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British Journal of Anaesthesia 106 (6): 84050 (2011)

Advance Access publication 25 April 2011 . doi:10.1093/bja/aer091

Cognitive function after sevoflurane- vs propofol-based


anaesthesia for on-pump cardiac surgery: a randomized
controlled trial
J. Schoen *, L. Husemann, C. Tiemeyer, A. Lueloh, B. Sedemund-Adib, K.-U. Berger, M. Hueppe and
M. Heringlake
Department of Anesthesiology, University of Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany
* Corresponding author. E-mail: julika.schoen@uk-sh.de

Editors key points

Patients developing
intraoperative cerebral
desaturation showed
worse early postoperative
cognitive test results than
patients without cerebral
desaturation.
Hypnotic drug selection
might be one of the
factors attenuating the
effects of cerebral
desaturation on cognitive
outcome after on-pump
cardiac surgery.

Methods. One hundred and twenty-eight patients were randomly assigned to either i.v.
anaesthesia with propofol- (PROP) or sevoflurane-based anaesthesia (SEVO). An
intraoperative ScO2 , 50% was defined as desaturation. The Abbreviated Mental Test,
Stroop Test, Trail-Making Test, Word Lists, and mood-assessment tests were performed
before, 2, 4, and 6 days after cardiac surgery. Markers of general outcome were obtained.
Results. The analysis groups had differences in baseline cognitive performance. Analysis of
variance for repeated measures (incorporating covariance of baseline scores) showed that
in three of four cognitive tests, patients with cerebral desaturation showed worse results
than patients without desaturation. Patients assigned to sevoflurane-based anaesthesia
showed better results in all cognitive tests than patients after propofol. Interactions
between the anaesthetic regimen and desaturation were found in all four cognitive tests.
There were no differences in markers of organ dysfunction or general clinical outcome.
Conclusions. Patients with impaired cognitive performance before operation may be at
particular risk for intraoperative cerebral insult. A sevoflurane-based anaesthesia was
associated with better short-term postoperative cognitive performance than propofol.
Keywords: anaesthetics volatile, sevoflurane; brain, injury; clinical trials; surgery,
cardiovascular
Accepted for publication: 26 February 2011

Cognitive alterations after cardiac surgery are of growing


importance in an ageing population. After coronary artery
bypass grafting (CABG),1 2 35 63% of patients show cognitive dysfunction on discharge with one-third still suffering
from cognitive decline 5 months after surgery.3 4 Even
though some data suggest that long-term effects of
surgery and anaesthesia on cognitive function might be
superimposed by effects of normal ageing,5 a reduction in
the incidence of postoperative cognitive dysfunction is of
primary importance.
Several attempts have been made to reduce cerebral
damage during cardiac surgery, focusing on either the
reduction in macro- and microembolism3 or the optimization
of the cerebral oxygen delivery/demand ratio. A non-invasive
method for estimation of the cerebral oxygenation is the
measurement of the regional cerebral oxygen saturation

ScO2 by near-infrared spectroscopy.6 Deterioration of the


ScO2 during cardiac or non-cardiac surgery has been shown
to be associated with postoperative cognitive dysfunction,
focal cerebral deficits,7 8 longer hospital stay, and increased
postoperative morbidity.9 11 Maintaining ScO2 above a critical
value by structured interventions has led to a lower postoperative morbidity and shorter hospital stay in cardiac9
and non-cardiac patients.12
A possibility of attenuating cerebral injury after cardiopulmonary bypass (CPB) could be anaesthetic pre- and postconditioning. The application of inhalation anaesthetics before
and immediately after an ischaemic period has been
shown to attenuate the ischaemia reperfusion injury of
several organs. Neuronal anaesthetic preconditioning has
been shown in vitro and in several animal studies,13 14 but
clinical data are scarce.15

& The Author [2011]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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Cognitive dysfunction
after cardiac surgery
might be associated with
decreases in cerebral
oxygen saturation.

Background. Cognitive dysfunction is a frequent complication after cardiac surgery and has
been found to be associated with decreases in cerebral oxygen saturation (ScO2 ) measured
with near-infrared spectroscopy. Sevoflurane has neuroprotective properties in vitro and in
animal models. This study was designed to determine cognitive and clinical outcomes after
sevoflurane- compared with propofol-based anaesthesia for on-pump cardiac surgery and
the impact of decreases in ScO2 under different anaesthesia regimens.

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Cognitive function after sevoflurane- vs propofol-based anaesthesia

The present study was designed to determine whether


patients after sevoflurane-based anaesthesia differ from
patients after propofol-based anaesthesia in postoperative
cognitive test results and the incidence of major organ dysfunction after on-pump cardiac surgery. To control for intraoperative changes in cerebral perfusion, the second objective
was the impact of intraoperative cerebral desaturation on
postoperative cognitive and major organ function. The third
objective was whether the impact of cerebral desaturation
on postoperative function was dependent on the anaesthesia
regimen used. The question whether patients are able to complete cognitive testing at all as early as 2 days after cardiac
surgery was another secondary objective.

Methods
Patients and study design

Justification of sample size


The size and direction of a possible difference in cognitive
function between different anaesthesia regimens cannot be
determined on the basis of empirical data. According to
Cohen,16 an effect size of d0.50 is a low-to-median effect
and should be clinically relevant. Assuming an a error of
5% and a b error of 20%, a sample size of N126 with
n63 in each group is considered sufficient to identify relevant group differences.

