Biblio AA Mars 2015

1. March 2015 • Volume 120 • Number 3 www.anesthesia-analgesia.org 649
Copyright © 2015 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000000624
T
he 4th International Workshop on Perioperative
Neurotoxicity in the elderly is part of a continu-
ing series to reflect the mounting interest and prog-
ress in the area. This meeting was held in conjunction
with the Euroanaesthesia 2014 Congress in Stockholm,
Sweden, on May 29, 2014. Hosted by the Department of
Anesthesiology and Intensive Care Medicine at Karolinska
Institutet, Stockholm, and organized by Niccolò Terrando,
Lars Eriksson (Karolinska Institutet, Sweden), and Roderic
Eckenhoff (University of Pennsylvania, PA), it included sci-
entists from 10 countries and topics ranging from delirium
to dementia, and molecular mechanisms to epidemiology.
In earlier workshops, there was an emphasis on the pre-
clinical rationale underlying perioperative neurotoxicity. In
this fourth workshop, there was a clear shift to translational
and clinical research to test the hypotheses flowing from
these previous laboratory studies. In this summary, we will
attempt to convey the progress, challenges, and remaining
questions. This is not meant to be a scholarly review of the
subject, and some of the points made herein reflect opinion
and unpublished data. We recognize that there is a paral-
lel concern for the immature brain. However, this was not
the focus of this workshop because it is being adequately
handled by other working groups.
NOMENCLATURE
There is agreement that the current nomenclature is con-
fusing and constitutes an impediment to future progress.
For example, some investigators “diagnose” postoperative
cognitive dysfunction (POCD) statistically at various times
after surgery, whether or not the patient (or family) notices a
decline. Some attendees insisted that POCD, in fact, requires
the patient to be asymptomatic, whereas others asserted that
outside formal studies, postoperative cognitive complaints
are very clearly symptomatic. Moreover, there is consider-
able confusion concerning whether POCD is always, or is
ever, reversible. Does POCD lead to dementia, or is demen-
tia that occurs any time after an operation a form of POCD?
Should postoperative delirium be considered an acute form
of POCD? Thus, an important outcome of the discussion was
the proposed creation of a consensus panel to draft a com-
prehensive nomenclature for what could be considered the
postoperative cognitive dysfunction syndromes (POCDS).
Within such a nomenclature, the importance of not imply-
ing causation was stressed. In fact, it was recognized that
some, perhaps most, surgery results in postoperative cogni-
tive improvement (POCI), especially in younger to middle-
aged populations. Some reported POCI is artifactual, a result
of learning and practice effects on repeated cognitive tests,
but a portion may reflect real cognitive improvement due to
the benefits of the surgery (e.g., pain relief, improved mobil-
ity) outweighing any detrimental effects. In summary, the
group agreed that a consensus nomenclature should allow
improved comparisons among studies and greater precision
when discussing these cognitive disorders and in evaluating
potential risk factors and mechanisms.
PRECLINICAL WORK
Of considerable recent interest has been the role of inflamma-
tion in cognitive dysfunction, in general. This is likely to be
relevant to the POCDs because of the very strong preclinical
support. Some of the potential mechanisms whereby cyto-
kines contribute to sickness behavior were discussed; Colm
Cunningham (Trinity College, Ireland), Daqing Ma (Imperial
College, UK), and Mervyn Maze (University of California,
San Francisco, CA) presented recent work showing con-
vincingly that inflammatory stimuli such as lipopolysac-
charide or peripheral surgery produce neuroinflammation
and short-term behavioral dysfunction in rodents and that
this dysfunction is considerably greater and more durable in
animals with a preexisting vulnerability (genetic, advanced
age, metabolic syndrome, neurodegeneration, etc.). This is a
critical and now widespread observation in animal models,
To learn the latest developments in the various forms of postoperative cognitive dysfunction, a
group of scientists and physicians met in Stockholm for a full day of presentations and interac-
tive discussions. This article summarizes the discussion; highlighting progress, challenges, and
new directions in the area of perioperative neurotoxicity in our aging population. (Anesth Analg
2015;120:649–52)
Perioperative Neurotoxicity in the Elderly: Summary
of the 4th International Workshop
Niccolò Terrando, PhD,* Lars I. Eriksson, MD, PhD,† and Roderic G. Eckenhoff, MD‡
From the *Department of Physiology and Pharmacology, Section for Anes-
thesiology and Intensive Care Medicine, Karolinska Institutet, Stockholm,
Sweden; †Department of Anesthesiology, Surgical Services and Intensive
Care Medicine Karolinska Institutet and Karolinska University Hospital,
Stockholm, Sweden; and ‡Department of Anesthesiology & Critical Care,
Perelman School of Medicine, University of Pennsylvania, Philadelphia,
Pennsylvania.
