Experimental and clinical evidences for glucose control in intensive care: is infused glucose the key point for study interpretation?
Experimental and clinical evidences for glucose control in intensive care: is infused glucose the key point for study interpretation?
Aurlien Mazeraud 3 4
Andrea Polito 0 1 2 4 5
Djillali Annane 0 1 2 5
0 Medical and Surgical Intensive Care Unit, CHU Raymond Poincare (AP-HP), University of Versailles Saint Quentin en Yvelines , 104 boulevard Raymond Poincare, 92380 Garches , France
1 Universite de Versailles Saint-Quentin en Yvellines , 55 Avenue de Paris, 78000 Versailles , France
2 Medical and Surgical Intensive Care Unit, CHU Raymond Poincare (AP-HP), University of Versailles Saint Quentin en Yvelines , 104 boulevard Raymond Poincare, 92380 Garches , France
3 Universite Paris Descartes Sorbonne Paris Cite, Institut Pasteur , rue du Dr Roux, 75015 Paris , France
4 Institut Pasteur, Human Histopathology and Animal Models , Pr Chretien F, 28, rue du docteur Roux, 75015 Paris , France
5 Universite de Versailles Saint-Quentin en Yvellines , 55 Avenue de Paris, 78000 Versailles , France
Stress-induced hyperglycemia has been considered an adaptive mechanism to stress up to the first intensive insulin therapy trial, which showed a 34% reduction in relative risk of in-hospital mortality when normalizing blood glucose levels. Further trials had conflicting results and, at present, stress-induced hyperglycemia management remains non-consensual. These findings could be explained by discrepancies in trials, notably regarding the approach to treat hyperglycemia: high versus restrictive caloric intake. Stress-induced hyperglycemia is a frequent complication during intensive care unit stay and is associated with a higher mortality. It results from an imbalance between insulin and counter-regulatory hormones, increased neoglucogenesis, and the cytokine-induced insulin-resistant state of tissues. In this review, we summarize detrimental effects of hyperglycemia on organs in the critically ill (peripheric and central nervous, liver, immune system, kidney, and cardiovascular system). Finally, we show clinical and experimental evidence of potential benefits from glucose and insulin administration, notably on metabolism, immunity, and the cardiovascular system.
In an ICU, stress induces insulin resistance and
overproduction of glucose, resulting in a syndrome called
stressinduced hyperglycemia (SIH) . SIH is common during
critical illness and is associated with high mortality
[1-3]. Its incidence is approximately 50% in septic shock
 and 13% in surgical patients . Up to the beginning
of the 21st century, hyperglycemia was considered an
adaptive mechanism to stress. In 2001, the landmark
Leuven study by Van den Berghe and colleagues 
reported a 34% relative risk reduction of in-hospital
mortality when blood glucose was maintained at between 80
and 110 mg/dL. Since then, glucose metabolism during
critical illness has been the focus of an increasing
number of experimental and clinical studies. A decade later,
after seven additional major randomized control trials,
physicians remain confused about how to manage SIH.
The heterogeneity of studies includes differences in
population, ICU setting, staff experience, feeding
strategy, blood glucose monitoring, variability, definition of
hypoglycemia, insulin protocol, infusion site, its
continuation after ICU discharge, and finally differences in the
choice of the relevant major outcome. In the two
positive trials from Leuven, mean non-protein daily caloric
intake was approximately 20 kcal/kg per day, essentially
via glucose administration initially given intravenously:
up to 200 to 300 g/day in the 2001 trial, with a median
total daily insulin administration of 71 units (confidence
interval of 48 to 100). By contrast, in NICE-SUGAR
(Normoglycemia in Intensive Care Evaluation and
Surviving Using Glucose Algorithm Regulation), which
suggested increased mortality with intensive insulin therapy,
caloric intake was 11.04 6.08 kcal/kg per day, with
19.5% given intravenously, and cumulative mean daily
dose of insulin was 50.2 38.1 units per day . Thus,
there were two markedly different therapeutic
approaches - that is, intensive gluco- and insulin therapy
(liberal glucose intake, or the Leuven approach) and
intensive insulin therapy (IIT) (restrictive glucose intake,
or the NICE-SUGAR approach) . The aim of this
review is to discuss experimental evidence of organ injury
and insulin sensitivity during SIH and expose differences
in strategies for its control that include a liberal or a
rather restrictive glucose intake.
The risk associated with hyperglycemia
After several large clinical trials, there is still no
consensus on what blood glucose level (BGL) is too much.
