The Intensive
Insulin/Intensive Care Debate
Waits for
NICE-SUGAR
by David W. Sharp
Medicine
Top Ten
Papers
Rank
Papers
Cites
Sep-Oct
08
Rank
Jul-Aug
08
1
R.J. Motzer, et
al.,
"Sunitinib versus
interferon alfa in
metastatic
renal-cell
carcinoma," New
Engl. J. Med.,
356(2): 115-24, 11
January 2007. [10
institutions
worldwide] *124NE
65
4
2
B. Escudier, et
al.,
"Sorafenib in
advanced clear-cell
renal-cell
carcinoma," New
Engl. J. Med.,
356(2): 125-34, 11
January 2007. [15
institutions
worldwide] *124NE
58
2
3
S.E. Nissen, K.
Wolski, "Effect of
rosiglitazone on
the risk of
myocardial
infarction and
death from
cardiovascular
causes," New
Engl. J. Med.,
356(24): 2457-71,
14 June 2007.
[Cleveland Clinic,
OH] *178DR
50
3
4
G. Hudes, et
al.,
"Temsirolimus,
interferon alpha,
or both for
advanced renal-cell
carcinoma," New
Engl. J. Med.,
356(22): 2271-81,
31 May 2007. [17
institutions
worldwide] *172PO
47
†
5
J. Yu, et
al., "Induced
pluripotent stem
cell lines derived
from human somatic
cells,"
Science,
318(5858): 1917-20,
21 December 2007.
[Genome Ctr.
Wisconsin, Madison;
U. Wisconsin,
Madison] *243HE
43
1
6
R. Sladek, et
al., "A
genome-wide
association study
identifies novel
risk loci for type
2 diabetes,"
Nature,
445(7130): 881-5,
22 February 2007.
[14 institutions
worldwide] *138CR
39
5
7
T.M. Frayling,
et al., "A
common variant in
the FTO
gene is associated
with body mass
index and
predisposes to
childhood and adult
obesity,"
Science,
316(5826): 889-94,
11 May 2007. [19
institutions
worldwide] *166HM
34
†
8
L.J. Scott, et
al., "A
genome-wide
association study
of type 2 diabetes
in Finns detects
multiple
susceptibility
variants,"
Science,
316(5829): 1341-5,
1 June 2007. [12
U.S. and Finland
institutions]
*173PS
31
7
9
E. Zeggini, et
al.,
"Replication of
genome-wide
association signals
in UK samples
reveals risk loci
for type 2
diabetes,"
Science,
316(5829): 1336-41,
1 June 2007. [10
U.K. institutions]
*173PS
31
6
10
L.D. Wood, et
al., "The
genomic landscapes
of human
breast
and colorectal
cancers,"
Science,
318(5853):
1108-13, 16
November 2007.
[14
institutions
worldwide]
*231OC
Just before a highly cited 2001 paper was timed
out of eligibility for the Top Ten, your Science
Watch columnist got round to a brief mention of it
(15[4]: 5,September/October 2004). I refer
to the article by Dr. Greta Van den Berghe and her
colleagues on the use of tight glycemic control in
surgical intensive-care patients (New Engl. J.
Med., 345[19]:1359-67, 2001). Mortality was
reduced by an intensive regimen of insulin treatment
(IIT) to keep blood-glucose levels at or below 110
mg/dL (6.1 mmol/L). However, when these workers
looked at medical intensive-care units, the
beneficial effect on mortality was not replicated
(New Engl. J. Med., 354[5]: 449-61, 2006).
Both papers attracted a huge amount of interest,
reflected in commentaries, correspondence, and
citations.
Another indicator of the importance of the work of this
Belgian group has been the setting up of other trials.
One of these is itself now climbing the citation ladder
(F.M. Brunkhorst, et al., New Engl. J.
Med., 358[2]:125-39, 2008); #18, total cites 80,
latest count 26). This German trial looked at patients
with severe sepsis in multidisciplinary intensive-care
units, noting that it was in patients with sepsis that
most of the mortality benefit reported in the 2001
paper had been recorded. The trial, which also compared
two approaches to fluid resuscitation, was stopped
early on safety grounds. On neither death rates (28-day
mortality 24.7% in the IIT group and 26.0% in the
conventional-therapy group) nor on a score for organ
failure was there a significant difference between the
two trial arms. A safety concern with IIT is that
glucose concentrations may fall too far, and in this
trial serious hypoglycemia was roughly four times more
common in the patients given IIT.
The type of patient has varied (the latest
study from Van den Berghe's group is in pediatric
intensive care [D. Vlasselaers, et al.,
Lancet, 373(9663): 547-56, 14 February 2009]);
so has the insulin protocol, and also the method of
glucose measurement, which may be important (M.G.
Scott, et al.,Clin. Chem., 55[1]:
18-20, 2009). Last year saw the publication of a
meta-analysis on data from no fewer than 29 clinical
trials involving 8,432 patients (R.S. Wiener, et
al., J. Am. Med. Assoc., 300[8]: 934-44,
2008). This revealed no difference in in-hospital
mortality between tight blood-glucose control (21.6%)
and usual care (23.3%) (relative risk 0.93 with a 95%
confidence interval of 0.85-1.03) and episodes of
hypoglycemia were more than five times more common with
IIT. In their own recent reviews Van den Berghe and
colleagues agree on the need for more trials but argue
that on the basis of the prevailing evidence IIT
confers a benefit in sepsis "equal to the benefit found
in critical illness without sepsis and critical illness
generally" (Curr. Pharm. Res., 14[19]:
1887-97, 2008) and elsewhere that "current evidence
favors strict control of blood glucose levels to
normoglycemia below 110 mg/dL" (Horm. Res.,
71[1]: 2-11, 2009).
By the end of this year the picture should be a good
deal clearer. Recruitment for a trial in 6,100 patients
coordinated at the George Institute for International
Health in Sydney, Australia, was completed in August,
2008, and the main outcome is 90-day mortality, so the
statistical analysis and even the writing up will have
been well advanced as Science Watch goes to
press. In this trial, in over 35 intensive-care units
in Australasia and North America, the comparison groups
had assigned target blood glucose levels of 4.5-6.0 or
8.0-10.0 mmol/L. Whatever their current views,
intensive-care specialists the world over will be
awaiting with keen interest the outcome of NICE-SUGAR,
the name surely being preferred to Normoglycaemia in
Intensive Care Evaluation and Survival Using Glucose
Algorithm Regulation (T.M. Merz, S. Finfer, Minerva
Anestesiol., 20 January 2009: e-pub ahead of
print). All that is on record to date by way of results
is a rate of hypoglycemic episodes (defined as a drop
in blood sugar to 2.2 mmol/L or less and as a serious
adverse event) of 8.0 per 100 patients in the group
with the lower target blood glucose contrasting with
only 0.3 per 100 in the other group (N. Clark, S.
Finfer, and the
NICE-SUGAR study investigators).
A former deputy editor of The Lancet,
David W. Sharp, M.A. (Cambridge), is a freelance writer
living in Minchinhampton, Gloucestershire,
U.K.
KEYWORDS: SEPSIS, INTENSIVE INSULIN THERAPY, GRETA VAN
DEN BERGHE, F.M. BRUNKHORST, NICE-SUGAR, HYPOGLYCEMIA.