SlideShare a Scribd company logo
1 of 4
Download to read offline
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and unpublished data.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
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
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,
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.

More Related Content

What's hot

June 2016 IEP
June 2016 IEPJune 2016 IEP
June 2016 IEPskrentz
 
Topic of the month...Paraneoplastic syndromes
Topic of the month...Paraneoplastic syndromesTopic of the month...Paraneoplastic syndromes
Topic of the month...Paraneoplastic syndromesProfessor Yasser Metwally
 
Thesis section...nonsurgical management of brain tumors
Thesis section...nonsurgical management of brain tumorsThesis section...nonsurgical management of brain tumors
Thesis section...nonsurgical management of brain tumorsProfessor Yasser Metwally
 
Letter: Is the Stupp Protocol an expensive and unsustainable standard of care...
Letter: Is the Stupp Protocol an expensive and unsustainable standard of care...Letter: Is the Stupp Protocol an expensive and unsustainable standard of care...
Letter: Is the Stupp Protocol an expensive and unsustainable standard of care...Ahmad Ozair
 
Hearing Loss in Wegener’s Granulomatosis
Hearing Loss in Wegener’s GranulomatosisHearing Loss in Wegener’s Granulomatosis
Hearing Loss in Wegener’s GranulomatosisJeffrey Spiegel
 
Hombro doloroso
Hombro dolorosoHombro doloroso
Hombro dolorosofreefallen
 
Pharmacological neuroprotection in blinding eye diseases
 Pharmacological neuroprotection in blinding eye diseases Pharmacological neuroprotection in blinding eye diseases
Pharmacological neuroprotection in blinding eye diseasesAlexander Decker
 
Final project of Understanding the brain: The Neurobiology of Everyday Life
Final project of Understanding the brain: The Neurobiology of Everyday LifeFinal project of Understanding the brain: The Neurobiology of Everyday Life
Final project of Understanding the brain: The Neurobiology of Everyday LifeValentinaNietoserna
 
Penetrating pelvic trauma. Cases analysis. panam j trauma crit care 2013
Penetrating pelvic trauma. Cases analysis. panam j trauma crit care 2013Penetrating pelvic trauma. Cases analysis. panam j trauma crit care 2013
Penetrating pelvic trauma. Cases analysis. panam j trauma crit care 2013Juan de Dios Díaz Rosales
 
Basic approaches usa_urss
Basic  approaches usa_urssBasic  approaches usa_urss
Basic approaches usa_urssJeane Araujo
 
Brain monitoring using intraparenchymal cathters
Brain monitoring using intraparenchymal cathtersBrain monitoring using intraparenchymal cathters
Brain monitoring using intraparenchymal cathterspgpapanikolaou
 
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...Artigo - Practice Guidelines for the Perioperative Management of Patients wit...
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...SMA - Serviços Médicos de Anestesia
 
Characteristics, therapies, and outcome of children with necrotizing soft tis...
Characteristics, therapies, and outcome of children with necrotizing soft tis...Characteristics, therapies, and outcome of children with necrotizing soft tis...
Characteristics, therapies, and outcome of children with necrotizing soft tis...Grupo Pediatras Chiquinquira
 

What's hot (20)

June 2016 IEP
June 2016 IEPJune 2016 IEP
June 2016 IEP
 
Topic of the month...Paraneoplastic syndromes
Topic of the month...Paraneoplastic syndromesTopic of the month...Paraneoplastic syndromes
Topic of the month...Paraneoplastic syndromes
 
Thesis section...nonsurgical management of brain tumors
Thesis section...nonsurgical management of brain tumorsThesis section...nonsurgical management of brain tumors
Thesis section...nonsurgical management of brain tumors
 
Letter: Is the Stupp Protocol an expensive and unsustainable standard of care...
Letter: Is the Stupp Protocol an expensive and unsustainable standard of care...Letter: Is the Stupp Protocol an expensive and unsustainable standard of care...
Letter: Is the Stupp Protocol an expensive and unsustainable standard of care...
 