Whereas the Leuven trial demonstrated deleterious
effects from uncontrolled glucose levels, subsequent trials
comparing strategies to control BGL reported conflicting
SIH is undoubtedly associated with mortality in stroke
, brain injury , and myocardial infarction 
patients; trauma, cardiothoracic surgery, thermally injured,
and mixed ICU patients ; and non-ICU hospitalized
patients. The aim of this section is to summarize current
knowledge about the mechanisms of hyperglycemia
Pathogenesis of stress-induced hyperglycemia
Critical illness is characterized by an imbalance between
insulin and endogenous or exogenous
counterregulatory hormones (glucagon and glucocorticoids). As
a result, glucose production is increased and its storage
is decreased secondary to downregulated glycogen
synthesis and enhanced glycogenolysis . In animal
models, adrenaline infusion induces hyperglycemia via
stimulation of hepatic and renal neoglucogenesis .
This pathway represents the major source of
endogenous glucose during critical illness .
SIH is also the consequence of insulin resistance .
Experimental data on the mechanisms of sepsis-induced
acute insulin resistance are scarce. Most of the
knowledge about the mechanisms of acute insulin resistance
comes from trauma/hemorrhage experimental models
and studies in type 2 diabetes . Under healthy
conditions, insulin binding to its receptor results in the
phosphorylation of insulin receptor substrates, which
transmit insulin metabolic and growth signals. One
major effector of the metabolic pathway is glucose
transporter family (GLUT) 4, which facilitates glucose
transport across cell membranes in muscle and adipose
tissue. During injury, inhibitor of kappa B kinase and
Jun B pathways are activated, leading to expression of
inflammatory markers such as TNF. First, Jun B negatively
regulates insulin receptor substrate and then TNF
downregulates GLUT 4 gene transcription . These
mechanisms could account for insulin resistance during sepsis
Whether this mechanism of response to aggression is
deleterious during critical illness is still a matter of
debate . In fact, insulin resistance is variable from one
tissue to another and appears to be moderate in the
heart and diaphragm but is major in skeletal muscles
and adipocytes . In fact, despite this insulin
resistance, glucose utilization is enhanced in sepsis secondary
to different GLUT overexpression .
Glucose transport across cell membranes is the
ratelimiting step of cellular glucose metabolism. Each GLUT
is characterized mostly by organ specificity, insulin
sensitivity, and the Michaelis constant (Km). Km is defined
as the transporters specific value of glycemia for which
50% of transport capacities are reached. These
characteristics (Table 1) could explain differences in organ
sensitivity to insulin and modulation of glucose uptake with
glycemia. This heterogeneity may be seen as a protective
effect of vital organs while placing other organs in a
Hyperglycemia is responsible for reactive oxygen
species (ROS) overproduction in diabetes via four major
pathways: advanced glycated endproduct release, de novo
indirect activation of C kinase protein, increased polyol,
and hexosamine pathway flux redox homeostasis .
On one hand, some ROS production can be essential for
immune cell respiratory burst to kill pathogens or for
endothelial cell functions. On the other hand, during
hyperglycemia, excess ROS may worsen organ failure
Hyperglycemia and the central nervous system
Brain cells are dependent on glucose to maintain their
membrane ionic gradient. However, the detrimental
cerebral effects of hyperglycemia have been observed in
critical illness [2,12,23].
Brain glucose metabolism has some particularities:
Glucose crosses bloodbrain barrier and cellular
membranes via a high-affinity and insulin-insensitive
process involving GLUT 1 and GLUT 3 .
Neurons and astrocytes cooperate to metabolize
carbohydrates, as suggested by lactate shuttles
between these cells.
During hypoxemic or hypoperfusion stress, GLUT 1
and 3 are upregulated (up to 300% in trauma) with a
subsequent increase in glucose uptake .
Hyperglycemia has been shown to enhance the
breakdown of the bloodbrain barrier via induction of matrix
metalloproteinase  and to induce apoptosis ,
mostly via enhanced superoxide production. Indeed, in
epidemiologic studies on stroke, hyperglycemia is
associated with edema, infarct size, mortality in non-diabetic
patients, and poor functional status at 1 year .
Nevertheless, trials aiming at controlling BGL in stroke,
subarachnoid hemorrhage , brain injury , and
neuro-intensive care  patients did not report
improved outcome with tight glucose control.
