Fabio Silvio Taccone

Katia Donadello
Pierre Kalfon
Give me less sugar: how to manage glucose
levels in post-anoxic injury?
Received: 12 April 2014
Accepted: 15 April 2014
Published online: 1 May 2014
Springer-Verlag Berlin Heidelberg and ESICM 2014
F. S. Taccone (
)
) K. Donadello
Department of Intensive Care, Hopital Erasme, Route de Lennik,
808, 1070 Brussels, Belgium
e-mail: [email protected]
Tel.: ?32-2-5555587
P. Kalfon
Service de Reanimation Polyvalente, Hopital Louis Pasteur,
Hopitaux de Chartres, 28018 Le Coudray, France
Despite recent advances in the management of comatose
survivors after cardiac arrest (CA), a high proportion of
these patients will eventually die because of severe car-
diovascular failure or extended brain injury [1]. The
combination of these haemodynamic and neurological
alterations with a post-CA systemic inammatory
response, similar to that observed in sepsis, is commonly
dened as the post-cardiac arrest syndrome [2]. How-
ever, beyond these abnormalities, the development of
metabolic derangements, such as hyperglycaemia, can
also potentially contribute to secondary brain injury and
poor neurological outcome [3]. Indeed, experimental
studies suggest that elevated blood glucose levels after the
return of spontaneous circulation may exacerbate post-
anoxic injury [4, 5]; nevertheless, the impact of hyper-
glycaemia in this specic clinical setting remains unclear.
Retrospective analyses of patients after resuscitation
from out-of-hospital CA (OHCA) showed that hyper-
glycaemia was common during the post-resuscitation
period and might have been associated with poor outcome
[6, 7]. However, interventional studies of tight glucose
control (TGC) in CA patients showed that this strategy
was not associated with improved outcomes when com-
pared to a less strict glycaemic management [8].
Moreover, TGC could determine a higher incidence of
hypoglycaemia, and in a multicentre cohort of CA
patients the lowest blood glucose was associated with
hospital mortality [9]. There are also two other factors
that complicate glycaemic control in such a patient pop-
ulation. First, the use of targeted temperature
management (TTM) after CA can further alter glucose
metabolism because of reduced glucose utilization,
decreased insulin sensitivity and impaired secretion of
endogenous insulin due to cooling procedures [3]. Sec-
ond, blood glucose variability (BGV), i.e. the degree at
which a patients blood glucose uctuates between high
and low levels, was a stronger predictor of poor outcome
than absolute glucose level itself in these patients [3, 10].
Taken together, these data suggest the need for large
cohort studies to better understand the pathogenesis of the
alterations of glucose homeostasis as well as the impact of
elevated glucose and/or large BGV concentrations in
post-anoxic injury.
In this issue of Intensive Care Medicine, Daviaud et al.
[11] report on their evaluation of the relationship between
blood glucose levels and outcome in a large cohort
(n = 381) of OHCA patients admitted over a 5-year
period and treated with moderate glycaemic control (tar-
get glucose: 5.17.7 mmol/L). Median glucose levels and
median BGV, dened as the difference between the
highest and the lowest blood glucose concentrations
(Dmax - min) over the rst 48 h, were lower in patients
with a good outcome than in those with a poor outcome
(7.6 vs. 9.0 mmol/L, p \0.01; 7.1 vs. 9.6 mmol/L,
p \0.01, respectively). In their multivariate analysis,
increased median glucose levels, but not BGV, were
independently associated with poor outcome at hospital
discharge. These authors suggest that a strategy
Intensive Care Med (2014) 40:903906
DOI 10.1007/s00134-014-3309-5
EDITORIAL
combining both glucose control and minimization of
glycaemic variations might improve outcome in CA
patients.
This study has a number of strengths which need to
be highlighted. First, the authors included a sample size
of nearly 400 patients, which allowed them to apply
several statistical approaches in their analysis of the
possible link between glucose levels and outcome in
this cohort. Second, no missing data on glucose level
measurements were reported, thus limiting the potential
bias of retrospective data collection. Third, most
patients were treated with TTM, while in previous
studies the patients were analysed before the era of
hypothermia implementation [6, 7].
