next of
kin. The study protocol was approved by the research ethical
committee of the Federal University of Maranhão.
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85
Patients were randomized to a CRS or to an IIT using
sealed envelopes. Randomization was performed according
to a computer-generated random number table.
Group 1 (CRS). Patients received intravenous hydration
with a glucose-free solution (Ringer III) and enteral nutritional
formula containing 33.3% carbohydrates, 16.7% proteins, and
50% lipids (Glucerna, Abbott Laboratories). These patients
received regular insulin subcutaneously 4 times daily, aiming
to maintain blood glucose levels less than 180 mg/dL, and in
stable patients, ideally less than 150 mg/dL.
Group 2 (IIT). Continuous intravenous insulin infusion
was adjusted to maintain glycemic levels less than 150 mg/dL,
and in stable patients, ideally between 80 and 120 mg/dL.
Patients were submitted to capillary glycemic measurements
every 2 hours. The insulin dose was adjusted according to an
algorithm run by nurses and overseen by physicians. These
patients received glucosaline (5% glucose + 0.9 NaCl)
hydration and enteral nutrition with a formula containing
45% carbohydrates, 17% proteins, and 38% lipids (Diason,
Nutricia Clinical Care Ltd).
2.1. Outcome measures
The primary outcome measure was the incidence of
hypoglycemia, defined as a blood glucose level 40 mg/dL or
less. Secondary outcome measures were ICU mortality,
infectious complications (pneumonia, urinary tract infection,
surgical infection, and catheter-related sepsis, defined
according to Centers for Disease Control (CDC) criteria),
length of ICU stay, and new, that is, not present at time of
randomization, organ dysfunctions defined as renal (need for
renal replacement therapies), pulmonary (need of mechanical
ventilation), hemodynamic (need of inotropic/vasopressor
drugs), neurological (Glasgow coma score b9, if N13 before
randomization), and hepatic (total bilirubin levels N2.0 mg/dL
and transaminases higher than 2 times the normal value).
2.2. Statistical analysis
Data are presented as means ± standard deviation or
medians with interquartile intervals. The χ2 test was used to
evaluate the association between categorical variables and the
Student t test or Mann-Whitney U test for continuous variables.
Multivariate logistic regression analysis was performed to
evaluate the impact of age, sex, diabetes, group, APACHE
(Acute Physiology and Chronic Health Evaluation) III score,
and hypoglycemia on mortality and neurological dysfunc-
tion. We also evaluated the impact of age, sex, diabetes,
group, APACHE III score, and organ dysfunction on the
occurrence of hypoglycemia through the same model of
logistic regression. The significant differences identified in
the multivariate logistic regression analysis were submitted
to the odds ratio (OR) estimation, with the respective
confidence interval (CI). All statistical tests were 2-sided and
were considered to be significant at P b .05. SAS version
9.1.3 (SAS Institute, Cary, NC) was used for all analyses.
86 J.R.A. de Azevedo et al.