Hyperglycemia and the peripheral nervous system
Neuromyopathy is a frequent complication of critical
illness, such as septic shock and acute respiratory distress
Table 1 Summary of different glucose transporter characteristics
Bloodbrain barrier, astrocytes,
cardiomyocytes, liver, endothelium
Liver, kidney, beta pancreatic cells
Accounts for insulin resistance. Glycemia-dependent transporter
Rate-limiting step of glucose transport in brain. Upregulated
up to 1.7-fold in sepsis
Second important transporter in brain
GLUT, glucose transporter.
syndrome, with an incidence of up to 50% of patients
with these conditions. In the first Leuven study, the risk
of developing a critical illness neuromyopathy (CINM)
was lowered from 49% to 25% (P < 0.0001) in the
interventional group, facilitating weaning from mechanical
ventilation. The mechanisms of hyperglycemic
neuromyopathy are poorly understood and may involve
activation of apoptotic and inflammation pathways in
response to acute hyperglycemia in muscles  or ROS
overproduction as suggested in type 2 diabetic
neuropathy or CINM pathogenesis .
Hyperglycemia and other organs
In resting conditions, GLUT 2 is the predominant
transporter for glucose in hepatic parenchymal cells [24,31].
This low-affinity transporter modulates glucose
transport proportionally to BGL. After lipopolysaccharide
(LPS) stimulation, GLUT 2 decreases, whereas GLUT 1
increases , resulting in an enhanced insulin- and
glycemia-independent uptake of up to 2.4-fold [31,32].
Analyses of liver cells from the control group of the
Leuven study revealed dramatic lesions to the mitochondria.
These mitochondria abnormalities may result from
excessive glucose uptake, with subsequent overproduction
of ROS , which could have been diminished with
In the Leuven study, patients with normoglycemia had
almost 50% fewer bloodstream infections (7.8% versus
4.2%, P = 0.003) . Indeed, each step of the immune
response to stress is altered with hyperglycemia. First, in
diabetes, chronic high BGL induces overexpression of
surface and circulating cell adhesion molecules [34-36],
whereas LPS challenge is less effective in upregulating
cell adhesion molecules . This enhanced overall
immune cell adhesion paradoxically results in a less
effective chemotactism and transmigration capacity of
immune cells . Second, worse polymorphonuclear
killing capacities against pathogens, as assessed by
concentrations of lysosomal enzyme or burst respiratory
intensity, are observed when BGL is poorly controlled
with a dose-effect relationship in diabetes . Finally,
the production of chemokines and other
proinflammatory factors is decreased under hyperglycemic
In septic shock, GLUT 2 and 3 expressions are
decreased in the tubular epithelial cells of the kidney,
whereas GLUT 1 expression is increased. This may
account for enhanced glycosuria and acute renal failure
during septic shock . In the Leuven study, renal
replacement therapy was twice less frequent in patients
with normoglycemia, whereas insulin per se was
associated with worse renal outcome . This kidney
protection may result directly from lower BGL, since high BGL
directly inhibits transcription of an anti-apoptotic gene
in renal tubules  or from improvement in lipid
profile, ROS production, and endothelial protection .
Heart and endothelium
SIH has been shown to be an important prognostic
factor in acute coronary syndromes . The heart has a
remarkable ability to switch from free fatty acid
oxidation to carbohydrate oxidation under hypoxemic
conditions . During acute myocardial infarction, SIH
activates T cells in the atherosclerotic plaque and
increases tissue levels of inflammatory markers and nitric
oxide and ROS production, resulting in endothelial
dysfunction . Consequently, coronary blood flow and
reserve during myocardial infarction are impaired .
Furthermore, acute hyperglycemia increases infarct size
and suppresses cardioprotective signal transduction via
mitochondrial potassium ATP channel inhibition .
In shock, although BGLs are high, glucose represents
only 12% of substrate oxidation by cardiomyocytes .
Therefore, one could argue that hyperglycemia without
insulin infusion does not confer a metabolic benefit and
presents rather deleterious consequences on an ischemic
Analysis of critical differences between trials
In the Leuven studies, patients were given intravenous
glucose at 8 to 12 g/hour, with mean intravenous glucose
feeding of 120 g during the first 15 hours, to a goal of
200 to 260 g/day afterward. This study shows higher
intravenous glucose and insulin administration than in
any other study (Table 3), whereas epidemiologic studies
have shown that both are correlated with an increased
Other trials of glucose control in the ICU used lower
glucose intake and insulin doses. In none of these
studies did the experimental intervention achieve
maintenance of normal BGL like in the Leuven study.