Although the study of Daviaud et al. [11] clearly
challenges the role of BGV on poor outcome after CA,
a number of important issues need to be discussed to
identify possible explanations for the differences with
previously reported results, including study limitations.
First of all, the best method to assess BGV remains to
be dened. Even if high BGV can be associated with
increased oxidative stress, neuronal damage and mito-
chondrial alterations, studies conducted in critically ill
patients have used different denitions of BGV, such as
the standard deviation (SD) of all glucose measure-
ments, the coefcient of variation, the concomitant
presence of both hyper- and hypoglycaemia or other
indices, such as the glucose variability index, the gly-
caemic lability index or the mean amplitude of
glycaemic excursion [12]. In previous studies on CA
patients, BGV was assessed using the difference
between the Dmax - min over a 24-h period [3] or the
SD and mean absolute glucose change per patient per
hour [10]. It is clear that the diversity of the indicators
used hampers the comparability of these studies and
hence limits any potential recommendations on glucose
management strategies aiming to control BGV in CA
patients [3, 10, 11]. Moreover, the relationship between
BGV and mortality could be blurred by the frequency
of observations (i.e. less frequent measurements of
glucose levels lead to an underestimation of BGV) and
the use of TGC [13]. Both glucose sampling methods
and the glucose levels that were targeted with contin-
uous insulin infusions were different among the three
studies evaluating BGV after CA [3, 10, 11], thus
increasing the number of confounders on the evaluation
of patients outcome in this setting (Table 1).
Second, regarding mortality, a convincing relation-
ship with BGV and outcome has been clearly
demonstrated in non-diabetic critically ill patients [14].
As such, Beiser et al. [15] showed that in non-diabetic
CA patients both minimum glucose values outside the
range of 3.99.4 mmol/L and maximum values outside
the range of 6.213.3 mmol/L were associated with an
increased risk of poor outcome. In the study of Daviaud
et al. [11], diabetes mellitus was associated with high T
a
b
l
e
1
S
u
m
m
a
r
y
o
f
c
l
i
n
i
c
a
l
s
t
u
d
i
e
s
e
v
a
l
u
a
t
i
n
g
t
h
e
r
o
l
e
o
f
b
l
o
o
d
g
l
u
c
o
s
e
v
a
r
i
a
b
i
l
i
t
y
o
n
o
u
t
c
o
m
e
a
f
t
e
r
c
a
r
d
i
a
c
a
r
r
e
s
t
R
e
f
e
r
e
n
c
e
s
T
y
p
e
P
a
t
i
e
n
t
s
,
n
(
p
e
r
i
o
d
)
O
H
C
A
(
%
)
B
l
o
o
d
g
l
u
c
o
s
e
s
a
m
p
l
i
n
g
T
a
r
g
e
t
g
l
u
c
o
s
e
(
m
m
o
l
/
L
)
D
e

n
i
t
i
o
n
B
G
V
E
v
a
l
u
a
t
i
o
n
(
h
)
T
h
e
r
a
p
e
u
t
i
c
h
y
p
o
t
h
e
r
m
i
a
(
%
)
O
u
t
c
o
m
e
M
a
i
n

n
d
i
n
g
s
C
u
e
n
i
-
V
i
l
l
o
z
e
t
a
l
.
[
3
]
R
e
t
r
o
s
p
e
c
t
i
v
e
2
2
0
(
5
y
e
a
r
s
)
9
3
q
4
h
6
.
0

8
.
0
M
a
x
-
M
i
n
d
i
f
f
e
r
e
n
c
e
4
8
1
0
0
C
P
C
a
t
3
m
o
n
t
h
s
B
G
V
d
u
r
i
n
g
T
H
a
s
s
o
c
i
a
t
e
d
w
i
t
h
p
o
o
r
o
u
t
c
o
m
e
L
e
e
e
t
a
l
.
[
1
0
]
R
e
t
r
o
s
p
e
c
t
i
v
e
1
4
7
(
4
y
e
a
r
s
)
8
2
q
1
h
4
.
4

1
1
.
