Illustration: J. P. Rathmell.

Illustration: J. P. Rathmell.

“... avoiding even mild hypoglycemia may be equally as important as avoiding hyperglycemia when it comes to preventing postoperative delirium, just as avoiding the rocks of Scylla was equally as important as avoiding the whirlpool of Charybdis for sailors in Homer’s Odyssey.”

The face of delirium is intuitively recognizable to most clinicians (at least in severe cases)—the wandering eyes, the lack of attention and focus, and the sense that a patient is “not all there.” Delirium is a serious postoperative complication with long-term sequelae for patients and families, including persistent cognitive dysfunction,1  increased hospital length of stay,2  and increased mortality risk.3  The recognition of these potentially devastating outcomes is reflected by the increasing number of articles published on this topic recently (fig. 1) and has led to an investigation by Saager et al.4  in this issue of the effects of intraoperative tight glycemic control on the incidence and severity of postoperative delirium.

Fig. 1.

This figure was made using Microsoft Excel (Microsoft Corporation, USA), with data obtained from performing a PubMed search using the terms “Postoperative Delirium” and each successive publication year from 1984 through 2014.

Fig. 1.

This figure was made using Microsoft Excel (Microsoft Corporation, USA), with data obtained from performing a PubMed search using the terms “Postoperative Delirium” and each successive publication year from 1984 through 2014.

Despite the straightforward clinical presentation of delirium, its well-defined prognostic implications, and a large research focus, we still lack a clear understanding of what postoperative delirium is at a brain systems level, and also struggle with how to best diagnose delirium. These limitations are not surprising considering that delirium is a disorder of consciousness, and we lack a brain circuit level understanding of consciousness itself. The entire situation is reminiscent of the words of Voltaire who once remarked: “Doctors pour drugs of which they know little, to cure diseases of which they know less, into human beings of whom they know nothing.”

To be fair, there is some evidence that delirium reflects alterations in specific neurotransmitters (reviewed in Inouye et al.5). But the brain is not simply a soup bowl of neurotransmitters. The 80+ billion neurons that make up the brain6  are better conceptualized as a circuit board with 80+ billion nodes, each of which is connected to 10,000+ other nodes in the circuit. To say that delirium results from altered neurotransmitter levels is like saying that an error in the function of a computer program results from altered electricity levels inside the computer. Although true, neither statement is particularly informative. Neuroimaging and electroencephalography studies demonstrate that delirium is associated with disruption of cortical and subcortical functional connectivity,7–9  but the extent of connectivity disruption necessary or sufficient to cause delirium is unknown.

According to the definition in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, inattention is a necessary component of delirium. However, inattention can be measured by a deficit in either simple attention or working memory. Simple attention can be measured by saying the letters SAVEAHAART aloud and instructing the patient to squeeze the tester’s hand every time he or she hears the letter “A.”10  Working memory is a more complex cognitive function that requires patients to transiently hold and process information and can be measured by asking a patient to recite the months of the year backward. Working memory declines with age.11  Thus, classifying patients as delirious if they cannot complete a working memory task risks mislabeling a presurgery working memory deficit as delirium. This is a potential problem if presurgery baseline cognitive assessments are unavailable, as in the study by Saager et al.

Other challenges to accurately diagnose delirium include the influence of practice effects on repeated delirium assessments12  and the difficulty in quantifying the degree of “clinically meaningful” postsurgery cognitive change necessary for delirium.13  Education level (“cognitive reserve”) and varying cognitive effort on the part of patients may also affect the sensitivity of delirium detection.14  These challenges may explain why studies have detected delirium rates after cardiac surgery ranging from more than 50%15  to less than 15%16  and argue strongly for a multidisciplinary approach to delirium detection, monitoring, and treatment.