Accepted for publication November 13, 2014.
Members of the Fourth International Workshop on Perioperative
Neurotoxicity Research Consortium are listed in the Appendix.
Funding: Partial support provided by Baxter and by Masimo.
The authors declare no conflicts of interest.
Reprints will not be available from the authors.
Address correspondence to Roderic G. Eckenhoff, MD, Department of Anes-
thesiology & Critical Care, University of Pennsylvania, Perelman School of
Medicine, 311a John Morgan, 3620 Hamilton Walk, Philadelphia, PA 19104.
Address e-mail to roderic.eckenhoff@uphs.upenn.edu.
Special ArticleE
Section Editor: James DiNardo
Society for Pediatric Anesthesia

2. 650 www.anesthesia-analgesia.org anesthesia analgesia
E SPECIAL ARTICLE
which might partially explain why clinical studies have been
so inconsistent; the size and character of subgroups with
vulnerabilities are rarely known and likely differ among
studies. Potential mechanisms linking anesthesia, surgery,
and neuroinflammation include calcium dysregulation
(Huafeng Wei, University of Pennsylvania, PA), tauopathy
(Robert Whittington, Columbia University, NY), and amy-
loidopathy (Zhongcong Xie, MGH, Harvard University,
MA), but the linkage to cognitive decline remains largely
hypothetical. To begin to address this, Jianbin Tong (Central
South University, China) showed a loss of hippocampal den-
dritic spines associated with surgery-induced neuroinflam-
mation in aged rats. Furthermore, Hugh Hemmings (Cornell
University, NY) found that anesthetic exposure alone could
cause a similar loss of dendritic spines in rodent neurons.
These studies illustrate how surgery and anesthesia might
contribute to cognitive decline through a modulation of
neuronal and synaptic plasticity. Despite this intriguing pre-
clinical evidence for a causal role of anesthesia and surgery,
further preclinical studies are needed to better understand
the immune-to-brain signaling after peripheral injury, to
what extent this signaling is modulated by different anes-
thetics, how (or if) the ensuing inflammatory response leads
to cognitive decline, and whether dysfunction of inflamma-
tory resolution leads to a more prolonged cognitive decline.
Finally, given that the elderly seem to be at highest risk of
POCDS, it is important that these preclinical studies take
place in aged animals. Of course, all these questions ulti-
mately will need to be translated to elderly humans.
HUMAN BIOMARKERS
Because of the growing appreciation for the potential role
of preexisting vulnerabilities for POCDS, and because of
the need for objective measures of postoperative injury,
an array of human biomarkers is beginning to be studied.
The workshop started with a keynote presentation from Kaj
Blennow (Gothenburg University, Sweden), a world expert
in cerebrospinal fluid (CSF) and blood biomarkers of brain
injury, most notably Alzheimer disease (AD), and also head
trauma and surgery. Evidence is accruing for more sensi-
tive and specific biomarkers, which provides hope that the
study of POCDS will transition from the highly variable
(but still necessary) cognitive assays to continuous quan-
titative measures of neuronal injury and pathology. Novel
and extremely sensitive analytical technologies will permit
early detection of neurodegeneration and/or brain injury
in humans. It has been proposed in the AD field that these
early biomarkers can reflect the pathologic state while still
reversible, preceding the poorly reversible cognitive effects
by many years. Biomarkers are thus viewed as a promising
tool in evaluating progression and modulation of disease
trajectory. Early prospective studies on CSF AD biomark-
ers (amyloid-β and tau) were presented by Miles Berger
(Duke University, NC), Zhongcong Xie (MGH, Harvard
University, MA), and Lis Evered (St. Vincent’s Hospital,
Australia) most of which show only a small effect of uncom-
plicated surgery in nonselected individuals. In general, CSF
amyloid-β is not acutely sensitive to surgery, but CSF tau,
a marker of neuronal injury, seems to be. However, preop-
erative CSF amyloid-β and/or tau levels appear to predict
POCDS both acutely and at 1 year postoperatively. Again,
this suggests the importance of preexisting vulnerabilities
and subgroup analyses in future clinical studies. Biomarker
studies in patients hold the promise of both illuminating the
pathophysiology of POCDS and providing objective mark-
ers of disease progression.