Hearing Loss in Wegener’s Granulomatosis
Hearing Loss in Wegener’s GranulomatosisHearing Loss in Wegener’s Granulomatosis
Hearing Loss in Wegener’s Granulomatosis
 
Hombro doloroso
Hombro dolorosoHombro doloroso
Hombro doloroso
 
2015 Science Fair Paper
2015 Science Fair Paper2015 Science Fair Paper
2015 Science Fair Paper
 
Vertebroplastia
VertebroplastiaVertebroplastia
Vertebroplastia
 
Pharmacological neuroprotection in blinding eye diseases
 Pharmacological neuroprotection in blinding eye diseases Pharmacological neuroprotection in blinding eye diseases
Pharmacological neuroprotection in blinding eye diseases
 
Non surgical tto for cts
Non surgical tto for ctsNon surgical tto for cts
Non surgical tto for cts
 
Magnims
MagnimsMagnims
Magnims
 
Final project of Understanding the brain: The Neurobiology of Everyday Life
Final project of Understanding the brain: The Neurobiology of Everyday LifeFinal project of Understanding the brain: The Neurobiology of Everyday Life
Final project of Understanding the brain: The Neurobiology of Everyday Life
 
Penetrating pelvic trauma. Cases analysis. panam j trauma crit care 2013
Penetrating pelvic trauma. Cases analysis. panam j trauma crit care 2013Penetrating pelvic trauma. Cases analysis. panam j trauma crit care 2013
Penetrating pelvic trauma. Cases analysis. panam j trauma crit care 2013
 
Basic approaches usa_urss
Basic  approaches usa_urssBasic  approaches usa_urss
Basic approaches usa_urss
 
Brain monitoring using intraparenchymal cathters
Brain monitoring using intraparenchymal cathtersBrain monitoring using intraparenchymal cathters
Brain monitoring using intraparenchymal cathters
 
Z7g01211008780
Z7g01211008780Z7g01211008780
Z7g01211008780
 
Analytical Study on Deep Neck Space Infections
Analytical Study on Deep Neck Space InfectionsAnalytical Study on Deep Neck Space Infections
Analytical Study on Deep Neck Space Infections
 
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...Artigo - Practice Guidelines for the Perioperative Management of Patients wit...
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...
 
Characteristics, therapies, and outcome of children with necrotizing soft tis...
Characteristics, therapies, and outcome of children with necrotizing soft tis...Characteristics, therapies, and outcome of children with necrotizing soft tis...
Characteristics, therapies, and outcome of children with necrotizing soft tis...
 
gudrunardottir et al 2016 on line
gudrunardottir et al 2016 on linegudrunardottir et al 2016 on line
gudrunardottir et al 2016 on line
 

Similar to Terrando et al-2015-anesthesia_&_analgesia

ACUTE-SCI-LIT-REVIEW-NEURO-2016
ACUTE-SCI-LIT-REVIEW-NEURO-2016ACUTE-SCI-LIT-REVIEW-NEURO-2016
ACUTE-SCI-LIT-REVIEW-NEURO-2016Alexandra Duff
 
Radiological pathology of cerebrovascular disorders
Radiological pathology of cerebrovascular disordersRadiological pathology of cerebrovascular disorders
Radiological pathology of cerebrovascular disordersProfessor Yasser Metwally
 
When One Hemisphere Innervates Both Sides Of The Body
When One Hemisphere Innervates Both Sides Of The BodyWhen One Hemisphere Innervates Both Sides Of The Body
When One Hemisphere Innervates Both Sides Of The BodyThe Brain Recovery Project
 
Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Pro...
Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Pro...Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Pro...
Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Pro...DrAlokSharma
 
How Neuronavigators Changed Our Traditional Surgeries Discussion.docx
How Neuronavigators Changed Our Traditional Surgeries Discussion.docxHow Neuronavigators Changed Our Traditional Surgeries Discussion.docx
How Neuronavigators Changed Our Traditional Surgeries Discussion.docxwrite4
 