Anaesthesia protocol for the volatile group (SEVO)


Anaesthesia was induced with etomidate 0.2 0.3 mg kg21
and sufentanil 1 mg kg21 and maintained with remifentanil
0.20.25 mg kg21 min21 and sevoflurane 0.61 mean alveolar concentration aiming at a BIS of 4050. Pancuronium
bromide 0.07 0.1 mg kg21 was used for relaxation.
During the study period, there was no approval of the
technical inspection authority to apply sevoflurane during
CPB. During CPB, propofol 35 mg kg21 h21 was applied
according to BIS (aim 4050). After the release of the
aortic cross-clamp, sevoflurane was continued and the propofol infusion stopped. During sternal closure, 1 g of metamizol and piritramid 15 mg were given i.v. For transport to the
intensive care unit (ICU), the remifentanil infusion was
stopped, and propofol 2 mg kg21 h21 was started and maintained until normothermia, haemodynamic stability, and
sufficient spontaneous breathing were achieved. Piritramide
and pethidin were applied for analgesia as required. An
overview of the two different protocols is given in Table 1.

Anaesthesia protocol for the i.v. group (PROP)


Induction of anaesthesia and postoperative treatment in the
i.v. group was identical to the volatile anaesthesia group, but
anaesthesia was maintained with remifentanil 0.20.25 mg
kg21 min21 and propofol 35 mg kg21 h21 as required to
achieve a BIS of 4050.

Neurocognitive and psychometric tests


All patients performed a set of psychometric and neurocognitive tests on the day before surgery and 2, 4, and 6 days
after surgery. For all cognitive tests, parallel versions were
used at random at the different measurements. The tests
were selected on the basis of the Statement of Consensus
on Assessment of Neurobehavioral Outcomes After Cardiac
Surgery17 and adapted to a preceding study of our group.18
Most of the tests are taken from the Nuremberg Geriatric

Table 1 Anaesthesia protocol in the study groups. CPB,


cardiopulmonary bypass; MAC, mean alveolar concentration; BIS,
bispectral index

Intervention
Oral premedication followed a standardized institutional protocol. All patients were equipped with a radial artery catheter, central venous catheter, and pulmonary artery
catheter. Additionally, all patients were equipped with
bi-hemispherical near-infrared spectroscopy sensors (INVOS
Cerebral Oximeter 5100, Somanetics, Troy, MI, USA) (see
below) and a bispectral index (BIS) probe on the forehead.
Before CPB, all patients received 400 IU kg21 heparin,
achieving an activated clotting time above 500 s. Surgery
was performed in moderate hypothermia using antegrade
blood cardioplegia according to Buckberg and a-stat pH

I.V. group (PROP)

Volatile group
(SEVO)

Induction of
anaesthesia

Etomidate 0.2 0.3 mg kg21, sufentanil 1 mg


kg21, pancuronium 0.07 0.1 mg kg21

Maintenance of
anaesthesia
before and after
CPB

Remifentanil 0.2
0.25 mg kg21 min21,
propofol 3 5 mg
kg21 h21 achieving a
BIS of 40 50

During CPB

Propofol 3 5 mg kg21 h21 according to BIS


(aim 40 50)

Remifentanil 0.2
0.25 mg kg21 min21,
sevoflurane 0.6 1
MAC (age-adapted)
achieving a BIS of
40 50

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The study is registered in the European Clinical Trials Database no. 2005-004928-39 and the ISRCTN Register
(ISRCTN44821042).
After approval of the local ethical committee and written
informed consent, 128 patients undergoing elective cardiac
surgery with CPB were enrolled in this prospective randomized study. Exclusion criteria were age below 18 yr, overt
neurological diseases or dementia, significant stenosis of
the carotid arteries, pregnancy, contraindications for sevoflurane, insufficient knowledge of the German language,
and emergency indication.
The randomization was performed after written informed
consent was obtained. Multiple randomization lists stratified
by age (,65 and 65 yr) and type of operative procedure
(CABG, valve, or combined procedures) were used to
provide equal groups.

management. After weaning from CPB, protamine was


applied as appropriate.

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Cerebral oxygen saturation measurement


Regional cerebral oxygen saturation (ScO2 ) measurement was
started before induction of anaesthesia with the patient
breathing room air, using this value as the baseline.
Cerebral desaturation was defined as intraoperative
ScO2 , 50%.
Measurement was continued throughout the surgical procedure and ICU stay until extubation. The INVOS monitor was
covered to the attending physician throughout the data collection. The analysis of the collected data was performed
after cessation of the study period.

Markers of organ function and clinical outcome


parameters
On the day before surgery, after admission to the ICU, and
days 2, 4, and 6 after surgery, blood tests included electrolytes, creatinine, liver enzymes, white and red blood cell
counts, creatine kinase, troponin, S100-b, and C-reactive
protein. Haemodynamic variables, temperature, and blood
gas analyses were obtained several times intraoperatively
at defined stages of cardiac surgery. The duration of
surgery and CPB, aortic cross-clamp time, intraoperative
need for cardiac assist devices, inotropic agents, vasopressors, blood components, and insulin were documented.
The clinical outcome was compiled in the four major
organ systems: brain, kidney, heart, and lung, as described
in Table 2. One point was added for each developing complication, comprising a Major complication Score (MaCS) with a
minimum of 0no complication and a maximum of
4complications in major organ systems.

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Table 2 Definition of major organ system complications. AMT,


Abbreviated Mental Test; CI, cardiac index; ICU, intensive care unit
Organ system
complication

Definition

Brain

AMT ,6 at any of the 3 postoperative


measurements and/or focal cerebral deficit

Kidney

Increase in creatinine .0.3 mg dl21 within


48 h

Heart

CI ,2.5 for more than 2 h during ICU stay


and/or need for noradrenalin .0.5 mg h21
and/or dobutamine .25 mg h21 and/or
milrinone .1.2 mg h21 at any time during
ICU stay

Lung

Need for mechanical ventilation for more


than 12 h and/or need for reintubation

Statistical analysis
If not stated otherwise, data are given as mean (SD). The
Kolmogorov Smirnov test was used for identification of the
normality of distribution. Univariate statistics were performed by Students t-test for independent samples or the
x 2 test (nominal data) as appropriate. Binary logistic
regression was performed to determine predictors for the
ability to perform cognitive tests 2 days after cardiac surgery.
The analysis was performed with a 22-factorial plan with
the randomized factor anaesthesia-protocol and the factor
desaturation. Reasons for omitting the tests were documented and analysed separately. Missing data were then amended
by the means of the respective groups. Group differences were
analysed by analysis of variances for repeated measures with
the factors, time, anaesthesia protocol, and desaturation
(MANOVA). In the case of preoperative group differences, the preoperative test result was incorporated as the covariate (MANCOVA).
Statistical significance was assessed at the 5% level.
The statistical analysis was performed without a-adjustment;
therefore, the results are considered mainly explanatory.

