Dementia Clinical Trial
Official title:
Association Between Changes in Cerebral Gray Matter Volume and Postoperative Cognitive Dysfunction in Elderly Patients Following Sevoflurane Anesthesia (POCD-MRI)
Despite an ongoing controversy in the scientific literature, the link between anesthesia and
dementia and/or cerebral atrophy remains unclear. Recent retrospective data suggests an
association of surgery with a reduction in brain volume. With the present prospective cohort
study, we would like to reproduce and verify these results, and investigate a possible
association with the postoperative cognitive performance.
We will measure cerebral gray matter volumes in elderly patients before, 3 and 12 months
after major non-cardiac surgery and determine cognitive functions at the same time.
Study hypothesis:
1. Surgery under general anesthesia in elderly patients is associated with a loss of gray
matter.
2. The degree of cognitive dysfunction is associated with the loss of grey matter in brain
areas relevant for cognitive functions.
Background:
Anesthesia care for elective surgery of patients that are in their seventies or eighties is
an ever-growing entity in clinical practice, given the demographic development in many
countries of the Western world. Cognitive decline of variable degree is frequently observed
after major surgery in elderly patients. A potential association between anesthesia and the
development of dementia and brain atrophy in elderly patients is controversial. However, it
is not uncommon that during preoperative visits by the anesthesiologist, patients express
fear to suffer some sort of cognitive decline after the operation, and raise concerns about
psychological or neurological long-term adverse effects (e.g. memory loss) related to
anesthesia. Clinicians have identified this problem decades ago, and are adding postoperative
cognitive dysfunction (POCD) to the list of frequent complications of anesthesia in elderly
patients; yet, there is a lack of prospective clinical data and poor understanding of the
pathophysiology of POCD, and no preventive strategy or treatment has been described so far.
One study reported an incidence of postoperative cognitive dysfunction (POCD) of 41% in
surgical patients 60 years of age, or older. In a previous study conducted by our group, as
many as 47% of patients over 65 years presented with POCD one week after surgery. In many
patients, this is a transient problem, but some patients retain permanent deficits, with
increased mortality and important consequences on the socioeconomic situation. An association
between surgery and long-term cognitive decline has not been established yet; however,
patients who develop postoperative delirium (a transient, but particularly severe form of
POCD) have an increased risk of developing dementia in the years following surgery. However,
in a cohort follow-up study, the diagnosis of POCD itself did not represent a significant
risk factor for dementia. The pathophysiology of postoperative cognitive decline remains
unclear. However, studies in animals have shown that the systemic inflammatory response
elicited by the surgical procedure is associated with microglial activation and postoperative
cognitive impairment. Furthermore, volatile anesthetics have been shown to be neurotoxic in
cell cultures, and in some animal experiments exposure to clinical concentrations of volatile
anesthetics was associated with postoperative cognitive decline. A recent retrospective
analysis of cohort data suggests that surgery may be associated with a decrease in brain
volume in patients. However, due to methodological limitations in this study, no analysis of
a potential link between atrophy and cognitive functions was made.
Study Design:
Prospective cohort study
Study Groups:
Two groups of patients will be investigated. Seventy patients undergoing major surgical
procedures will be recruited for this study, and 30 healthy study participants (no surgical
intervention) will be recruited to serve as controls. In all patients, baseline cognitive
functions and structural MRI imaging including determination of gray matter volumes relevant
for cognitive functions (hippocampus) will be performed.
- Group 1: Surgery group Sevoflurane (n = 70)
- Group 2: Control group (n = 30)
Recruitment:
Study participants of the Surgery group Sevoflurane (Group 1) will be recruited as patients
of the Basel University Hospital, a tertiary medical care center in Basel, Switzerland,
associated with the University of Basel, Switzerland. Study participants of the Control group
(Group 2) will be recruited randomly.
Endpoints:
Targeted primary endpoint of the study is the difference in change of hippocampal volume over
time between patients with POCD and patients without POCD.
Secondary endpoint is the correlation between change in cerebral volume and change in
cognitive function.
Anesthetic Management:
Anesthesia will be standardized (general anesthesia using sevoflurane and fentanyl for
maintenance, thiopental for induction and atracurium or rocuronium for neuromuscular
blockade). Intraoperatively, the dose of anesthetics will be controlled using an EEG derived
index (depth of anesthesia monitoring (Bispectral Index (BIS), Aspect Medical Systems), and
end-tidal sevoflurane concentration monitoring). Furthermore, intraoperative bilateral
cerebral near-infrared spectroscopy (NIRS) monitoring (NIRO-200, Hamamatsu Photonics, Japan)
will be applied. Data will be downloaded directly from the monitors and the anesthesia
machine (Dräger Perseus) using ICM+ software.
Neuropsychological Assessment:
The cognitive assessment test battery CERAD-Plus consistent of the Consortium to Establish a
Registry for Alzheimer's Disease - Neuropsychological Assessment Battery (CERAD-NAB), Trail
Making Tests A+B, and phonetic fluency (s-words), as well as the Test for Attentional
Performance (TAP) developed to analyze different aspects of attention, will be performed
preoperatively, at 7 days, 3 month and 12 months postoperatively. Training of all study
personnel and supervision of cognitive testing will be carried out by the Memory Clinic at
Basel University Hospital. Cognitive functions will be quantified using the CERAD total
score, in its demographically corrected form. A correction for short-term practice effects
will be carried out based on previous work.