Epilepsia 2015 - trinka - a definition and classification of status epilept...
Epilepsia   2015 - trinka - a definition and classification of status epilept...Epilepsia   2015 - trinka - a definition and classification of status epilept...
Epilepsia 2015 - trinka - a definition and classification of status epilept...Jayanta Ghosal
 
Brain cancer סקיי גרוס
Brain cancer סקיי גרוסBrain cancer סקיי גרוס
Brain cancer סקיי גרוסSky Gross, PhD
 
Outcome of Lumbar Fusion
Outcome of Lumbar FusionOutcome of Lumbar Fusion
Outcome of Lumbar FusionPaul Coelho, MD
 
Piquet_AAN neuro-rheum course Part 1.pdf
Piquet_AAN neuro-rheum course Part 1.pdfPiquet_AAN neuro-rheum course Part 1.pdf
Piquet_AAN neuro-rheum course Part 1.pdf69dtrzdp2s
 
The Coagulopathy of Trauma: A Review of Mechanisms
The Coagulopathy of Trauma: A Review of MechanismsThe Coagulopathy of Trauma: A Review of Mechanisms
The Coagulopathy of Trauma: A Review of MechanismsEmergency Live
 

Similar to Terrando et al-2015-anesthesia_&_analgesia (20)

ACUTE-SCI-LIT-REVIEW-NEURO-2016
ACUTE-SCI-LIT-REVIEW-NEURO-2016ACUTE-SCI-LIT-REVIEW-NEURO-2016
ACUTE-SCI-LIT-REVIEW-NEURO-2016
 
Biomarcadores en epilepsia
Biomarcadores en epilepsiaBiomarcadores en epilepsia
Biomarcadores en epilepsia
 
Radiological pathology of cerebrovascular disorders
Radiological pathology of cerebrovascular disordersRadiological pathology of cerebrovascular disorders
Radiological pathology of cerebrovascular disorders
 
When One Hemisphere Innervates Both Sides Of The Body
When One Hemisphere Innervates Both Sides Of The BodyWhen One Hemisphere Innervates Both Sides Of The Body
When One Hemisphere Innervates Both Sides Of The Body
 
SNONewsVol3Issue1
SNONewsVol3Issue1SNONewsVol3Issue1
SNONewsVol3Issue1
 
Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Pro...
Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Pro...Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Pro...
Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Pro...
 
How Neuronavigators Changed Our Traditional Surgeries Discussion.docx
How Neuronavigators Changed Our Traditional Surgeries Discussion.docxHow Neuronavigators Changed Our Traditional Surgeries Discussion.docx
How Neuronavigators Changed Our Traditional Surgeries Discussion.docx
 
Epilepsia 2015 - trinka - a definition and classification of status epilept...
Epilepsia   2015 - trinka - a definition and classification of status epilept...Epilepsia   2015 - trinka - a definition and classification of status epilept...
Epilepsia 2015 - trinka - a definition and classification of status epilept...
 
2012, Veeravagu, et al, IM SC Mets, Contemp NS
2012, Veeravagu, et al, IM SC Mets, Contemp NS2012, Veeravagu, et al, IM SC Mets, Contemp NS
2012, Veeravagu, et al, IM SC Mets, Contemp NS
 
Brain cancer סקיי גרוס
Brain cancer סקיי גרוסBrain cancer סקיי גרוס
Brain cancer סקיי גרוס
 
Outcome of Lumbar Fusion
Outcome of Lumbar FusionOutcome of Lumbar Fusion
Outcome of Lumbar Fusion
 
CIACI_2015
CIACI_2015CIACI_2015
CIACI_2015
 
Piquet_AAN neuro-rheum course Part 1.pdf
Piquet_AAN neuro-rheum course Part 1.pdfPiquet_AAN neuro-rheum course Part 1.pdf
Piquet_AAN neuro-rheum course Part 1.pdf
 