Results
Recruitment
A total of 153 patients fulfilled the inclusion criteria during
the study period, but 25 patients refused to participate in
the study, leaving 128 patients for randomization.
Sixty-four patients were randomized for each anaesthesia
regimen; 11 patients could not be analysed for various
reasons (Fig. 1), leading to the final n60 patients in the propofol group and n57 in the sevoflurane group. In the propofol group, n14 (25%) patients had intraoperative cerebral
desaturation and n42 (75%) patients had no desaturation.
In n4 patients, the ScO2 measurement could not be analysed correctly. In the sevoflurane group, n20 (37%)
patients had desaturation and n34 (63%) had no desaturation; in n3 patients, the measurement could not be analysed. The incidence of desaturation was not significantly
different in the anaesthesia groups (P0.172).

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Inventory (NGI).19 All tests can be requested in printed form


from the corresponding author.
The German self-report inventory BSKE (Befindlichkeitsskalierung anhand von Kategorien und Eigenschaftswortern)20 was used to measure the positive and the
negative mood.
The Abbreviated Mental Test (AMT)21 was used to assess
cognitive impairment, dementia, or postoperative delirium.22
Information processing was assessed by a German TrailMaking Test (TMT).23 A modified version of the Stroop Test
was used to measure directed attention and interference.23
For the assessment of memory ability, patients were required
to reproduce 10 previously read words without a time
restriction [Word List (WL-N)].
All neurocognitive tests were performed by three trained
investigators who instructed the patients in a standardized
manner. The investigators were blinded to the anaesthesia
protocol.
If patients were still on respirator or haemodynamically
unstable in the ICU or if they were disorientated or unresponsive, they were referred to as cannot perform test. Patients
who had to stop testing due to fatigue or other discomfort
were documented as did not complete test. These two
groups were compiled in the group not able to be tested.

Schoen et al.

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Cognitive function after sevoflurane- vs propofol-based anaesthesia

Assessed for eligibility n=153

Refused to participate
n=25

Randomized n=128

Allocated to sevofluranebased anaesthesia n=64


Received allocated
intervention n=62
Operation cancelled n=2

Lost to follow up:


operative re-exploration
n=2

Lost to follow up:


operative re-exploration
n=3
patient died n=2

Analysed n=60

Analysed n=57

Fig 1 Flow chart of patient recruitment and reasons for exclusion from the analysis of patients after a sevoflurane- or propofol-based anaesthesia during on-pump cardiac surgery.

Cognitive function
Analysis of the baseline cognitive tests on the day before
surgery showed a main effect of cerebral desaturation in
the AMT and in the WL-N. Patients with subsequent intraoperative cerebral desaturation had lower scores in the
AMT and remembered fewer words in the WL-N (Table 3).
To adjust for the differences in the baseline measurements, an analysis of covariance with repeated measures
was performed for the AMT and WL-N with the preoperative
test result as the covariate (MANCOVA).
Table 4 summarizes the results of the analysis of variance
for repeated measures.
A main effect for intraoperative desaturation was present in
three of the four cognitive tests. Patients with intraoperative
desaturation showed worse results in the AMT, Stroop Test,
and TMT. A main effect was found for the anaesthesia
regimen in all four cognitive tests. Patients with sevofluranebased anaesthesia showed better results in all tests. Further,
a main effect for the time of measurement was found in all
cognitive tests. Worst results were found on day 2 after surgery.
Interactions were found between the anaesthesia
regimen and desaturation in all four tests; patients with

desaturation under propofol showed worse results than


those with desaturation under sevoflurane. The interaction
between anaesthesia and time reached significance only in
one test, whereas the interaction between time and desaturation was significant in three tests; patients with and
without desaturation showed timecourse differences in
the linear trend. The interaction between time, anaesthesia,
and desaturation was significant in all four tests. Figure 2A D
illustrates the results.

Organ function
There were no relevant differences in patient characteristic
data, baseline laboratory results, and surgery-related data
(Table 3). There was a significant main effect regarding cerebral desaturation in the baseline ScO2 . Patients who subsequently developed cerebral desaturation had lower
baseline ScO2 immediately before surgery (Table 3).
The analysis of variance for repeated measures showed no
relevant main effects or interaction between the anaesthesia
regimen and intraoperative cerebral desaturation in creatinine, troponin I, S100-b, or C-reactive protein (Fig. 3A D).

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Allocated to propofol-based
anaesthesia n=64
Received allocated
intervention n=62
Unexpected off-pump
procedure n=1
Accidentally wrong type of
anaesthesia n=1

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Schoen et al.