NICESUGAR is the only study showing increased mortality
with tight BGL control. In that study, total caloric intake
was much lower than in the Leuven study. In the
Specialized Relative Insulin and Nutrition Tables (SPRINT)
study, a 35% lowering of hospital mortality for patients
with a long stay in the ICU (P = 0.02) was observed after
implementation of tight glucose control when glucose
was administered enterally to allow a caloric intake of
25 kcal/kg per day. Likewise, the cumulative insulin dose
per day was close to that observed in the experimental
group of the Leuven study (67.2 units in SPRINT versus
71 units). These findings are in line with the latest IIT
meta-analysis by Marik and Preiser , who suggested
Table 2 Trials calendar
that intravenous calorie administration plays a pivotal
role for improvement of outcome during IIT. In
contrast, the last Leuven trial, EPaNIC (Early versus late
Parenteral Nutrition in Intensive Care), showed that
parenteral nutrition administration to achieve a caloric
intake of 20 to 25 kcal/kg per day might be detrimental.
This raises the question of the effect of an exclusive and
important glucose infusion during IIT in critical illness.
It was then suggested that, in the Leuven trial,
difference in observed mortality was secondary to a higher
mortality in the control group due to an excessive
glucose load. Nevertheless, control mortality in the Leuven
study matched the mortality expected from estimation
of the EuroSCORE (European System for Cardiac
Operative Risk Evaluation). Secondly, a recent meta-analysis
suggested that intravenous glucose intake was an
independent predictive factor for good outcome in the
Leuven studies . But whether blood glucose control
or insulin administration mediated positive effects in this
study was not studied.
In 2003, Van den Berghe and colleagues 
performed a post-hoc analysis of their first study. The
authors showed that both total amount of infused insulin
and glycemic control were associated with lower
mortality (independently of age, delayed ICU admission, Acute
Physiology and Chronic Health Evaluation II score,
2001 The first Leuven RCT (1,548 patients) reported a 34% relative risk reduction in hospital mortality with maintenance of BGL of between 80 and
110 mg/dL .
2006 The second Leuven RCT (1,200 patients) confirmed a 10% absolute reduction in hospital mortality for long-stay medical ICU patients with
maintenance of BGL of between 80 and 110 mg/dL .
The VISEP study, with the same glycemic goals (537 patients with septic shock), was terminated prematurely because of an unacceptably high
incidence of hypoglycemia (17.0% versus 4.1%; P < 0.001) and no evidence for survival benefit at 90 days (39.7% versus 35.4%; P = 0.31) .
Arabi et al.  RCT (523 patients) also failed to show survival benefit (adjusted hazard ratio 1.09, 95% confidence interval 0.70 to 1.72) and
showed increased hypoglycemic rates (28.6% versus 3.1% of patients; P < 0.0001).
SPRINT (BGL goal of 72 to 110 mg/dL) is an observational study with historic control. Nutritional and insulin protocols provided less variable
and tighter glucose control (standard deviation of blood glucose was 38% lower compared with the retrospective control) with subsequent
improvement in organ failures and outcome for long-stay ICU patients: failure-free days were different (SPRINT = 41.6%; Pre-SPRINT = 36.5%;
P < 0.0001) .
2009 The NICE-SUGAR trial (6,104 mixed ICU patients) compared a strategy of BGL control of between 81 and 108 mg/dL versus a more liberal
strategy (<180 mg/dL). This RCT found an increase in mortality with IIT (27.5 versus 24.9; P = 0.02) and increased incidence of hypoglycemia (6.8%
versus 0.5%; P < 0.001) .
2010 COITTSS (509 patients with septic shock) compared a strategy of BGL control of between 80 and 110 mg/dL versus maintenance of BGL of
less than 150 mg/dL. This trial did not find any difference in in-hospital mortality between the two strategies (45.9% versus 42.9%; P = 0.05) .
BGL, blood glucose level; COITTSS, Corticosteroids and Intensive Insulin Therapy for Septic Shock; IIT, intensive insulin therapy; NICE-SUGAR, Normoglycemia in
Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation; RCT, randomized controlled trial; SPRINT, Specialized Relative Insulin and Nutrition
Tables; VISEP, Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis.
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reason for ICU admission, history of malignancy or
diabetes, and at-admission hyperglycemia). The strength of
association between the mortality rate and the mean
BGL seemed to be stronger than with the total daily
infused insulin . Nevertheless, no statistical
comparison was made between these factors in this study.