Another form of biomarker is brain imaging. Joseph
Mathew (Duke University, NC) presented work in cardiac
surgerypatients,whichdemonstratespostoperativechanges
in functional magnetic resonance imaging (MRI), which
correlated with POCD. Preoperative amyloid burden, mea-
sured using 18
F-florbetapir positron emission tomography
(PET) imaging, was not correlated with POCD. Amyloid-β
burden as revealed by PET imaging changes quite slowly,
so repeat PET a year later is being conducted in a small
number of these subjects to assess whether cardiac surgery
is associated with accelerated amyloidopathy, as has been
previously proposed. Several other amyloid PET studies are
in progress, and data should be available in a year or 2. It is
relevant to note here that tau and microglia/monocyte PET
ligands are now available and might be useful to better doc-
ument more acute changes in disease trajectory after sur-
gery. Also using imaging, Charles Brown (Johns Hopkins
University, MD) found an association between number of
hospitalizations and structural changes on brain MRI in the
ARIC (Atherosclerosis Risk in Communities) cohort, which,
while not directly surgery (yet), suggests that the stress of
illness during hospitalization may be linked to worsening
neuropathology and cognitive decline.
Finally,geneticbiomarkersforcognitivedisordersarestart-
ing to be used to stratify POCDS studies. For example, Katie
Schenning (Oregon Health Science University, OR), when
analyzing the OBAS (Oregon Brain Aging Study) and ISAAC
(Intelligent Systems for Assessing Aging Changes) databases,
reported a significant association between surgery and subse-
quent dementia and that the association was stronger in the
apoEε4 allele carriers. Studies on the impact of apoEε4 on cog-
nitive outcomes after surgery have been inconsistent, but it is
emerging as one of the strongest predictors of late-onset AD
and thus, requires further study in the perioperative arena.
No studies have emerged on the impact of surgery on cog-
nitive outcomes in carriers of early-onset AD genetics, such
as PS-1, APPswe, or trisomy-21 (i.e., Down syndrome). Such
studies would be useful because these patients clearly possess
the vulnerabilities that we mention earlier.
CLINICAL STUDIES
Although neuroinflammation after anesthesia and sur-
gery is consistently reported in animal models, the evi-
dence for this in surgical patients is still scant. However,
several attendees reported intriguing preliminary results.
For example, Mervyn Maze (University of California San
Francisco, CA) presented very preliminary data on an asso-
ciation between both blood and CSF interleukin-6 and post-
operative delirium, while Tianlong Wang (Capital Medical
University, China) found an association between several
cytokines, including urine biomarkers, and POCDS, as well
as a strengthened interaction in the elderly. In exploring the
transition of peripheral inflammation to neuroinflammation
after surgery, Sven-Erik Ricksten (Gothenburg University,
Sweden) reported evidence for a disrupted blood-brain bar-
rier using both biomarkers and MRI. This is consistent with

3. Perioperative Neurotoxicity
March 2015 • Volume 120 • Number 3 www.anesthesia-analgesia.org 651
the recent evidence of blood-brain barrier impairment and
endothelial dysfunction after surgery in animals and there-
fore is at least 1 example of successful translation. However,
despite this evidence for enhanced neuroinflammation, glu-
cocorticoid administration (versus placebo) studies have
not yet been effective at preventing POCDS. Thus, while
translational studies on the role of neuroinflammation in
POCDS are few and inconclusive at this point, the strength
of the preclinical studies calls for more work in the area.