Table 3 Patient characteristics, baseline cognitive tests, surgery-related data, and baseline laboratory results. If not mentioned otherwise, data
are shown as mean (SD) (range) for age, or mean (SD). ScO2 , regional cerebral oxygen saturation; AMT, Abbreviated Mental Test; Stroop, Stroop
Test; TMT, Trail-Making Test; WL-N, Word List; CRP, C-reactive protein; Trop I, troponin I; CK, creatine kinase; CABG, coronary artery bypass
grafting; Valve, valve replacement or repair; CPB, cardiopulmonary bypass; AoX, aortic cross-clamp
Propofol group

Sevoflurane group

Anova

No desaturation
(n542)

Desaturation
(n514)

No desaturation
(n534)

Desaturation
(n520)

Main effect
desaturation

Main effect
anaesthesia

Interaction

62.7 (8.5)
(43 76)

67.6 (8.5)
(53 79)

65.1 (7.3)
(44 76)

64.2 (8.7)
(52 82)

0.380

0.104

0.027

EuroScore

3.2 (2.5)

4.4 (3.0)

4.0 (3.1)

4.3 (3.5)

0.241

0.579

0.518

Gender

Male, n34
(81%)

Male, n9
(64.3%)

Male, n27
(79.4%)

Male, n11
(55%)

Female, n8
(19%)

Female, n5
(35.7%)

Female, n7
(20.6%)

Female, n9
(45%)

Baseline ScO2

66.0 (4.6)

57.6 (8.6)

66.2 (6.0)

60.2 (7.8)

0.000

0.073

0.107

Baseline AMT
(score)

8.7 (0.9)

8.0 (1.2)

8.8 (0.9)

8.4 (0.9)

0.007

0.178

0.470

Baseline Stroop
(s)

51.4 (15.9)

58.3 (21.0)

51.7 (16.6)

45.55 (7.3)

0.904

0.062

0.049

Baseline TMT (s)

33.9 (14.9)

44.07 (26.5)

34.2 (15.0)

36.5 (20.0)

0.294

0.070

0.058

Baseline WL-N
(words)

5.6 (1.1)

4.7 (1.5)

5.3 (1.5)

4.9 (1.0)

0.019

0.876

0.393

Creatinine
clearance (ml
min21)

102.5 (27.9)

91.1 (37.3)

91.9 (28.4)

93.7 (28.7)

0.447

0.528

0.293

Age (yr)

Missing n1

7.6 (7.5)

16.0 (28.9)

8.2 (9.1)

14.1 (16.6)

0.019

0.826

0.686

Trop I (mg
litre21)

0.04 (0.16)

0.06 (0.16)

0.02 (0.06)

0.15 (0.49)

0.166

0.608

0.373

CK (mg litre21)

82.1 (45.3)

102.1 (79.8)

102.4 (67.9)

83.8 (48.1)

0.954

0.938

0.121

CK-MB (mg
litre21)

10.0 (5.4)

11.5 (5.4)

9.4 (3.1)

12.1 (9.3)

0.084

0.988

0.604

S100-b (mg
litre21)

0.06 (0.03)

0.07 (0.02)

0.06 (0.04)

0.08 (0.05)

0.286

0.670

0.482

Type of surgery

CABG, n29
(69%)

CABG, n5
(35.7%)

CABG, n21
(61.8%)

CABG, n14
(70%)

Valve, n8
(19%)

Valve, n3
(21.4%)

Valve, n5
(14.7%)

Valve, n2
(10%)

Combination,
n5 (11.9%)

Combination,
n6 (42.9%)

Combination,
n8 (23.5%)

Combination,
n4 (20%)

Duration of
operation (min)

226 (52)

244 (83)

251 (53)

245 (66)

0.650

0.310

0.329

Duration of CPB
(min)

88 (20)

109 (27)

114 (40)

105 (38)

0.380

0.104

0.027

Duration of AoX
(min)

73 18

87 (28)

94 (37)

87 (35)

0.593

0.077

0.103

There were no significant group differences in the MaCS


(Table 2). However, more patients with desaturation under
propofol had one or more complications (P0.018; Fig. 4).
There were no group differences regarding ventilation
time or length of stay in the ICU, in the high dependency
unit, or the hospital (data not shown).

Ability to perform tests


Two days after surgery, 62 patients (53.0%) completed the
cognitive tests. Twenty (17.1%) patients refused to do the
tests, and in seven cases (6.0%), the data were incomplete

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or missing for unknown reasons. Twenty-eight (23.9%)


patients were labelled not able to be tested (see the
Methods section). The characteristics of patients who were
not able to be tested 2 days after cardiac surgery are
shown in Table 5. These patients were older, had more
often a lower educational level, and suffered from diabetes
mellitus compared with the patients who did complete the
tests. Patients who had refused testing were excluded from
this analysis. More patients who were not able to be tested
had received a propofol-based anaesthesia (P0.046).
The type and duration of operation, CPB time, and aortic

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CRP (mg dl21)

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Cognitive function after sevoflurane- vs propofol-based anaesthesia

Table 4 Analysis of variance with repeated measures for the cognitive tests. *Analysis of covariance. AMT, Abbreviated Mental Test; WL-N, Word
List
AMT*

Trail-Making Test

WL-N*

Stroop Test
F

Desaturation

6.37

0.013

5.21

0.024

5.53

0.020

0.27

0.602

Anaesthesia

24.47

0.000

12.16

0.001

18.45

0.000

15.09

0.000

Time

4.18

0.017

12.71

0.000

41.51

0.000

11.25

0.000

Anaesthesiadesaturation

12.36

0.001

15.18

0.000

19.20

0.000

9.78

0.002

Timeanaesthesia

2.12

0.122

2.56

0.069

3.00

0.050

6.92

0.001

Timedesaturation

0.31

0.734

4.06

0.013

3.27

0.038

8.02

0.000

Timeanaesthesiadesaturation

3.78

0.025

3.06

0.040

10.50

0.000

6.11

0.003

Main effect

Interaction

Discussion
In the present study, patients who developed intraoperative
cerebral desaturation showed worse early postoperative cognitive test results than those without cerebral desaturation.
Cerebral desaturation has been defined as intraoperative
regional cerebral oxygen saturation below 50% of the
absolute value measured with near-infrared spectroscopy.
However, patients who subsequently developed cerebral
desaturation did not only start with lower baseline cerebral
oxygen saturation but also showed worse baseline test
results in two of the four cognitive tests used. The differences
in baseline cognitive status could be eliminated statistically
for the analysis of the postoperative tests results, but the
fact that patients suffering desaturation had lower baseline
cognitive performance by chance allows investigation of a
known cerebral insult (subsequent desaturation events) in
the setting of decreased cognitive performance pre-insult.
Stern24 has introduced the model of cognitive reserve. It
refers to the individual differences in the cognitive processes
that allow some people to cope better with brain pathology
than others and has been related to intelligence, age, educational level, and social activity, many of which were

