Tight blood glucose control: a recommendation applicable to any critically ill patient?
ABSTRACT The issue of tight glucose control with intensive insulin therapy in critically ill patients remains controversial. Although compelling evidence supports this strategy in postoperative patients who have undergone cardiac surgery, the use of tight glucose control has been challenged in other situations, including in medical critically ill patients and in those who have undergone non-cardiac surgery. Similarly, the mechanisms that underlie the effects of high-dose insulin are not fully elucidated. These arguments emphasize the need to study the effects of tight glucose control in a large heterogeneous cohort of intensive care unit patients.
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ABSTRACT: This manuscript attempts to review the effects associated with hyperglycaemia in critically ill patients and the effects of various insulin regimens. The available clinical findings and pertinent experimental data are examined. Intensive insulin therapy titrated to maintain blood glucose level between 4.4 and 6.1 mmol/l during intensive care unit stay has recently been shown to significantly decrease mortality, septic morbidity, sepsis-related organ failure, transfusion requirements and polyneuropathies. Prior studies have already documented that hyperglycaemia on admission is related to susceptibility to infections and worse outcomes following myocardial and cerebral ischaemic events. Additional effects of insulin, unrelated to the control of glycaemia, have also been reported. Intensive insulin therapy is probably warranted in most categories of critically ill patients, although some of the underlying mechanisms of its beneficial effects still need to be elucidated.Current Opinion in Clinical Nutrition and Metabolic Care 10/2002; 5(5):533-7. · 4.52 Impact Factor
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ABSTRACT: BACKGROUND: Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. METHODS: We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter [11.9 mmol per liter] and maintenance of glucose at a level between 180 and 200 mg per deciliter [10.0 and 11.1 mmol per liter]). RESULTS: At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conveN Engl J Med. 11/2001; 345:1359-1367.
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ABSTRACT: Maintenance of normoglycemia with insulin reduces mortality and morbidity of critically ill patients. Here we report the factors determining insulin requirements and the impact of insulin dose vs. blood glucose control on the observed outcome benefits. A prospective, randomized, controlled trial. A 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital. A total of 1,548 patients were randomly assigned to either strict normalization of blood glucose (80-110 mg/dL) with insulin infusion or the conventional approach, in which insulin is only given to maintain blood glucose levels at 180-200 mg/dL. It was feasible and safe to achieve and maintain blood glucose levels at <110 mg/dL by using a titration algorithm. Stepwise linear regression analysis identified body mass index, history of diabetes, reason for intensive care unit admission, at-admission hyperglycemia, caloric intake, and time in intensive care unit as independent determinants of insulin requirements, together explaining 36% of its variation. With nutritional intake increasing from a mean of 550 to 1600 calories/day during the first 7 days of intensive care, normoglycemia was reached within 24 hrs, with a mean daily insulin dose of 77 IU and maintained with 94 IU on day 7. Insulin requirements were highest and most variable during the first 6 hrs of intensive care (mean, 7 IU/hr; 10% of patients required >20 IU/hr). Between day 7 and 12, insulin requirements decreased by 40% on stable caloric intake. Brief, clinically harmless hypoglycemia occurred in 5.2% of intensive insulin-treated patients on median day 6 (2-14) vs. 0.8% of conventionally treated patients on day 11 (2-10). The outcome benefits of intensive insulin therapy were equally present regardless of whether patients received enteral feeding. Multivariate logistic regression analysis indicated that the lowered blood glucose level rather than the insulin dose was related to reduced mortality (p <.0001), critical illness polyneuropathy (p <.0001), bacteremia (p =.02), and inflammation (p =.0006) but not to prevention of acute renal failure, for which the insulin dose was an independent determinant (p =.03). As compared with normoglycemia, an intermediate blood glucose level (110-150 mg/dL) was associated with worse outcome. Normoglycemia was safely reached within 24 hrs and maintained during intensive care by using insulin titration guidelines. Metabolic control, as reflected by normoglycemia, rather than the infused insulin dose, was related to the beneficial effects of intensive insulin therapy.Critical Care Medicine 02/2003; 31(2):359-66. · 6.12 Impact Factor
ICU = intensive care unit.