1
S
D
M
A
G
C
4
8
1
0
0
C
P
C
a
t
3
0
d
a
y
s
B
G
V
d
u
r
i
n
g
T
H
a
s
s
o
c
i
a
t
e
d
w
i
t
h
p
o
o
r
o
u
t
c
o
m
e
D
a
v
i
a
u
d
e
t
a
l
.
[
1
1
]
R
e
t
r
o
s
p
e
c
t
i
v
e
a
n
a
l
y
s
i
s
o
f
d
a
t
a
b
a
s
e
3
8
1
(
5
y
e
a
r
s
)
1
0
0
q
3
h
5
.
1

7
.
7
M
a
x
-
M
i
n
d
i
f
f
e
r
e
n
c
e
4
8
8
2
C
P
C
a
t
h
o
s
p
i
t
a
l
d
i
s
c
h
a
r
g
e
B
G
V
w
a
s
n
o
t
a
s
s
o
c
i
a
t
e
d
w
i
t
h
o
u
t
c
o
m
e
B
G
V
B
l
o
o
d
g
l
u
c
o
s
e
v
a
r
i
a
b
l
i
l
t
y
,
O
H
C
A
o
u
t
-
o
f
-
h
o
s
p
i
t
a
l
c
a
r
d
i
a
c
a
r
r
e
s
t
,
M
A
G
C
m
e
a
n
a
b
s
o
l
u
t
e
g
l
u
c
o
s
e
c
h
a
n
g
e
p
e
r
p
a
t
i
e
n
t
p
e
r
h
o
u
r
,
C
P
C
c
e
r
e
b
r
a
l
p
e
r
f
o
r
m
a
n
c
e
c
a
t
e
g
o
r
y
,
q
4
h
e
v
e
r
y
4
h
,
q
3
h
e
v
e
r
y
3
h
,
q
1
h
e
v
e
r
y
h
o
u
r
,
T
H
t
h
e
r
a
p
e
u
t
i
c
h
y
p
o
t
h
e
r
m
i
a
904
BGV but did not signicantly inuence the results of the
multivariate analysis. However, as only 14 % of patients
suffered from diabetes, it is possible that such an analysis
was largely underpowered.
Third, Daviaud et al. measured glucose levels using
capillary glucometers; however, these devices have been
shown to have a low accuracy in critically ill patients
when compared to glucose measurements performed on
venous/arterial blood. In particular, mean differences with
the blood values may vary from 0.2 to 1.4 mmol/L (limits
of agreement from 1.7 to 2.5 mmol/L), especially within
the hypoglycaemic range [16]. Also, the use of vaso-
pressors and the presence of oedema, both of which are
common after CA, were important determinants of inac-
curacy and might increase the risk of errors of capillary
glucometers in this setting. Thus, capillary samples may
not provide an adequate estimation of blood glucose
levels and may have signicantly inuenced the assess-
ment of BGV in this study.
Finally, there are still some missing clues between
glucose management and outcome in CA patients.
Although the potential importance of BGV to determine
mortality/poor neurological recovery in such a population
has to be recognized, there are as yet no data on the
association of BGV with other outcomes, such as the
development of acute renal or respiratory failure and the
onset of sepsis. Also, a better understanding of all the
clinical and therapeutic factors associated with high BGV
is needed; indeed, one may distinguish between the
sources of glucose level variability induced by some
interventions (i.e. corticosteroids in case of circulatory
failure or early enteral nutrition), which are relatively
controllable, and those due to changes in patient condi-
tion, such as the occurrence of infections or the need of
high vasopressor dose. Moreover, high glucose concen-
trations and variability after CA might be an
epiphenomenon, i.e. a marker of severe injury with lim-
ited pathogenic inuence per se on brain damage, and
future prospective studies that included several other
variables would be necessary to answer this issue. Finally,
a recent study has shown that loss of glucose complexity,
as evaluated by uctuation analysis of glucose levels over
time, was also associated with higher mortality in criti-
cally ill patients: the lack of complexity may represent the
failure of regulatory systems to maintain glucose
homeostasis as a consequence of the underlying disease
[17]. It might therefore be useful to adopt associated
analyses of BGV and complexity in future studies on CA
patients. The use of continuous glucose monitoring could
be a reliable approach to better evaluate BGV in this
setting.