significant predictors of postoperative cognitive performance


in our study (Table 5). The association of desaturation events
with subsequent poor cognitive test results might therefore
be understood as a physiological insult which has its greatest
effect in patients with low cognitive reserve.
Intraoperative cerebral desaturation measured with nearinfrared spectroscopy has been shown to be associated with
postoperative central nervous system dysfunction. The definition of which threshold is regarded as potentially harmful
desaturation varies. Yao and colleagues7 described a cerebral
desaturation below 40% of the absolute values to be predictive of postoperative cognitive impairment. Slater and
colleagues10 showed that a desaturation of more than
3000 s % below 50% of the absolute values was associated
with cognitive decline and prolonged hospital stay. In the
present study, only a total of nine patients in both groups
showed desaturations below 40% of the absolute value.
We therefore decided to choose the cut-off value of
ScO2 , 50% described by Slater and colleagues. In our
cohort, the mean area under the curve below 50% was
2295 s % for both hemispheres added. The declines in cerebral oxygenation observed in the present study must therefore be regarded as moderate desaturation. The differences
in cognitive test results in the present study between
patients with and without cerebral desaturation support
the tighter threshold of ScO2 .
The first postoperative cognitive tests were conducted 2
days after surgery. According to Silbert and colleagues,25
cognitive testing should be possible as early as 18 h after
cardiac surgery with a completion rate above 60%.
However, in the present study, only 53% completed the cognitive tests on day 2 after surgery. We did not discriminate
the reasons for not being able to conduct the tests. This
could be ongoing sedation in the ICU or inability to communicate with the investigators due to disorientation. Interestingly, the patients who could or could not conduct the
cognitive testing had a comparable preoperative EuroScore,
type of surgery, and duration of surgery and CPB and comparable intraoperative haemodynamics but differed in the
baseline ScO2 . Patients who could not completely accomplish

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cross-clamp were comparable and the groups did not differ


in any intraoperative haemodynamic parameter or requirements of vasopressors or inotropic drugs (data not shown).
Patients who were not able to be tested had lower baseline
ScO2 (P0.008) and had more often suffered intraoperative
cerebral desaturation with ScO2 , 50% (P0.025) or
ScO2 , 45% (P0.001). Both groups had comparable ventilation times, but patients who could not complete the tests
had a longer ICU stay.
The parameters of age, educational level, baseline ScO2 ,
intraoperative cerebral desaturation below ScO2 , 50%, and
the anaesthesia regimen were inserted in a binary logistic
regression model. It identified age above 65 yr, low educational level, and desaturation with ScO2 , 50% as independent predictors of the inability to accomplish cognitive tests
2 days after surgery (Table 6).

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Schoen et al.

A 9.5

B 100

9.0

90
Stroop Test (s)

AMT scores

8.5
8.0
7.5
7.0

Propofol without desaturation


Propofol with desaturation
Sevoflurane without desaturation
Sevoflurane with desaturation

80
70
60
50

6.5

40

6.0
POD 4

Before surgery POD 2

POD 6

Time of measurement

POD 4

POD 6

Time of measurement

C 120

D 6.0
5.5

100
WL-N Words

TMT (s)

5.0
80

60

4.5
4.0
3.5

40
3.0
2.5

20
Before surgery POD 2

POD 4

POD 6

Time of measurement

Before surgery POD 2

POD 4

POD 6

Time of measurement

Fig 2 Results of the cognitive tests in patients after a sevoflurane- or propofol-based anaesthesia during on-pump cardiac surgery in patients
with and without cerebral desaturation. (A) AMT. Means and standard error of the mean. (B) Stroop Test. Means and standard error of the mean.
(C) TMT. Means and standard error of the mean. (D) Word List. Means and standard error of the mean. AMT, Abbreviated Mental Test; POD, postoperative day; TMT, trail-making-test; WL-N, Word List.

the cognitive tests had a longer ICU stay even though the
group differences in ventilation time did not reach statistical
significance. Old age, low educational level, and intraoperative cerebral desaturation were identified as independent
risk factors for not being able to perform a cognitive test
2 days after surgery. The predictive power of age, educational
level, and low ScO2 on the ability to take part in cognitive
testing supports the theory that these factors characterize
a group of patients with low cognitive reserve.
Even though the distinct effects in animal and in vitro
studies are suggestive of a clinical significance of anaesthetic
preconditioning of the brain,13 clinical data on neuroprotective effects of volatile anaesthetics are scarce.15 26 A small
retrospective study showed no effects of sevoflurane on
long-term cognitive function after CABG;26 another small

846

prospective study showed no benefit of isoflurane compared


with propofol regarding cognitive function. The present study
shows prospectively that patients after sevoflurane-based
anaesthesia showed better results than patients after
propofol-based anaesthesia in four independent cognitive
tests, despite a comparable pre- and intraoperative risk
profile. This finding suggests neuroprotective properties of
sevoflurane.
As the differences in cognitive performance did not affect
ventilation times, or length of stay in the ICU or the hospital,
they could be interpreted as a short-term effect on recovery
after anaesthesia27 with questionable clinical relevance. But
early cognitive disturbances have been shown to be associated with a higher risk of long-term cognitive impairment
with severe impact on the quality of life.4 28