Despite these challenges, the clear long-term sequelae of postoperative delirium mandate that we as physicians attempt to prevent it even if we do not fully understand what causes it or how best to measure it.17  Recent attention has focused on inflammation as a contributor to postoperative delirium18  and possibly to longer term cognitive dysfunction as well.19,20  Hyperglycemia has also been identified as a possible contributor to adverse postoperative outcomes21  and has been correlated with increased inflammation.22  Conversely, insulin administration decreases inflammation.23 

On the basis of these findings, Saager et al.4  now report the results of a randomized double-blind trial that examined the effect of tight intraoperative glycemic control (via a hyperinsulinemic–normoglycemic clamp) versus standard glycemic control, on the incidence of postoperative delirium in patients undergoing cardiac surgery. Surprisingly, and contrary to the hypothesis of authors, patients in the tight glycemic control arm of the study had a higher incidence of delirium.

Are these results valid? Aside from insulin administration, intraoperative characteristics were generally similar among patients in both study arms (table 2 of Saager et al.4 ). Surgery duration, clamp time, and bypass time were all slightly longer in the tight glycemic control arm, although these differences were small relative to the differences in insulin administration. Thus, it is likely that the differences in delirium outcomes between the study arms are primarily due to the differences in insulin administration.

What do these results mean? This trial was based on the rationale that hyperglycemia has been associated with adverse events, although not with delirium itself per se,21  and that insulin therapy has antiinflammatory effects that would decrease delirium incidence if delirium is caused by inflammation. However, even mild hypoglycemia is associated with alterations in cognitive performance,24  and brain function and connectivity.24–26  Indeed, hypoglycemic episodes in patients with type II diabetes even predict the development of dementia.27  Consistent with this literature, Saager et al.4  report a trend toward increased delirium rates with each 10 mg/dl decrease in glucose levels. This finding barely missed statistical significance (P = 0.06), likely due to insufficient power (a type II error). Thus, one interpretation of the study results is that the increased incidence of mild hypoglycemia in the tight glycemic control arm adversely affected neurocognitive function and led to postoperative delirium.

Where do we go from here? The results of this trial fit nicely with other studies showing that tight glycemic control is associated with increased adverse event rates compared with standard glycemic control28  and suggest that providers should consider avoiding tight glycemic control in cardiac surgery. Saager et al.4  should be praised for the extraordinary effort that went into carrying out this study on the effect of tight intraoperative glycemic control on postoperative complications including delirium. Overall, the results suggest that avoiding even mild hypoglycemia may be equally as important as avoiding hyperglycemia when it comes to preventing postoperative delirium, just as avoiding the rocks of Scylla was equally as important as avoiding the whirlpool of Charybdis for sailors in Homer’s Odyssey.

This article also raises several questions for future inquiry: Would tight glycemic control be more beneficial during the postoperative period than during surgery itself? This issue is relevant because mild hypothermia increases insulin resistance,29  and thus, mild hypothermia during cardiopulmonary bypass may also attenuate the antiinflammatory effects of insulin. More broadly, these results suggest that improving our understanding of what delirium is at a brain systems level and from a neuropsychological perspective may allow us to design interventions that will have a high likelihood of preventing delirium and its long-term sequelae.

Competing Interests

The authors are not supported by, nor maintain any financial interest in, any commercial activity that may be associated with the topic of this article.