The Coagulopathy of Trauma: A Review of Mechanisms
The Coagulopathy of Trauma: A Review of MechanismsThe Coagulopathy of Trauma: A Review of Mechanisms
The Coagulopathy of Trauma: A Review of Mechanisms
 
definitieve binnenwerk opmaak
definitieve binnenwerk opmaakdefinitieve binnenwerk opmaak
definitieve binnenwerk opmaak
 
Dokotorat_abstract_MJMS
Dokotorat_abstract_MJMSDokotorat_abstract_MJMS
Dokotorat_abstract_MJMS
 
Cefaleas
CefaleasCefaleas
Cefaleas
 
Snc Who 2007
Snc Who 2007Snc Who 2007
Snc Who 2007
 
ALA
ALAALA
ALA
 
20150300.0 00007
20150300.0 0000720150300.0 00007
20150300.0 00007
 

More from samirsharshar

Vademecum prise en charge périanesthésique
Vademecum prise en charge périanesthésiqueVademecum prise en charge périanesthésique
Vademecum prise en charge périanesthésiquesamirsharshar
 
Manifeste et Code du Service d'Anesthésie
Manifeste et Code du Service d'AnesthésieManifeste et Code du Service d'Anesthésie
Manifeste et Code du Service d'Anesthésiesamirsharshar
 
Thiruvenkatarajan et al-2015-anaesthesia
Thiruvenkatarajan et al-2015-anaesthesiaThiruvenkatarajan et al-2015-anaesthesia
Thiruvenkatarajan et al-2015-anaesthesiasamirsharshar
 
N8rskov et al-2014-anaesthesia
N8rskov et al-2014-anaesthesiaN8rskov et al-2014-anaesthesia
N8rskov et al-2014-anaesthesiasamirsharshar
 
Koh et al-2014-anaesthesia
Koh et al-2014-anaesthesiaKoh et al-2014-anaesthesia
Koh et al-2014-anaesthesiasamirsharshar
 
Lankhorst et al-2015-anaesthesia
Lankhorst et al-2015-anaesthesiaLankhorst et al-2015-anaesthesia
Lankhorst et al-2015-anaesthesiasamirsharshar
 
Heesen et al-2015-anaesthesia
Heesen et al-2015-anaesthesiaHeesen et al-2015-anaesthesia
Heesen et al-2015-anaesthesiasamirsharshar
 
Wijeysundera et al-2015-anesthesia_&_analgesia
Wijeysundera et al-2015-anesthesia_&_analgesiaWijeysundera et al-2015-anesthesia_&_analgesia
Wijeysundera et al-2015-anesthesia_&_analgesiasamirsharshar
 
Warner 2015-anesthesia &-analgesia
Warner 2015-anesthesia &-analgesiaWarner 2015-anesthesia &-analgesia
Warner 2015-anesthesia &-analgesiasamirsharshar
 
Shafer 2015-anesthesia &-analgesia
Shafer 2015-anesthesia &-analgesiaShafer 2015-anesthesia &-analgesia
Shafer 2015-anesthesia &-analgesiasamirsharshar
 
Schulz st%f cbner-2015-anesthesia-&_analgesia
Schulz st%f cbner-2015-anesthesia-&_analgesiaSchulz st%f cbner-2015-anesthesia-&_analgesia
Schulz st%f cbner-2015-anesthesia-&_analgesiasamirsharshar
 
Lee et al-2015-anesthesia_&_analgesia
Lee et al-2015-anesthesia_&_analgesiaLee et al-2015-anesthesia_&_analgesia
Lee et al-2015-anesthesia_&_analgesiasamirsharshar
 
Koch 2015-anesthesia &-analgesia
Koch 2015-anesthesia &-analgesiaKoch 2015-anesthesia &-analgesia
Koch 2015-anesthesia &-analgesiasamirsharshar
 
Kancir et al-2015-anesthesia_&_analgesia
Kancir et al-2015-anesthesia_&_analgesiaKancir et al-2015-anesthesia_&_analgesia
Kancir et al-2015-anesthesia_&_analgesiasamirsharshar
 
Huitink et al-2014-anaesthesia
Huitink et al-2014-anaesthesiaHuitink et al-2014-anaesthesia
Huitink et al-2014-anaesthesiasamirsharshar
 