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Before surgery POD 2

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Cognitive function after sevoflurane- vs propofol-based anaesthesia

Propofol without desaturation


Propofol with desaturation
Sevoflurane without desaturation
Sevoflurane with desaturation

A 100

B 0.8
0.6

90

Troponin T (mg litre1)

Creatinine (mmol litre1)

95

85
80
75
70

0.4

0.2

0.0
65

Before surgery POD 1

POD 2

POD 4

POD 6

Before surgery POD 1

Time of measurement

POD 2

POD 4

POD 6

Time of measurement

C 0.22

D 250
C-reactive protein (mg dl1)

0.20

S100-b (mg litre1)

0.18
0.16
0.14
0.12
0.10
0.08
0.06

200
150
100
50
0

0.04
Before surgery

POD 1

POD 2

POD 4

POD 6

Time of measurement

Before surgery

POD 1

POD 2

POD 4

POD 6

Time of measurement

Fig 3 Course of markers of organ function in patients after a sevoflurane- or propofol-based anaesthesia during on-pump cardiac surgery in
patients with and without cerebral desaturation. (A) Creatinine. Means and standard error of the mean. (B) Troponin T. Means and standard
error of the mean. (C) S100-b. Means and standard error of the mean. (D) C-reactive protein. Means and standard error of the mean.

The most interesting hypothesis of the present study


was the question whether a sevoflurane-based in comparison with a propofol-based anaesthesia regimen might
attenuate the effects of cerebral desaturation on cognitive
outcome after on-pump cardiac surgery. And indeed we
found a significant interaction between the anaesthesia
regimen and cerebral desaturation in all cognitive tests.
This result has to be interpreted carefully, as the groups
showed preoperative interaction with regard to age, with
patients receiving propofol and suffering desaturation
being older. This means that the group might have lower
cognitive reserve and therefore be more vulnerable to cerebral damage. The great number of more complex
surgical procedures in this group indicates that patients
receiving propofol and having desaturation might sustain
greater surgical trauma and might therefore be prone to

greater cerebral damage. However, the longer duration of


CPB in the sevoflurane group likewise means cerebral
hazard.
Keeping in mind these limitations, this finding might be
carefully interpreted as a preconditioning effect of sevoflurane on cerebral tissue. In an animal study by Zhu and colleagues,29 sevoflurane has recently been shown to
precondition the brain to inflammatory changes and ischaemia.30 The results of the present study are at least suggestive
of a clinical relevance of the preconditioning effects of sevoflurane on neuronal tissue. Whether these effects are based
on reduction in inflammatory response or ischaemiaprotective mechanisms cannot be differentiated by the
present data. However, this assumption has to be verified
in a more homogeneous population with a completely comparable preoperative condition and surgical trauma.

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60

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Schoen et al.

100
80
P=0.018

80
70

60
50
40
30
20
10
0
Propofol with
desaturation

Sevoflurane
Sevoflurane with
without desaturation
desaturation

No major complications
One or more major complications
Fig 4 Proportion of patients with no versus one or more major organ complications in the postoperative course.

We found no impact of the anaesthetic regimen on major


outcome criteria, like major organ dysfunction, ventilation
time, or length of stay in the ICU or the hospital, or laboratory results. However, these findings are in line with recent
observations of De Hert and colleagues,31 who could not
show any differences in troponin T in an unselected group
of patients after on-pump cardiac surgery between i.v. and
volatile anaesthesia.
Interestingly, we did find a disproportionately high
number of patients with one or more major organ complications in the group with cerebral desaturation under
propofol-based anaesthesia. Previously, our own group
could show an association between preoperative cerebral
oxygenation and postoperative morbidity and mortality.32
A low cerebral saturation can be interpreted either as a
sign of temporarily inadequate regional or global haemodynamic condition. An association between intraoperative
cerebral desaturation and postoperative morbidity would
therefore make sense even though the documented intraoperative parameters did not indicate any group differences
in the global haemodynamic condition. The alternative
interpretation would be the theory of ScO2 being an indicator
of underlying cerebral small vessel disease that might reduce
cognitive reserve.
The major limitation of the present study is the group size.
Despite the power analysis to calculate the sample size, the
effective group size was much smaller due to the inability of
patients to perform cognitive tests and a large number of
missing values having to be amended. This certainly
weakens the information given by the present study. On

848

the other hand, the differences in the number of dropouts


in the study groups have to be interpreted as results of the
intervention.
Another limitation is the lack of long-term outcome
testing. The effect of early cognitive function on long-term
cognitive performance was not subject to the present
study. But it has been shown that early cognitive deficits
can be associated with long-term functional decline and
impaired quality of life.4
A major limitation in this context is that we had no standardized test on delirium as a global cerebral deficit. The
CAM-ICU would have been a suitable tool to detect hyperand hypoactive delirium.33 We only used the AMT, which
can be interpreted as a global cognitive test22 but is not
specific for delirium. So, we cannot state any differences
between sevoflurane and propofol regarding the incidence
of postoperative delirium.
The data seem to be weakened by the fact that patients of
both groups received propofol during CPB and after operation
for sedation in the ICU. This interference in the treatment
could not be avoided due to technical reasons. The characteristic of anaesthetic preconditioning is that the protective
effect outlasts the duration of application of the volatile
anaesthetic.34 The fact that we applied propofol during the
potentially harmful period of CPB, therefore, does not contradict the assumption of the preconditioning effects of
sevoflurane.
In conclusion, the present study shows that an intraoperative cerebral desaturation is associated with a worse
early cognitive outcome after on-pump cardiac surgery,

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Propofol without
desaturation

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Cognitive function after sevoflurane- vs propofol-based anaesthesia