References

References
1.
Saczynski
JS
,
Marcantonio
ER
,
Quach
L
,
Fong
TG
,
Gross
A
,
Inouye
SK
,
Jones
RN
:
Cognitive trajectories after postoperative delirium.
N Engl J Med
2012
;
367
:
30
9
2.
Smith
PJ
,
Rivelli
SK
,
Waters
AM
,
Hoyle
A
,
Durheim
MT
,
Reynolds
JM
,
Flowers
M
,
Davis
RD
,
Palmer
SM
,
Mathew
JP
,
Blumenthal
JA
:
Delirium affects length of hospital stay after lung transplantation.
J Crit Care
2015
;
30
:
126
9
3.
Abelha
FJ
,
Luís
C
,
Veiga
D
,
Parente
D
,
Fernandes
V
,
Santos
P
,
Botelho
M
,
Santos
A
,
Santos
C
:
Outcome and quality of life in patients with postoperative delirium during an ICU stay following major surgery.
Crit Care
2013
;
17
:
R257
4.
Saager
L
,
Duncan
AE
,
Yared
J-P
,
Hesler
BD
,
You
J
,
Deogaonkar
A
,
Sessler
DI
,
Kurz
A
:
Intraoperative tight glucose control using hyperinsulinemic normoglycemia increases delirium after cardiac surgery.
Anesthesiology
2015
;
122
:
1214
23
5.
Inouye
SK
,
Westendorp
RG
,
Saczynski
JS
:
Delirium in elderly people.
Lancet
2014
;
383
:
911
22
6.
Azevedo
FA
,
Carvalho
LR
,
Grinberg
LT
,
Farfel
JM
,
Ferretti
RE
,
Leite
RE
,
Jacob Filho
W
,
Lent
R
,
Herculano-Houzel
S
:
Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain.
J Comp Neurol
2009
;
513
:
532
41
7.
Choi
SH
,
Lee
H
,
Chung
TS
,
Park
KM
,
Jung
YC
,
Kim
SI
,
Kim
JJ
:
Neural network functional connectivity during and after an episode of delirium.
Am J Psychiatry
2012
;
169
:
498
507
8.
Mashour
GA
,
Avidan
MS
:
Postoperative delirium: Disconnecting the network?
Anesthesiology
2014
;
121
:
214
6
9.
van Dellen
E
,
van der Kooi
AW
,
Numan
T
,
Koek
HL
,
Klijn
FA
,
Buijsrogge
MP
,
Stam
CJ
,
Slooter
AJ
:
Decreased functional connectivity and disturbed directionality of information flow in the electroencephalography of intensive care unit patients with delirium after cardiac surgery.
Anesthesiology
2014
;
121
:
328
35
10.
Ely
EW
,
Inouye
SK
,
Bernard
GR
,
Gordon
S
,
Francis
J
,
May
L
,
Truman
B
,
Speroff
T
,
Gautam
S
,
Margolin
R
,
Hart
RP
,
Dittus
R
:
Delirium in mechanically ventilated patients: Validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU).
JAMA
2001
;
286
:
2703
10
11.
Gazzaley
A
,
Sheridan
MA
,
Cooney
JW
,
D’Esposito
M
:
Age-related deficits in component processes of working memory.
Neuropsychology
2007
;
21
:
532
9
12.
Duff
K
,
Callister
C
,
Dennett
K
,
Tometich
D
:
Practice effects: A unique cognitive variable.
Clin Neuropsychol
2012
;
26
:
1117
27
13.
Heaton
RK
,
Temkin
N
,
Dikmen
S
,
Avitable
N
,
Taylor
MJ
,
Marcotte
TD
,
Grant
I
:
Detecting change: A comparison of three neuropsychological methods, using normal and clinical samples.
Arch Clin Neuropsychol
2001
;
16
:
75
91
14.
Esposito
F
,
Gendolla
GH
,
Van der Linden
M
:
Are self-efficacy beliefs and subjective task demand related to apathy in aging?
Aging Ment Health
2014
;
18
:
521
30
15.
Rudolph
JL
,
Jones
RN
,
Levkoff
SE
,
Rockett
C
,
Inouye
SK
,
Sellke
FW
,
Khuri
SF
,
Lipsitz
LA
,
Ramlawi
B
,
Levitsky
S
,
Marcantonio
ER
:
Derivation and validation of a preoperative prediction rule for delirium after cardiac surgery.
Circulation
2009
;
119
:
229
36
16.
Sauër
AM
,
Slooter
AJ
,
Veldhuijzen
DS
,
van Eijk
MM
,
Devlin
JW
,