3. Results 144 (123-174.2) mg/dL compared to 133.6 (119.7-153.3)

3.1. Study population
Three hundred fifty-one patients were submitted to
randomization. Fourteen were excluded from the analysis.
Two patients were excluded after randomization due to
withdrawal of consent (G1 = 1, G2 = 1), 9 patients died (G1 =
5, G2 = 4), and 2 patients were discharged (G1 = 2) less than
12 hours after randomization. One patient was excluded due
to having terminal cancer (G1). Thus, 337 patients were
analyzed, 169 in group 1 and 168 in group 2. Sixty percent of
the patients were medical, 25% were surgical, and 15% were
trauma victims. Both groups were comparable regarding age,
sex, APACHE III score, and prevalence of diabetes. There
was also no difference between the 2 groups regarding
nosologies (Table 1). The analysis by intention to treat also
did not show a significant difference in demographic data
between the 2 groups.
A total of 201 (57.2%) patients remained in the ICU for
more than 5 days, 103 from group 1 and 98 from group 2. In
this subgroup of patients, as well as in the general
population, both treatment strategies were comparable
regarding demographic data.
3.2. Blood glucose levels, insulin therapy,
and hypoglycemia
Patients in group 1 (n = 169) received 2 (0-6.5) units of
insulin per day, whereas patients in group 2 (n = 168)
received 52 (35-74.5) units of regular insulin per day (P b
.001). The median blood glucose level in group 1 was
mg/dL in group 2 (P = .003). The 2 groups did not differ
regarding the time they started nutritional support, as well as
regarding the percentage of nutritional requirements they
received by the end of the third day of ICU (Table 2).
Hypoglycemia (defined as blood glucose level below 40 mg/
dL) occurred in 27 (16%) patients in the IIT group and in 6
(3.5%) patients from CRS group (P b .001). The intention-to-
treat analysis has also shown an expressively higher
incidence of hypoglycemia in the IIT group (G1 = 3.9%,
G2 = 15.1%; P b .001).
In the subgroup of patients that remained in the ICU for
more than 5 days, the dose of regular insulin per day and
blood glucose levels, as well as the incidence of hypogly-
cemia in the CRS and IIT, accompanied the tendencies of the
general group. The median length of insulin use (G1= 9 days,
G2= 7 days; P = .06) were similar (Table 2).
The logistic regression analyses showed that hypoglyce-
mia was an independent risk factor for death (OR, 4.66; CI
95%, 2.2-9.7; P = .001) and neurological dysfunction (OR,
3.42; CI 95%, 1.4-8.0; P = .023). Risk factors for
hypoglycemia, detected by multivariate regression analyses,
were group (OR, 5.20; CI 95%, 2.0-12.0; P b .001), an
APACHE III score greater than 50 (OR, 6.71; CI 95%, 1.6-
28.6; P = .001), and respiratory failure (OR, 4.13; CI 95%,
1.9-8.7; P = .002) (Table 4).
3.3. Mortality, infectious complications,
and organ dysfunctions
Forty-two (25%) patients in the CRS group died during
their ICU stay, as compared with 38 (22.6%) patients from

Table 1 Baseline characteristics of the patients

All patients Group in ICU N5 d
CRS IIT P CRS IIT P
(group 1, n = 169) (group 2, n = 168) (group 1, n = 103) (group 2, n = 98)
Age (y) 56.1 ± 20.4 56.4 ± 21.0 .9 55.3 ± 20.4 56.4 ± 22.0 .7
Sex, male/female 89/80 93/75 .6 55/48 56/42 .5
APACHE III score, mean ± SD 66.9 ± 29.0 67.8 ± 24.1 .9 67.1 ± 26.5 74.1 ± 23.8 .06
Nosologies
Medical patients
Neurological disease 19 27 11 20
Pulmonary disease 23 16 17 7
Sepsis/Septic shock 12 22 14 17
Cardiovascular disease 20 9 13 7
Gastrointestinal disease 12 15 5 6
Others 17 13 10 6
Surgical patients
Trauma 21 28 13 17
Abdominal surgery 29 17 16 11
Neurosurgery 9 13 6 6
Orthopedic surgery 3 5 1
Others 5 6 2 1
Previous diabetes, n (%) 49 (28.9) 57 (33.9) .3 29 (28.1) 30 (30.6) .7

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Carbohydrate-restrictive strategy in critically ill patients 87

Table 2 Insulin therapy and blood glucose levels

All patients Group in ICU N5 d
CRS IIT P CRS IIT P
(group 1, n = 169) (group 2, n = 168) (group 1, n = 103) (group 2, n = 98)
Duration of insulin use (d)
Median 5 4 9 7
Interquartile range 2-10 3-8 0.2 6-14 5-9.2 .006
Insulin dose (IU/d)
Median 2 52 2.1 56.5
Interquartile range 0-6.5 35-74.5 b.001 0.1-6 42-75.7 b.001
Blood glucose levels (mg/dL)
Median 144.0 133.6 148.0 133.6
Interquartile range 123.9-174.2 119.7-153.3 .003 128.7-174 118.9-149.7 .001
Hypoglycemia, n (%) 6 (3.5) 27 (16.0) b.001 5 (4.8) 22 (22.4) b.001
Nutritional support
At third day, n (% CR) 80 (88.8) 97 (92.3) .4 60 (85.7) 69 (89.6) .4
% CR indicates % caloric requirements patients were receiving.