Available online http://ccforum.com/content/8/6/427
Until the end of the past millenium, relatively little attention was
given to control of blood sugar levels. In critically ill patients,
hyperglycaemia was considered to be physiological because it
results from the metabolic and hormonal changes that
accompany the stress response to injury. In most intensive care
units (ICUs), blood sugar was checked every 4–6hours and
hyperglycaemia (defined as blood sugar levels >10–12mmol/l
[180–216mg/dl]) was corrected by subcutaneous or
intravenous insulin. The presence of pre-existing diabetes
mellitus or post-neurosurgical status often prompted more
intense control of hyperglycaemia. Furthermore, the issue of
glucose control was discussed in few sessions or satellite
symposia during intensive care meetings.
The deleterious effects of hyperglycaemia during critical
illness have been characterized over the past few years, and
include an increased susceptibility to infections and
thromboses, macrovascular and microvascular changes, and
delayed wound healing, among other effects (for review ).
Renewed interest in control of hyperglycaemia in critically ill
patients (Fig. 1) followed the publication of a study
conducted by Van den Berghe and coworkers in 2001 .
Those investigators reported a 43% decrease in relative
intensive care mortality as well as consistent decreases in
several surrogate markers of disease severity in patients
Tight blood glucose control: a recommendation applicable to any
critically ill patient?
Philippe Devos1and Jean-Charles Preiser2
1Resident, Department of Intensive Care, Centre Hospitalier Universitaire du Sart Tilman, Liege, Belgium
2Clinical Director, Department of Intensive Care, Centre Hospitalier Universitaire du Sart Tilman, Liege, Belgium
Corresponding author: Jean-Charles Preiser, Jean-Charles.Preiser@chu.ulg.ac.be
Published online: 27 October 2004
This article is online at http://ccforum.com/content/8/6/427
© 2004 BioMed Central Ltd
Critical Care 2004, 8:427-429 (DOI 10.1186/cc2989)
Related to Research by Vriesendorp et al., see page 513
The issue of tight glucose control with intensive insulin therapy in critically ill patients remains
controversial. Although compelling evidence supports this strategy in postoperative patients who have
undergone cardiac surgery, the use of tight glucose control has been challenged in other situations,
including in medical critically ill patients and in those who have undergone non-cardiac surgery.
Similarly, the mechanisms that underlie the effects of high-dose insulin are not fully elucidated. These
arguments emphasize the need to study the effects of tight glucose control in a large heterogeneous
cohort of intensive care unit patients.
Keywords cardiac surgery, critically ill, hyperglycemia, insulin, metabolism
Number of publications retrieved from the Medline (Pubmed®)
database using the keywords ‘insulin therapy’ or ‘hyperglycemia’ plus
‘critically ill’ from 1998 to September 2004.
Van den Berghe’s study 
Critical Care December 2004 Vol 8 No 6Devos and Preiser
randomly assigned to tight glucose control by intensive
intravenous insulin therapy. A post hoc multivariate logistic
regression analysis of these data suggested that control of
hyperglycaemia played a more important role than did the
amount of insulin administered . Interestingly enough, at
least two recent retrospective, large-scale studies [4,5]
confirmed that outcome was improved in patients whose
average blood glucose was maintained below 8 mmol/l
(144 mg/dl; Table 1).
Although the findings reported by Van den Berghe and
coworkers are impressive, some concern arose regarding the
applicability of these results to other types of patients. Of the
patients studied, 63% were admitted for follow up after
cardiac surgery; this high proportion was felt to be consistent
with a particular benefit from tight glucose control with
intensive insulin in these patients, but there is uncertainty
regarding whether tight glucose control is beneficial in
patients who have not undergone cardiac surgery. Fear of
life-threatening hypoglycaemia and increased workload and
costs probably underlie the reluctance of many intensivists to
launch systematic protocols of tight glucose control. Indeed,
many intensivists still use a high glucose threshold
(10 mmol/l [180 mg/dl]) . In a European survey
(unpublished data) we found considerable variation in the
glycaemic thresholds employed in ICUs, which ranged from
6 to 11.1 mmol/l (108–200 mg/dl).