van Dijk
D
:
Intraoperative dexamethasone and delirium after cardiac surgery: A randomized clinical trial.
Anesth Analg
2014
;
119
:
1046
52
17.
Berger
M
,
Nadler
J
,
Mathew
JP
:
Preventing delirium after cardiothoracic surgery: Provocative but preliminary evidence for bispectral index monitoring.
Anesth Analg
2014
;
118
:
706
7
18.
Cape
E
,
Hall
RJ
,
van Munster
BC
,
de Vries
A
,
Howie
SE
,
Pearson
A
,
Middleton
SD
,
Gillies
F
,
Armstrong
IR
,
White
TO
,
Cunningham
C
,
de Rooij
SE
,
MacLullich
AM
:
Cerebrospinal fluid markers of neuroinflammation in delirium: A role for interleukin-1β in delirium after hip fracture.
J Psychosom Res
2014
;
77
:
219
25
19.
Nadelson
MR
,
Sanders
RD
,
Avidan
MS
:
Perioperative cognitive trajectory in adults.
Br J Anaesth
2014
;
112
:
440
51
20.
Su
X
,
Feng
X
,
Terrando
N
,
Yan
Y
,
Chawla
A
,
Koch
LG
,
Britton
SL
,
Matthay
MA
,
Maze
M
:
Dysfunction of inflammation-resolving pathways is associated with exaggerated postoperative cognitive decline in a rat model of the metabolic syndrome.
Mol Med
2012
;
18
:
1481
90
21.
Ganai
S
,
Lee
KF
,
Merrill
A
,
Lee
MH
,
Bellantonio
S
,
Brennan
M
,
Lindenauer
P
:
Adverse outcomes of geriatric patients undergoing abdominal surgery who are at high risk for delirium.
Arch Surg
2007
;
142
:
1072
8
22.
Heier
M
,
Margeirsdottir
HD
,
Brunborg
C
,
Hanssen
KF
,
Dahl-Jørgensen
K
,
Seljeflot
I
:
Inflammation in childhood type 1 diabetes; influence of glycemic control.
Atherosclerosis
2015
;
238
:
33
7
23.
Hansen
TK
,
Thiel
S
,
Wouters
PJ
,
Christiansen
JS
,
Van den Berghe
G
:
Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels.
J Clin Endocrinol Metab
2003
;
88
:
1082
8
24.
Schafer
RJ
,
Page
KA
,
Arora
J
,
Sherwin
R
,
Constable
RT
:
BOLD response to semantic and syntactic processing during hypoglycemia is load-dependent.
Brain Lang
2012
;
120
:
1
14
25.
Sejling
AS
,
Kjaer
TW
,
Pedersen-Bjergaard
U
,
Diemar
SS
,
Frandsen
CS
,
Hilsted
L
,
Faber
J
,
Holst
JJ
,
Tarnow
L
,
Nielsen
MN
,
Remvig
LS
,
Thorsteinsson
B
,
Juhl
CB
:
Hypoglycemia-associated changes in the electroencephalogram in patients with type 1 diabetes and normal hypoglycemia awareness or unawareness.
Diabetes
2014
[Epub ahead of print]
26.
Teves
D
,
Videen
TO
,
Cryer
PE
,
Powers
WJ
:
Activation of human medial prefrontal cortex during autonomic responses to hypoglycemia.
Proc Natl Acad Sci USA
2004
;
101
:
6217
21
27.
Whitmer
RA
,
Karter
AJ
,
Yaffe
K
,
Quesenberry
CP
Jr
,
Selby
JV
:
Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.
JAMA
2009
;
301
:
1565
72
28.
NICE-SUGAR Study Investigators
Finfer
S
,
Liu
B
,
Chittock
DR
,
Norton
R
,
Myburgh
JA
,
McArthur
C
,
Mitchell
I
,
Foster
D
,
Dhingra
V
,
Henderson
WR
,
Ronco
JJ
,
Bellomo
R
,
Cook
D
,
McDonald
E
,
Dodek
P
,
Hébert
PC
,
Heyland
DK
,
Robinson
BG
;
NICE-SUGAR Study Investigators
:
Hypoglycemia and risk of death in critically ill patients.
N Engl J Med
2012
;
367
:
1108
18
29.
Sah Pri
A
,
Chase
JG
,
Pretty
CG
,
Shaw
GM
,
Preiser
JC
,
Vincent
JL
,
Oddo
M
,
Taccone
FS
,
Penning
S
,
Desaive
T
:
Evolution of insulin sensitivity and its variability in out of hospital cardiac arrest (OHCA) patients treated with hypothermia.
Crit Care
2014
;
18
:
586