Table 5 Characteristics of patients who could or could not perform the cognitive testing 2 days after cardiac surgery. If not mentioned
otherwise, data are shown as mean (SD) (range) for age, or mean (SD). *Students t-test for independent samples; x 2 test. CABG, coronary artery
bypass grafting; Valve, valve replacement or repair; CPB, cardiopulmonary bypass; rScO2 , regional cerebral oxygen saturation; ICU, intensive care
unit. Educational level: 0, no graduation; 1, compulsory school; 2, secondary school; 3, vocational diploma; 4, general qualification for university
entrance; 5, technical college; 6, university degree
Patients who did perform tests, n562
(53.0%)

Patients who could not completely perform tests,


n528 (23.9%)

P-value

62.2 (8.44) (42 82)

66.8 (6.60) (53 78)

0.016*

Height (m)

173.1 (8.38)

169.7 (9.11)

0.110*

Weight (kg)

80.9 (4.12)

85.4 (14.30)

0.178*

Gender

Male, n48 (77.4%)


Female, n14 (22.6%)

Male, n18 (64.3%)


Female, n10 (35.7%)

0.192

EuroScore

3.6 (2.93)

4.3 (2.72)

0.251*

Educational level

2.5 (1.87)

1.8 (1.51)

0.029*

Diabetes

n7 (11.3%)

n8 (28.6%)

0.042

Chronic kidney disease

n27 (43.5%)

n15 (53.6%)

0.378

Anaesthesia-protocol

Propofol n28 (45.2%)


Sevoflurane n34 (54.8%)

Propofol: n19 (67.9%)


Sevoflurane: n9 (32.1%)

0.046

Operation

CABG: n34 (54.8%)


Valve: n12 (19.4%)
Combination: n16 (25.8%)

CABG: n17 (60.7%)


Valve: n3 (10.7%)
Combination: n8 (28.6%)

0.595

Duration of operation (min)

234.4 (53.04)

253.9 (75.17)

0.235*

Duration of CPB (min)

102.1 (32.04)

106.2 (31.79)

0.553*

Duration of aortic cross-clamp


(min)

83.4 (29.06)

87.4 (30.60)

0.604*
0.008*

Mean baseline rScO2 (%)

65.5 (5.28)

60.7 (7.86)

Minimal rScO2 below 50%

n14 (23.3%)

n12 (48.0)

0.025

Minimal rScO2 below 45%

n4 (6.7%)

n9 (36.0%)

0.001

Ventilation time (h)

7.6 (3.3)

9.1 (7.5)

0.331*

ICU length of stay (h)

23.4 (10.7)

38.4 (29.1)

0.013*

Hospital length of stay (days)

7.9 (3.8)

7.9 (3.3)

0.995*

Table 6 Binary logistic regression (Model: Simultaneous, including all variables) analysis with preoperative predictors on the ability to perform
cognitive tests 2 days after surgery
Parameter

P-value

Specification

Prevalence could not perform tests (%)

Odds ratio

95% CI

Age

0.026

65 yr
.65 yr

23.4
42.5

Reference
4.70

1.20 18.36

Educational level

0.010

More than compulsory school


Compulsory school or no graduation

18.4
42.9

Reference
7.40

1.62 33.91

Baseline rScO2

0.438

.62%
62%

23.8
40.0

Reference
0.481

0.08 3.06

Minimal rScO2

0.038

50%
,50%

22.0
46.2

Reference
5.83

1.10 30.79

Anaesthesia

0.052

Propofol
Sevoflurane

40.4
20.9

Reference
0.27

0.07 1.01

and this effect may be exaggerated in patients who have


evidence of diminished cognitive reserve before operation.
Further, the possibility exists that sevoflurane-based volatile
anaesthesia regimen might be associated with better cognitive function compared with a propofol-based anaesthesia
regimen.
Further investigation is needed to confirm the impact
of sevoflurane on global cerebral deficits and to

identify possible subgroups of patients who particularly


benefit from volatile anaesthesia regarding cognitive
function.

Conflict of interest
J.S. and M.H. received honoraria for lectures from Covidien
Germany.

849

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Age (yr)

BJA

Schoen et al.

Funding
The study has been funded by a scientific grant by Abbott,
Wiesbaden, Germany, and technical support by Covidien
Germany.

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17

References

850

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19

20

21
22

23
24
25

26

27

28

29

30

31

32

33

34

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1 Arrowsmith J, Grocott H, Reves J, Newman M. Central nervous