Conicts of interest P. Kalfon is a board member of LK2 (Saint-
Avertin, France) and has shares in LK2. F.S. Taccone and
K. Donadello have no conict of interest to declare.
References
1. Lemiale V, Dumas F, Mongardon N
et al (2013) Intensive care unit mortality
after cardiac arrest: the relative
contribution of shock and brain injury
in a large cohort. Intensive Care Med
39:19721980
2. Peberdy MA, Callaway CW, Neumar
RW et al (2010) Part 9: post-cardiac
arrest care: 2010 American Heart
Association Guidelines for
Cardiopulmonary Resuscitation and
Emergency Cardiovascular Care.
Circulation 122:S768S786
3. Cueni-Villoz N, Devigili A, Delodder F
et al (2011) Increased blood glucose
variability during therapeutic
hypothermia and outcome after cardiac
arrest. Crit Care Med 39:22252231
4. Molnar M, Bergquist M, Larsson A,
Wiklund L, Lennmyr F (2014)
Hyperglycaemia increases S100b after
short experimental cardiac arrest. Acta
Anaesthesiol Scand 58:106113
5. Vannucci RC, Rossini A, Towghi J
(1996) Effect of hyperglycemia on
ischemic brain damage during
hypothermic circulatory arrest in
newborn dogs. Pediatr Res 40:177184
6. Mullner M, Sterz F, Binder M,
Schreiber W, Deimel A, Laggner AN
(1997) Blood glucose concentration
after cardiopulmonary resuscitation
inuences functional neurological
recovery in human cardiac arrest
survivors. J Cereb Blood Flow Metab
17:430436
7. Skrifvars MB, Pettila V, Rosenberg PH,
Castren M (2003) A multiple logistic
regression analysis of in-hospital factors
related to survival at six months in
patients resuscitated from out-of-
hospital ventricular brillation.
Resuscitation 59:319328
8. Oksanen T, Skrifvars MB, Varpula T
et al (2007) Strict versus moderate
glucose control after resuscitation from
ventricular brillation. Intensive Care
Med 33:20932100
9. Nolan JP, Laver SR, Welch CA,
Harrison DA, Gupta V, Rowan K
(2007) Outcome following admission to
UK intensive care units after cardiac
arrest: a secondary analysis of the
ICNARC Case Mix Programme
Database. Anaesthesia 62:12071216
10. Lee BK, Lee HY, Jeung KW, Jung YH,
Lee GS, You Y (2013) Association of
blood glucose variability with outcomes
in comatose cardiac arrest survivors
treated with therapeutic hypothermia.
Am J Emerg Med 31:566572
11. Daviaud F, Dumas F, Demars N (2014)
Blood glucose level and outcome after
cardiac arrest: insights from a large
registry in the hypothermia era.
Intensive Care Med. doi:
10.1007/s00134-014-3269-9
12. Eslami S, Taherzadeh Z, Schultz MJ,
Abu-Hanna A (2011) Glucose
variability measures and their effect on
mortality: a systematic review.
Intensive Care Med 37:583593
13. Harmsen RE, Spronk PE, Schultz MJ,
Abu-Hanna A (2011) May frequency of
blood glucose measurement be blurring
the association between MAG and
mortality? Crit Care Med 39:224
14. Krinsley JS, Egi M, Kiss A, Devendra
AN et al (2013) Diabetic status and the
relation of the three domains of
glycemic control to mortality in
critically ill patients: an international
multicenter cohort study. Crit Care
17:R37
905
15. Beiser DG, Carr GE, Edelson DP,
Peberdy MA, Hoek TL (2009)
Derangements in blood glucose
following initial resuscitation from in-
hospital cardiac arrest: a report from the
national registry of cardiopulmonary
resuscitation. Resuscitation 80:624630
16. Inoue S, Egi M, Kotani J, Morita K
(2013) Accuracy of blood-glucose
measurements using glucose meters and
arterial blood gas analyzers in critically
ill adult patients: systematic review.
Crit Care 17:R48
17. Lundelin K, Vigil L, Bua S, Gomez-
Mestre I, Honrubia T, Varela M (2010)
Differences in complexity of glycemic
prole in survivors and nonsurvivors in
an intensive care unit: a pilot study. Crit
Care Med 38:849854
906