Furthermore, the respective effects of these two
entwined factors could be analyzed only in an
interventional study comparing gluco-insulinotherapy versus
tight glycemic control. Then a recent study by Arabi and
colleagues  with a 2 2 factorial design compared
IIT and permissive underfeeding (60% to 70% of daily
recommended caloric intake versus 90% to 100%). Their
study showed no mortality differences between groups
but was underpowered and non-blinded, and the
therapeutic goals were not achieved .
Finally, in 2011, the Leuven group performed the
EPaNIC study that evaluated the timing of parenteral
nutrition introduction. In that study, a strategy of early
parenteral nutrition initiation was performed with
administration of 400 kcal (100 g) at day 1 and 800 kcal at
day 2 exclusively via intravenous glucose administration,
and then a relay with mixed parenteral and enteral
nutrition was performed to achieve calculated daily
physiological caloric intake . The control group received
minimal glucose administration and enteral nutrition
was started at day 2 if oral intake was insufficient.
Results showed an increased rate of complications in the
parenteral nutrition group (infection and cholestasis),
whereas the late initiation of parenteral nutrition
resulted in a shorter duration of renal replacement
therapy, mechanical ventilation, and stay in the ICU. In that
study, the amount of administered glucose was three
times lower than in the 2001 study, and insulin doses
were also lower in both groups: 31 insulin units
(interquartile range (IQR) 19 to 48) in the control versus 58
insulin units (IQR 40 to 85) in the experimental group.
Furthermore, parenteral nutrition contains lipid at
recommended doses that could present detrimental effects
as fat oxidation is a high oxygen-consuming metabolic
pathway. A post-hoc analysis of EPaNIC concerning the
first 2 days in the ICU in that study before introduction
of parenteral nutrition might be of interest to clinicians
and help them determine whether high glucose
administration during IIT is beneficial for patients. We will
present clinical and experimental evidence that may
support the use of a glucose-insulin administration strategy.
Is gluco-insulinotherapy associated with a decreased
incidence of hypoglycemia?
The clinical signs of hypoglycemia are commonly
masked in sedated patients. Thus, in clinical trials,
hypoglycemia was defined empirically by a BGL value of
less than 40 mg/dL. Its incidence varied from 5.1% to
18.7% in patients with IIT and from 0.5% to 4.1% in
control groups. Seizures and comas have occasionally been
observed following severe hypoglycemic episodes
without establishing a clear causal relationship .
Neuronal death during or following hypoglycemia has also
been found in both animal and human models, but
hypoglycemia does not seem to affect neurocognitive
development in children  but may contribute to
longterm cognitive impairment following critical illness in
adults . The existence of a direct causal link between
hypoglycemia and mortality remains controversial, and
hypoglycemia could reflect only a more severe illness.
Some epidemiologic studies have found that only early
or spontaneous hypoglycemia was independently
associated with death in critically ill patients [58,59].
Preventive interventions are thus warranted in such a situation.
Whether an increased daily amount of carbohydrate
administered would decrease the risk of hypoglycermia
during tight BGL is unknown.
In a retrospective study by Arabi and colleagues ,
glucose intake was not a risk or protective factor of
hypoglycemia whereas insulin daily dosage was an
evident risk factor (73.5 36.7 in the group presenting
hypoglycemia versus 47.5 51.8; P < 0.0001) .
Actually, caloric intake lowering (gastroparesis, intravenous
glucose, or enteral nutrition lowering) without insulin
adjustment may be one of the most frequent risk factors
for hypoglycemia [54,55,60,61], and no study evaluated
the effect of gluco-insulinotherapy on hypoglycemia rate.
The recent EPaNIC study showed a decreased rate of
hypoglycemia during IIT when early parenteral nutrition
was initiated (1.9% versus 3.5%, P = 0.001), suggesting a
possible protective role of gluco-insulinotherapy to be
explored in an interventional study .
Effects of high insulin and glucose intake on organs
Gluco-insulinotherapy consists of a high amount of
glucose infused and higher insulinemia. Effects of insulin
on glycemia lowering are mediated mostly by an increase
in cellular uptake of glucose through GLUT 4
translocation to the membrane. GLUT 4 is located mostly on
adipocytes and skeletal muscle cells . Thus, mostly
GLUT 4-expressing cells consume glucose administered
intravenously during IIT.
During early sepsis, metabolic stress resulted in
glycogenolysis and depleted energetic reserves as shown in
skeletal muscle biopsies [33,62]. This ATP depletion was
correlated with poor outcome, and in addition recovery
from sepsis was preceded by normalization of the
phosphocreatine/ATP ratio . Indeed, energy
depletion during sepsis could be a risk factor for CINM, an
ICU complication associated with higher mortality .