IIT group (P = .6). Likewise, no differences were seen 4. Discussion

between the groups regarding infectious complications and
organ dysfunctions (Table 3). For the intention-to-treat
analysis, there was no difference in mortality between the
2 groups (G1 = 23.4%; group 2 = 26.4%; P = .49).
Among patients that remained in the ICU for more than
5 days, no differences were seen between CRS and IIT
regarding infectious complications, organ dysfunctions,
and mortality.
In a multivariate logistic-regression model, the inde-
pendent determinants of mortality were hypoglycemia and
an APACHE III score greater than 50. Using the same
model, the independent risk factors for neurological
dysfunction were age greater than 65 years and hypogly-
cemia (Table 4).
In this study, involving 2 ICUs with mixed populations
(medical, surgical, and trauma patients), the use of a CRS
aiming for glycemic control was comparable to IIT regarding
mortality and morbidity and was associated with a much
lower incidence of hypoglycemia.
We must emphasize that our study did not intend to
compare IIT to no glycemic control at all but to compare 2
strategies for glycemic control in critically ill patients. In 1
group, the control of blood glucose levels was obtained
using a glucose-free solution for intravenous hydration,
early enteral nutrition with a hypoglycidic formula, and
subcutaneous regular insulin when blood glucose level
surpassed 180 mg/dL. In the other group, we used high

Table 3 Mortality and morbidity

All patients Group in ICU N5 d
CRS IIT P CRS IIT P
(group 1, n = 169) (group 2, n = 168) (group 1, n = 103) (group 2, n = 98)
Death, n (%) 42 (25.0) 38 (22.6) .6 31 (30.3) 25 (25.5) .4
LOS in ICU days
Median 8 7 13 12
Interquartile range 4-14 4-15 .9 8-20 9-24 .7
Infectious complications
Pneumonia, n (%) 44 (26.0) 46 (27.3) .7 42 (40.7) 43 (43.8) .6
Urinary tract infection, n (%) 16 ( 9.4) 11 (6.5) .3 16 (15.5) 11 (11.2) .3
Surgical infection, n (%) 16 (9.4) 15 (8.9) .8 14 (13.5) 14 (14.2) .8
Catheter related, n (%) 8 (4.7) 10 (5.9) .6 8 (7.7) 10 (10.2) .5
Organ dysfunctions
Hemodynamic, n (%) 34 (20.1) 35 (20.8) .8 30 (29.1) 28 (28.5) .9
Pulmonary, n (%) 37 (21.8) 29 (17.2) .2 30 (29.1) 23 (23.4) .3
Neurologic, n (%) 21 (12.4) 18 (10.7) .6 18 (17.4) 15 (15.3) .6
Renal, n (%) 17 (10.0) 16 (9.5) .8 15 (14.5) 14 (14.2) .9
Hepatic, n (%) 4 (2.3) 3 (1.7) .7 3 (2.9) 3 (3.0) .9
LOS = Length of ICU stay; UTI = tract infection.