Some arguments against generalized use of tight glucose
control are reported in the present issue of Critical Care by
Vriesendorp and coworkers . In a retrospective study
performed at one centre in Amsterdam, those authors found
that, after oesophageal surgery in patients without significant
cardiovascular compromise (ASA class I–II), postoperative
hyperglycaemia was not a risk factor for infectious
complications. Only by univariate analysis were they able to
find an improvement in patients with blood glucose levels
below 9.3 mmol/l (167 mg/dl) in terms of length of ICU stay.
These findings differ strikingly from those of other studies
[2,4,5]. Although the report by Vriesendorp and coworkers
challenges the concept of tight glucose control, it can hardly
be considered a major piece of evidence against it. Indeed,
blood glucose concentrations were presented as means of
values recorded only over 48 hours, whereas the ICU stay
extended up to 71 days, with a median of 3 days. Insulin was
administered to only 9% of the patients during the 48-hour
period of observation. In addition, patients received a mean
of only 22.5 g glucose/day, and were fed early after surgery
with an enteral solution of ‘immunonutrients’ – a potential
confounding factor with respect to infectious morbidity.
Features of recent studies of glucose control in intensive care units
  
Target glucose levels (mmol/l)
Types of admission (n)
Surgical1548 462 573160
Cardiac surgery (% of total)63 8500
Median APACHE II score916 16 Not available
ICU mortality (%)
Intervention 4.6Not available14.8 3.3
Primary end-points ICU mortalityICU mortality ICU mortalityInfection rate,
length of hospital stay
Secondary end-pointsIn-hospital mortality, organ
dysfunction, tranfusion rate,
critical illness polyneuropathy,
transfusion rate, length
of ICU stay, infection
APACHE, Acute Physiology and Chronic Health Evaluation; ICU, intensive care unit.
However, despite these limitations, as well as others that are
acknowledged by the authors, the findings of the study
support the hypothesis that tight glucose control could be of
greater benefit to patients with cardiovascular disease than
to those without.
In conclusion, as recently suggested by Van den Berghe ,
further studies are needed to confirm the benefits of tight
blood glucose control with intensive insulin therapy in a
heterogeneous population of ICU patients. Hence, a large
randomized prospective multicentre trial is warranted. Such
study will also help in determining the physiological
importance of the effects of insulin and, more importantly, will
provide intensive care workers with key information for
guiding the management of blood glucose in critically ill
The author(s) declare that they have no competing interests.
1.Preiser JC, Devos P, Van den Berghe G: Tight control of gly-
caemia in critically ill patients. Curr Opin Clin Nutr Metab Care
2.Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyn-
inckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouil-
lon R: Intensive insulin therapy in the critically ill patients. N
Engl J Med 2001, 345:1359-1367.
3.Van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest
C, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P: Outcome
benefit of intensive insulin therapy in the critically ill: Insulin
dose versus glycemic control. Crit Care Med 2003, 31:359-
4. Finney SJ, Zekveld C, Elia A, Evans TW: Glucose control and
mortality in critically ill patients. JAMA 2003, 290:2041-2047.
5. Krinsley JS: Effect of an intensive glucose management proto-
col on the mortality of critically ill adult patients. Mayo Clin
Proc 2004, 79:992-1000.
6. McMullin J, Brozek J, Jaeschke R, Hamielec C, Dhingra V, Rocker
G, Freitag A, Gibson J, Cook D: Glycemic control in the ICU: a
multicenter survey. Intensive Care Med 2004, 30:798-803.
7.Vriesendorp TM, DeVries JH, Hulscher JBF, Holleman F, van Lan-
schot JJB, Hoekstra JBL: Early postoperative hyperglycaemia is
not a risk factor for infectious complications and prolonged
in-hospital stay in patients undergoing oesophagectomy: a
retrospective analysis of a prospective trial. Crit Care 2004, 8:
8.Van den Berghe G: Tight blood glucose control with insulin in
‘real-life’ intensive care. Mayo Clin Proc 2004, 79:977-978.
Available online http://ccforum.com/content/8/6/427