system complications of cardiac surgery. Br J Anaesth 2000; 84:
378 93
2 van Dijk D, Keizer AMA, Diephuis JC, Durand C, Vos LJ, Hijman R.
Neurocognitive dysfunction after coronary artery bypass
surgery: a systematic review. J Thorac Cardiovasc Surg 2000;
120: 632 9
3 Hogue CW Jr, Palin CA, Arrowsmith JE. Cardiopulmonary bypass
management and neurologic outcomes: an evidence-based
appraisal of current practices. Anesth Analg 2006; 103: 21 37
4 Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal
assessment of neurocognitive function after coronary-artery
bypass surgery. N Engl J Med 2001; 344: 395 402
5 Selnes OA, Pham L, Zeger S, McKhann GM. Defining cognitive
change after CABG: decline versus normal variability. Ann
Thorac Surg 2006; 82: 38890
6 Edmonds HL Jr, Ganzel BL, Austin EH 3rd. Cerebral oximetry for
cardiac and vascular surgery. Semin Cardiothorac Vasc Anesth
2004; 8: 147 66
7 Yao FS, Tseng CC, Ho CY, Levin SK, Illner P. Cerebral oxygen desaturation is associated with early postoperative neuropsychological
dysfunction
in
patients
undergoing
cardiac surgery.
J Cardiothorac Vasc Anesth 2004; 18: 5528
8 Goldman S, Sutter F, Ferdinand F, Trace C. Optimizing intraoperative cerebral oxygen delivery using noninvasive cerebral oximetry
decreases the incidence of stroke for cardiac surgical patients.
Heart Surg Forum 2004; 7: E376 81
9 Murkin JM, Adams SJ, Novick RJ, et al. Monitoring brain oxygen
saturation during coronary bypass surgery: a randomized, prospective study. Anesth Analg 2007; 104: 518
10 Slater JP, Guarino T, Stack J, et al. Cerebral oxygen desaturation
predicts cognitive decline and longer hospital stay after cardiac
surgery. Ann Thorac Surg 2009; 87: 36 45
11 Schoen J, Serien V, Hanke T, et al. Cerebral oxygen saturation
monitoring in on-pump cardiac surgery: a 1-year experience.
Appl Cardiopulm Pathophysiol 2009; 13: 24352
12 Casati A, Fanelli G, Pietropaoli P, et al. Monitoring cerebral oxygen
saturation in elderly patients undergoing general abdominal
surgery: a prospective cohort study. Eur J Anaesthesiol 2007;
24: 59 65
13 Kitano H, Kirsch JR, Hurn PD, Murphy SJ. Inhalational anesthetics
as neuroprotectants or chemical preconditioning agents in
ischemic brain. J Cereb Blood Flow Metab 2007; 27: 110828
14 Kapinya KJ, Lowl D, Futterer C, et al. Tolerance against ischemic
neuronal injury can be induced by volatile anesthetics and is
inducible NO synthase dependent. Stroke 2002; 33: 1889 98
15 Kanbak M, Saricaoglu F, Avci A, Ocal T, Koray Z, Aypar U. Propofol
offers no advantage over isoflurane anesthesia for cerebral protection during cardiopulmonary bypass: a preliminary study of
S-100{beta} protein levels: [Lanesthesie au propofol, compare a
lisoflurane, na pas davantage pour la protection cerebrale

pendant la circulation extracorporelle: une etude preliminaire


des niveaux de proteines S-100{beta}]. Can J Anesth 2004; 51:
712 7
Cohen J, editor. Statistical Power Analysis for Behavioral Sciences,
2nd Edn. Hillsdale, NJ: Lawrence Erlbaum, 1988
Murkin JM, Newman SP, Stump DA, Blumenthal JA. Statement of
consensus on assessment of neurobehavioral outcomes after
cardiac surgery. Ann Thorac Surg 1995; 59: 128995
Gameiro M, Eichler W, Schwandner O, et al. Patient mood and
neuropsychological outcome after laparoscopic and conventional
colectomy. Surg Innov 2008; 15: 1718
Aufdembrinke B, Ott H, Rohloff H. Measures of memory and information processing in elderly volunteers. Pschopharmacol Ser
1988; 6: 4864
Hueppe M, Uhlig T, Vogelsang H, Schmucker P. Personality traits,
coping styles, and mood in patients awaiting lumbar-disc
surgery. J Clin Psychol 2000; 56: 119 30
Hodkinson HM. Evaluation of a mental test score for assessment
of mental impairment in the elderly. Age Ageing 1972; 1: 233 8
Ni Chonchubhair A, Valacio R, Kelly J, OKeefe S. Use of the abbreviated mental test to detect postoperative delirium in elderly
people. Br J Anaesth 1995; 75: 4812
Oswald WD, Fleischmann UM. Das Nurnberger Altersinventar
(NAI). Gottingen: Hogrefe, 1997
Stern Y. Cognitive reserve. Neuropsychologia 2009; 47: 201528
Silbert BS, Scott DA, Doyle TJ, et al. Neuropsychologic testing
within 18 hours after cardiac surgery. J Cardiothorac Vasc
Anesth 2001; 15: 20 4
Kadoi Y, Goto F. Sevoflurane anesthesia did not affect postoperative cognitive dysfunction in patients undergoing coronary artery
bypass graft surgery. J Anesth 2007; 21: 3305
Gupta A, Stierer T, Zuckerman R, Sakima N, Parker SD, Fleisher LA.
Comparison of recovery profile after ambulatory anesthesia with
propofol, isoflurane, sevoflurane and desflurane: a systematic
review. Anesth Analg 2004; 98: 63241, table of contents
Newman MF, Grocott HP, Mathew JP, et al. Report of the substudy
assessing the impact of neurocognitive function on quality of life
5 years after cardiac surgery. Stroke 2001; 32: 287481
Zhu J, Jiang X, Shi E, Ma H, Wang J. Sevoflurane preconditioning
reverses impairment of hippocampal long-term potentiation
induced by myocardial ischaemia-reperfusion injury. Eur J Anaesthesiol 2009; 26: 9618
Sanders RD, Maze M. Neuroinflammation and postoperative
cognitive dysfunction: can anaesthesia be therapeutic? Eur J
Anaesthesiol 2010; 27: 3 5
De Hert S, Vlasselaers D, Barbe R, et al. A comparison of volatile
and non volatile agents for cardioprotection during on-pump coronary surgery. Anaesthesia 2009; 64: 953 60
Heringlake M, Garbers C, Kaebler J-K, et al. Preoperative cerebral
oxygen saturation and clinical outcomes in cardiac surgery.
Anesthesiology 2011; 114: 58 69
Klugkist M, Sedemund-Adib B, Schmidtke C, Schmucker P,
Sievers HH, Huppe M. Confusion Assessment Method for the
Intensive Care Unit (CAM-ICU): diagnosis of postoperative delirium in cardiac surgery. Anaesthesist 2008; 57: 464 74
Kehl F, Payne RS, Roewer N, Schurr A. Sevoflurane-induced preconditioning of rat brain in vitro and the role of KATP channels.
Brain Res 2004; 1021: 76 81