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88
Table 4 Multivariate logistic regression analysis: risk of death, neurological dysfunction, and hypoglycemia
Variable Mortality
P OR (95% CI)
Group .083 NS
Diabetes .391 NS
Sex(male) .014 1.67 (1.0-2.8)
Age N65 y .833 NS
Hypoglycemia .001 4.66 (2.2-9.7)
APACHE III N50 b.001 7.76 (3.0-19.9)
Respiratory failure b.001 5,65 (3.2-10.1)
NS = Non significant.
doses of insulin to keep blood glucose levels within a strict
range of normal values.
In their 2001 study, Van den Berghe et al [5] showed a low
incidence of hypoglycemia in the IIT group although
markedly higher than in the control group (5.1% vs 0.7%).
On the other hand, Leuven's study with medical patients [9]
showed that 25% of patients who stayed in the ICU for 3
days or more presented hypoglycemia compared to only
3.9% in the control group (P b .001). In that study, the
logistic-regression analysis identified hypoglycemia as an
independent risk factor for death. The VISEP study [10]
interrupted the inclusion of new cases due to a higher
incidence of hypoglycemia in the IIT group when compared
with the control group (17.0% vs 4.1%; P b .001). The
multicenter study GLUCONTROL [11], designed to include
3500 patients, was also interrupted prematurely. The reasons
were the high incidence of hypoglycemia and also the
expressively higher mortality in patients that presented with
this complication.
Although Van den Berghe et al [12], in a recent study in
which they analyzed the pooled data of the 2 previous studies
(n = 2748), suggest that the occurrence of hypoglycemia has
not had an immediate impact on mortality and has resulted in
only transitory symptoms, Krinsley and Grover [13],
analyzing 102 critically ill patients that complicated with
severe hypoglycemia compared to 306 controls admitted to
the same ICU, showed that severe hypoglycemia more than
doubled the risk of death, and the mortality was higher even
in patients who presented only 1 episode of hypoglycemia.
In our study, patients submitted to IIT presented an
expressively elevated incidence of hypoglycemia when
compared to those submitted to the CRS. Moreover, the
multivariate logistic regression analysis showed that
hypoglycemia was an independent risk factor for the
mortality and neurological dysfunction outcomes. The risk
factors for hypoglycemia identified in our study were an
APACHE III score higher than 50 and the occurrence of
respiratory insufficiency.
It is well documented that hypoglycemia is harmful to the
central nervous system [14,15]. Many authors have been
arguing that when IIT is used, the frequent monitoring of the
blood glucose levels prevent the patient remaining hypogly-
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J.R.A. de Azevedo et al.
Neurological dysfunction Hypoglycemia
P OR (95% CI) P OR (95% CI)
.153 NS b.001 5.20 (2.0-12.0)
.988 NS .113 NS
.435 NS .528 NS
.012 2.57 (1.3-5.0) .064 NS
.023 3.42 (1.4-8.0) – –
.421 NS .006 6.71 (1.6-28.6)
b.0001 9.00 (4.3-18.6) .002 4.13 (1.96-8.74)
cemic for long periods, reducing the risk of harmful effects
on the central nervous system. However, there are no studies
analyzing the cognitive adverse effects of hypoglycemia in
the mid and long terms. The authors limit themselves to
informing that the incidence of convulsion and hypoglyce-
mic coma is very low. In our study, the logistic regression
analysis identified hypoglycemia as an independent risk
factor for neurological dysfunction, defined by worsening on
the Glasgow Coma Scale score after the inclusion of the
patient in the protocol.
Some authors [16,17] have suggested that to maintain the
benefits of IIT reducing the incidence of hypoglycemia, the
maintenance of blood glucose levels within more elevated
limits than those proposed by the Leuven's group must be
evaluated, although Van den Berghe et al [18] have shown
that when comparing patients with glycemic levels between
80 and 110 mg/dL to those with blood glucose between 110
and 150 mg/dL, the benefits are more evident on the group
submitted to the strict control.
There has been a lack of initiatives aiming to search for
alternative methods of glycemic control that do not involve
the use of high doses of insulin with the objective of
maintaining the blood glucose levels within normal limits.
Dechelotte et al [19] compared critically ill patients submitted
to parenteral nutrition with or without addition of glutamine
and observed an expressive reduction on the incidence of
infectious complications and on the need of insulin to keep
adequate blood sugar levels in the group that received
glutamine. They attributed the better glycemic control to the
known effects of glutamine to improve the sensitivity to
insulin and also increase the endogenous secretion of the
hormone. As well as not being an applicable intervention for
most ICU patients, intravenous glutamine is expensive and
not available in many places. In a recent literature review,
Seematter and Tappy [20] suggests that lowering the glucose
load with the use of diabetic formulas or carbohydrates that
are metabolized independently from insulin may result in
glycemic control while minimizing the risks of hypoglycemia
and the high blood glucose levels variability, often observed
with the use of high doses of insulin.
A limitation of our study is that we have not analyzed the
impact of the blood glucose variability on morbidity and
Carbohydrate-restrictive strategy in critically ill patients
mortality. Some retrospective studies [21-23] suggest that this
variability is independently associated with increased
hospital mortality. The impact of the blood glucose variability
on mortality is significant even when it occurs between limits
of blood glucose levels that are considered to be appropriate.
The 2001 study by Leuven's group has closed an era of
permissive hyperglycemia in the critically ill patient. On the
other hand, it has brought some issues that must be addressed
to light:
– What level of blood glucose control is considered ideal
to achieve the most benefit combined with the lowest
risk of hypoglycemia?
– Which nosologies really get benefits from the strict
glycemic control?
– Is IIT the best method to control blood glucose in the
critically ill patient?
5. Conclusions
Our study analyzes an alternative approach for glycemic
control in patients admitted to the ICU, with a strategy of
restricting carbohydrate intake, and has shown that it is
possible to maintain the blood glucose levels within
acceptable limits, with lower incidence of hypoglycemia,
identified as a risk factor for mortality and neurological
dysfunction. Results regarding mortality, infectious compli-
cations, and organ dysfunctions were comparable between
the 2 groups. This much simpler strategy for glycemic
control may even be extended to the hospital ward.
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