In fact, skeletal muscle protein levels were higher in the
IIT group consistently with anabolic effects of insulin
. Insulin augments the number of GLUT 4 receptors
in adipose and skeletal muscle cells and the glucose
uptake by myocytes . This higher amount of energetic
substrate may be a protective factor against energy
depletion and sarcopenia and may lower the risk to
develop CINM. These findings are in line with the
observed lower rate of CINM and the late improvement
in survival in the Leuven trials [4,11].
Experiments from the Leuven cohort showed that
maintenance of normal BGL protected the liver and
skeletal muscles. In the liver, glucose uptake through
GLUT 2 is independent of BGLs. Indeed, untreated
hyperglycemia was associated with severely damaged
mitochondria with altered complex I and IV activities
. Furthermore, insulin administration during injury
partly suppresses gluconeogenesis . Gluconeogenesis
is an active process occurring mostly in the liver that
requires four molecules of ATP and two molecules of
GTP. This energy requirement may enhance hypoxic
injury in liver during stress and could be counteracted
with insulin administration [64-66].
Whether gluco-insulinotherapy rather than BGL
control protects the liver from hypoxic injury has been
studied in few human and experimental studies. One study
conducted by a different group showed beneficial effects
of insulin independently of BGLs on hepatocyte
apoptosis, cytolysis, and expression of inflammatory markers
. Further studies in the Leuven group did not
reproduce these results and showed a lower blood level of
transaminases in burn-injured rabbits with BGL control
rather than insulin administration . Liver injury may
be mediated by a mitochondriopathy in reaction to
cellular hyperglycemia and enhanced glycolysis and is likely
to mediate organ damage . As insulin sensitivity is
not overcome during IIT in the liver, glucose uptake by
hepatocytes is likely to be dependent on glycemia rather
than insulinemia .
In sepsis models, insulin has been shown to improve
immune cell function independently of glycemia. It
inhibits the apoptosis of activated macrophages, may
modulate antigen presentation, and improves
chemotaxis and phagocytic properties. Finally, insulin may
modulate the balance between lymphocyte T helper type
and lymphocyte T helper type 2 cells, favoring
antiinflammation and repair function . Such effects of
insulin on the immune system may account for the
reduced rate of bloodstream infection during IIT .
During sepsis, the heart shows little or no insulin
resistance  and lowers its glucose consumption
[48,70]. In porcine models, glucose and insulin infusion
favored glucose and lactate utilization. This results in
improvement in inotropic function without higher
oxygen consumption observed in different studies [67,71].
In fact, during acute coronary syndrome, glucose insulin
potassium therapy was associated with substantial
survival and may prevent arrhythmias . However, the
benefit of glucose insulin potassium infusion in patients
with myocardial infarction remains controversial. In the
ICU, IIT was not associated with reduced time or doses
of inotropic support  and was associated with a higher
incidence of cardiovascular death in NICE-SUGAR ,
but the Leuven study introduced IIT with an important
amount of intravenous glucose administered to
cardiovascular post-surgical patients. Such an inotropic effect
may have improved organ perfusion and contributed to
the lower renal failure rate and the better outcome in
In summary, gluco-insulinotherapy may present
protective effects on muscle or improve immune or cardiac
function. Contrary to Marik and Bellomo  in their recent
comment, we hypothesize that gluco-insulinotherapy may
be a more beneficial rather than a restrictive strategy. This
issue needs to be further studied.
The era of glucose control in the ICU started in 2001.
Untreated SIH no doubt favors morbidity and mortality.
Critical analyses of randomized controlled trials have
suggested that glucose control is more likely to be
associated with survival benefit when strict normal glucose
levels are achieved and early high glucose intake is
provided. An interventional study evaluating liberal and
restrictive glucose intake during IIT is warranted to
provide reliable evidence.
BGL: blood glucose level; CINM: critical illness neuromyopathy; EPaNIC: Early
versus late Parenteral Nutrition in Intensive Care; GLUT: glucose transporter;
IIT: intensive insulin therapy; LPS: lipopolysaccharide;
NICESUGAR: Normoglycemia in Intensive Care Evaluation and Surviving Using
Glucose Algorithm Regulation; ROS: reactive oxygen species; SIH:
stressinduced hyperglycemia; SPRINT: Specialized Relative Insulin and Nutrition
Tables; TNF: tumor necrosis factor.
The authors declare that they have no competing interests.
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