Several investigators are beginning to ask whether our
perioperative management can influence neuroinflam-
mation and cognitive outcomes; biomarkers will greatly
facilitate such studies. Claudia Spies (Charité, Germany) dis-
cussed the use of neuromonitoring to control for the depth
of anesthesia to evaluate POCDS and presented the launch
of a large-scale biobanking consortium to establish valid bio-
marker panels and clinical outcome prediction of the POCDS
among elderly patients in Europe. Miles Berger (Duke
University, NC) reported no difference in postoperative CSF
AD biomarkers in patients randomized to total IV anesthesia
(TIVA) or inhaled general anesthesia (GA) for neurological
surgery. However, he did note a lower level of the cytokine
monocyte chemotactic protein 1 in CSF after TIVA compared
with inhaled GA. Stacie Deiner (Icahn School of Medicine at
Mt. Sinai, NY) found that plasma stress markers (catechol-
amines) and the incidence of delirium did not differ between
patients who have received TIVA versus GA. Interestingly,
high plasma catechol levels in the recovery room after sur-
gery were a strong predictor of delirium. Jeff Silverstein
(Icahn School of Medicine at Mt. Sinai, NY) in the delirium
randomized controlled trial asked whether dexmedetomi-
dine administered during surgery reduces postoperative
delirium. Interestingly, preliminary analyses suggest the
opposite, and on examining the associations with long-term
outcomes (POCD), he reported a higher incidence of POCI
than decline. Robert Sanders (University College London,
UK) reported on the design of the Hip Fracture Surgery in
Elderly Patients (HIPHELD) study where xenon anesthesia
is being compared with sevoflurane but was unable to yet
present results. Thus, the ability of any particular anesthetic
or adjunct in the perioperative period to reduce the risk of
POCDS remains conjectural.
Finally, David Scott (St. Vincent’s Hospital, Australia)
presented results from a prospective trial demonstrat-
ing cognitive decline 1 year after surgery and found that
baseline cognitive performance was a significant predictor.
However, few if any centers routinely evaluate preoperative
cognitive ability primarily due to the cost and time required
to do so. Furthermore, it is clear that significant, preexisting
cognitive disorders are routinely missed in the busy periop-
erative arena. Thus, Deborah Culley (Brigham Women’s
Hospital, Harvard University, MA) presented a small study
using a very simple cognitive assay that requires little time
and was easily administered in a routine preoperative eval-
uation center. Such an evaluation may reveal vulnerable
and frail patients, thus allowing more informed discussions
of patient risk and allocation of resources.
EPIDEMIOLOGY
The above prospective clinical studies, designed to reveal a
link between anesthesia, surgery, and cognitive decline, are
difficult, time-consuming, and expensive. Thus, an interme-
diate translational step between the hypothesis-generating
preclinical work and prospective clinical studies is the retro-
spective analysis of a growing variety of databases. In gen-
eral, these databases were established for other purposes,
and thus relevant and important data are sometimes miss-
ing, populations are widely variable, and surgical proce-
dures (if documented) very different. When combined with
what is likely to be a small effect size at the population level,
firm conclusions regarding the relationship among anesthe-
sia, surgery, and long-term cognitive decline have been dif-
ficult to make. For example, Juraj Sprung (Mayo School of
Medicine, MN) presented recently published work arising
from the analysis of Olmsted County databases. No associa-
tions between any form of anesthesia, surgery, or dementia
diagnosis could be made. Conversely, as already mentioned,
both Katie Schenning (Oregon Health Science University,
OR) and Charles Brown (Johns Hopkins University, MD)
found significant associations between surgery and/or
general hospitalizations and cognitive decline. Other data
collected by Kirk Hogan (University of Wisconsin, WI), pre-
sented in absentia by Katie Schenning, also found a signifi-
cant association between surgery and cognitive decline in the
Wisconsin Registry for Alzheimer’s Prevention (WRAP) pro-
spective study. Importantly, this last study is one of the few
to enrich their population with a late-onset AD vulnerability;
all enrollees had to have at least one parent with AD. Taken
together, the epidemiology remains confusing in large part
due to the well-known limitations of retrospective studies.