Blood Samples:
Blood samples will be taken from study participants preoperatively, 12h postoperatively, and
on day 2 and 7, to determine levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor
necrosis factor-alpha (TNF-alpha). Blood samples will be stored for 1 year to allow
additional determinations.
Demographic, Procedural and Subjective Patient Data:
- Age, sex, and years of education.
- Cognitive testing as outlined: CERAD-Plus (CERAD-NAB, Trail Making Tests A+B, phonetic
fluency (s-words)), Test for Attentional Performance (TAP), preoperatively, at 7 days, 3
months and 12 months postoperatively.
- Charlson Comorbidity Score preoperatively, at 3 months and 1 year postoperatively
- Instrumental Activities of Daily Living (IADL) preoperatively, at 3 months and 1 year
postoperatively.
- Geriatric Depression Scale (GDS) preoperatively, at 3 months and 1 year postoperatively.
- Short Form Health Survey (SF-36) preoperatively, at 3 months and 1 year postoperatively.
- ASA physical status, type and duration of anesthesia, type and duration of surgery.
- Postoperative delirium (Confusion Assessment Method; CAM), repeat surgery and
postoperative infections.
- Subjective grading of cognitive functions on a VAS scale (0-10) preoperatively, at 7
days, 3 months and 1 year postoperatively.
- Subjective grading of change in cognitive functions on a five-point Likert scale (much
worse, worse, equal, better, much better) at 7 days, 3 months and 1 year
postoperatively.
- Subjective grading of successful surgery (Yes/No) at 7 days, 3 months and 1 year
postoperatively.
- Subjective grading of pain on a VAS scale (0-10) preoperatively, 7 days, 3 months and 1
year postoperatively.
Magnetic Resonance Imaging (MRI):
MRI will be performed preoperatively, at 3 months, and 1 year postoperatively on the same day
as cognitive function testing. No intravenous contrast dye will be administered. Training of
all study personnel and MRI evaluation, and/or supervision of MRI evaluation, will be carried
out by the Division of Neuroradiology at the University Hospital Basel. High resolution
anatomic and diffusion MRI will be performed using the hospital's 3T MAGNETOM Prisma™ MRI
scanner (Siemens, Zurich, Switzerland). For our initial MRI analysis, we assume that the same
regions as those described in mild cognitive impairment (MCI) and Alzheimer's disease (AD)
are relevant to POCD. We will perform a region of interest (ROI) analysis during this part of
the analysis. In a second step, we will perform a whole brain analysis.
The whole brain MRI protocol includes high resolution three-dimensional (3D)-T1 (MPRAGE
sequence, repetition time (TR) = 1620 ms, echo time (TE) = 2.48 ms, 192 slices), clinical
standard at the University Hospital Basel) and 3D-T2 (SPACE sequence, TR = 3200 ms, TE = 408
ms, 192 slices) imaging for segmentation. Furthermore, a diffusion sequence (DTI sequence, TR
= 5800 ms, TE = 77 ms, 50 slices, 64 directions, 8 B0) for quantitative imaging will be used.
We added a two-dimensional (2D)-PD/T2 weighted sequence (TSE sequence, TR = 4480 ms, TE1 = 9
ms, TE2 = 106 ms, 46 slices) for diagnostic purposes. The total acquisition time for the MRI
is approximately 24 minutes.
Statistical Analysis:
Cortical reconstruction and volumetric segmentation will be performed with the FreeSurfer
image analysis suite, which is documented and freely available for download online
(http://surfer.nmr.mgh.harvard.edu/). The technical details of these procedures are described
in prior publications.
Comparisons (preoperatively to 3 months postoperatively) of hippocampal volume and the
results of voxel-based volumetry of the medio-temporal lobe and lateral association areas of
the temporal and parietal lobes will be performed using region of interest (ROI) analysis.
The quantitative imaging results will be correlated to the CERAD total score performance
obtained on the same day as the MRI scans. The relationship of changes in volume (if present)
with intraoperative depth of anesthesia (BIS) and the administered dose of sevoflurane
expressed as age-corrected minimum alveolar concentration (MAC) equivalent multiplied by time
of administration will be calculated. We will also use multivariate approaches (voxel-wise
multivariate analysis (MANOVA) and classification/prediction procedure) on multi-parameter
MRI data in order to build optimal composite predictors of patients' neuropsychological
outcomes. In whole brain analysis, we will use a multiple regression and repeated measures
ANOVA whole brain voxel-wise analyses in FreeSurfer to correlate the estimated modulated gray
matter volume with the neuropsychological scores.
Sample Size Calculation:
Assuming that 41% of operated patients develop POCD, and a standard deviation of the
hippocampal volume change of 0.45 in both patients with POCD and without POCD, a total sample
size of 56 subjects may detect a difference of 0.4 mm3 in hippocampal volume with a power of
90% at a two-sided significance level of 5%. To compensate for the high loss to follow-up
which is unfortunately typical for studies on POCD, and estimated at 20%, we will recruit 70
patients in the surgery group.
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