The weight of evidence appears to favor anesthesia and sur-
gery being associated with one or more forms of the POCDS,
but definitive, prospective studies (such as a few of the above)
are sorely needed to conclude this with confidence.
POLICY
As indicated by all of the above, no anesthetic, periopera-
tive approach, or adjunct can currently be recommended
as an effective deterrent to all POCDS, although some
interventions have been reported to reduce the incidence
of postoperative delirium and early postoperative cog-
nitive dysfunction. Nonetheless, no anesthetic has been
clearly implicated or exonerated. Thus, in the absence of
clear evidence of causation, considerable discussion cen-
tered around what to tell surgical patients about the risk
of POCDS and whether this should be part of the consent
process. Because anesthesiologists currently inform patients
of risks at least as low as the estimates for POCDS, it was
recommended that the risk of POCDS (perhaps excluding
dementia for which there is the least evidence) be included
and documented in preoperative discussions, just as the risk
of cardiovascular events and mortality currently are. There
was a clear consensus that some form of standardized brain
function testing, like that of any other key organ system,
should eventually be included in the pre- and postopera-
tive period. Risk factors (vulnerabilities), once clearly iden-
tified, need to be documented to appropriately stratify and
discuss risk with patients and their families and implement
therapies designed at least to mitigate early POCDS. Finally,
the lack of firm answers to many of the questions posed in
this workshop should make it abundantly clear that more
research, primarily in the translational and clinical domain,

4. 652 www.anesthesia-analgesia.org anesthesia analgesia
E SPECIAL ARTICLE
is urgently needed. Should causal relationships emerge,
mechanistic studies should ultimately reveal approaches
for mitigation. E
DISCLOSURES
Name: Niccolò Terrando, PhD.
Contribution: This author helped prepare the manuscript.
Attestation: Niccolò Terrando approved the final manuscript.
Name: Lars I. Eriksson, MD, PhD.
Contribution: This author helped prepare the manuscript.
Attestation: Lars I. Eriksson approved the final manuscript.
Name: Roderic G. Eckenhoff, MD.
Contribution: This author helped prepare the manuscript.
Attestation: Roderic G. Eckenhoff approved the final
manuscript.
This manuscript was handled by: Gregory J. Crosby, MD.
APPENDIX
Miles Berger: Duke University, NC; Charles Brown: Johns
Hopkins University, MD; Kaj Blennow: Gothenburg
University, Sweden; Gregory Crosby: Brigham Women’s
Hospital, Harvard University, MA; Deborah Culley:
Brigham Women’s Hospital, Harvard University, MA;
Colm Cunningham: Trinity College Dublin, Ireland; Stacie
Deiner: Icahn School of Medicine at Mount Sinai, NY;
Maryellen Eckenhoff: University of Pennsylvania, PA;
Roderic G. Eckenhoff: University of Pennsylvania, PA; Lars
I. Eriksson: Karolinska Institutet, Sweden; Lis Evered: St.
Vincent’s Hospital, Australia; Hugh C. Hemmings: Cornell
University, NY; Daqing Ma: Imperial College London,
UK; Joseph Mathew: Duke University, NC; Mervyn
Maze: University of California San Francisco, CA; Sven-
Erik Ricksten: Gothenburg University, Sweden; Robert
Sanders: University College London, UK; David Scott: St.
Vincent’s Hospital, Australia; Jeff Silverstein: Icahn School
of Medicine at Mount Sinai, NY; Claudia Spies: Charité,
Germany; Juraj Sprung: College of Medicine, Mayo Clinic,
MN; Francois Stapelberg: University of Auckland, New
Zealand; Katie Schenning: Oregon Health Science
University, OR; Niccolò Terrando: Karolinska Institutet,
Sweden; Jianbin Tong: Central South University, China;
Tianlong Wang: Capital Medical University, China; Huafeng
Wei: University of Pennsylvania, PA; Robert Whittington:
Columbia University, NY; Ting Yang: Karolinska Institute,
Sweden; Zhongcong Xie: Massachusetts General Hospital,
Harvard Medical School, MA.