More from samirsharshar (20)

Architecte de pole
Architecte de poleArchitecte de pole
Architecte de pole
 
Bja 2015 114(4)
Bja 2015 114(4)Bja 2015 114(4)
Bja 2015 114(4)
 
Aa 2014 119-5
Aa 2014 119-5Aa 2014 119-5
Aa 2014 119-5
 
Vademecum prise en charge périanesthésique
Vademecum prise en charge périanesthésiqueVademecum prise en charge périanesthésique
Vademecum prise en charge périanesthésique
 
Vademecum du M.A.R.
Vademecum du M.A.R.Vademecum du M.A.R.
Vademecum du M.A.R.
 
Manifeste et Code du Service d'Anesthésie
Manifeste et Code du Service d'AnesthésieManifeste et Code du Service d'Anesthésie
Manifeste et Code du Service d'Anesthésie
 
20150300.0 00014
20150300.0 0001420150300.0 00014
20150300.0 00014
 
Thiruvenkatarajan et al-2015-anaesthesia
Thiruvenkatarajan et al-2015-anaesthesiaThiruvenkatarajan et al-2015-anaesthesia
Thiruvenkatarajan et al-2015-anaesthesia
 
N8rskov et al-2014-anaesthesia
N8rskov et al-2014-anaesthesiaN8rskov et al-2014-anaesthesia
N8rskov et al-2014-anaesthesia
 
Koh et al-2014-anaesthesia
Koh et al-2014-anaesthesiaKoh et al-2014-anaesthesia
Koh et al-2014-anaesthesia
 
Lankhorst et al-2015-anaesthesia
Lankhorst et al-2015-anaesthesiaLankhorst et al-2015-anaesthesia
Lankhorst et al-2015-anaesthesia
 
Heesen et al-2015-anaesthesia
Heesen et al-2015-anaesthesiaHeesen et al-2015-anaesthesia
Heesen et al-2015-anaesthesia
 
Wijeysundera et al-2015-anesthesia_&_analgesia
Wijeysundera et al-2015-anesthesia_&_analgesiaWijeysundera et al-2015-anesthesia_&_analgesia
Wijeysundera et al-2015-anesthesia_&_analgesia
 
Warner 2015-anesthesia &-analgesia
Warner 2015-anesthesia &-analgesiaWarner 2015-anesthesia &-analgesia
Warner 2015-anesthesia &-analgesia
 
Shafer 2015-anesthesia &-analgesia
Shafer 2015-anesthesia &-analgesiaShafer 2015-anesthesia &-analgesia
Shafer 2015-anesthesia &-analgesia
 
Schulz st%f cbner-2015-anesthesia-&_analgesia
Schulz st%f cbner-2015-anesthesia-&_analgesiaSchulz st%f cbner-2015-anesthesia-&_analgesia
Schulz st%f cbner-2015-anesthesia-&_analgesia
 
Lee et al-2015-anesthesia_&_analgesia
Lee et al-2015-anesthesia_&_analgesiaLee et al-2015-anesthesia_&_analgesia
Lee et al-2015-anesthesia_&_analgesia
 
Koch 2015-anesthesia &-analgesia
Koch 2015-anesthesia &-analgesiaKoch 2015-anesthesia &-analgesia
Koch 2015-anesthesia &-analgesia
 
Kancir et al-2015-anesthesia_&_analgesia
Kancir et al-2015-anesthesia_&_analgesiaKancir et al-2015-anesthesia_&_analgesia
Kancir et al-2015-anesthesia_&_analgesia
 
Huitink et al-2014-anaesthesia
Huitink et al-2014-anaesthesiaHuitink et al-2014-anaesthesia
Huitink et al-2014-anaesthesia
 

Recently uploaded

PREPARATION FOR EXAMINATION FON II .pptx
PREPARATION FOR EXAMINATION FON II .pptxPREPARATION FOR EXAMINATION FON II .pptx
PREPARATION FOR EXAMINATION FON II .pptxPupayumnam1
 
Hemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.Gawad
Hemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.GawadHemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.Gawad
Hemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.GawadNephroTube - Dr.Gawad
 
Case presentation on Antibody screening- how to solve 3 cell and 11 cell panel?
Case presentation on Antibody screening- how to solve 3 cell and 11 cell panel?Case presentation on Antibody screening- how to solve 3 cell and 11 cell panel?
Case presentation on Antibody screening- how to solve 3 cell and 11 cell panel?DrShinyKajal
 
The Orbit & its contents by Dr. Rabia I. Gandapore.pptx
The Orbit & its contents by Dr. Rabia I. Gandapore.pptxThe Orbit & its contents by Dr. Rabia I. Gandapore.pptx
The Orbit & its contents by Dr. Rabia I. Gandapore.pptxDr. Rabia Inam Gandapore
 
hypo and hyper thyroidism final lecture.pptx
hypo and hyper thyroidism  final lecture.pptxhypo and hyper thyroidism  final lecture.pptx
hypo and hyper thyroidism final lecture.pptxdr shahida
 
Denture base resins materials and its mechanism of action
Denture base resins materials and its mechanism of actionDenture base resins materials and its mechanism of action
Denture base resins materials and its mechanism of actionDr.shiva sai vemula
 
Tips and tricks to pass the cardiovascular station for PACES exam
Tips and tricks to pass the cardiovascular station for PACES examTips and tricks to pass the cardiovascular station for PACES exam
Tips and tricks to pass the cardiovascular station for PACES examJunhao Koh
 
Muscle Energy Technique (MET) with variant and techniques.
Muscle Energy Technique (MET) with variant and techniques.Muscle Energy Technique (MET) with variant and techniques.
Muscle Energy Technique (MET) with variant and techniques.Anjali Parmar
 
Renal Replacement Therapy in Acute Kidney Injury -time modality -Dr Ayman Se...
Renal Replacement Therapy in Acute Kidney Injury -time  modality -Dr Ayman Se...Renal Replacement Therapy in Acute Kidney Injury -time  modality -Dr Ayman Se...
Renal Replacement Therapy in Acute Kidney Injury -time modality -Dr Ayman Se...Ayman Seddik
 
CAS 110-63-4 BDO Liquid 1,4-Butanediol 1 4 BDO Warehouse Supply For Excellent...
CAS 110-63-4 BDO Liquid 1,4-Butanediol 1 4 BDO Warehouse Supply For Excellent...CAS 110-63-4 BDO Liquid 1,4-Butanediol 1 4 BDO Warehouse Supply For Excellent...
CAS 110-63-4 BDO Liquid 1,4-Butanediol 1 4 BDO Warehouse Supply For Excellent...ocean4396
 
Failure to thrive in neonates and infants + pediatric case.pptx
Failure to thrive in neonates and infants  + pediatric case.pptxFailure to thrive in neonates and infants  + pediatric case.pptx
Failure to thrive in neonates and infants + pediatric case.pptxclaviclebrown44
 
5CL-ADB powder supplier 5cl adb 5cladba 5cl raw materials vendor on sale now
5CL-ADB powder supplier 5cl adb 5cladba 5cl raw materials vendor on sale now5CL-ADB powder supplier 5cl adb 5cladba 5cl raw materials vendor on sale now
5CL-ADB powder supplier 5cl adb 5cladba 5cl raw materials vendor on sale nowSherrylee83
 
TEST BANK For Lewis's Medical Surgical Nursing in Canada, 4th Edition by Jane...
TEST BANK For Lewis's Medical Surgical Nursing in Canada, 4th Edition by Jane...TEST BANK For Lewis's Medical Surgical Nursing in Canada, 4th Edition by Jane...
TEST BANK For Lewis's Medical Surgical Nursing in Canada, 4th Edition by Jane...marcuskenyatta275
 
Circulation through Special Regions -characteristics and regulation
Circulation through Special Regions -characteristics and regulationCirculation through Special Regions -characteristics and regulation
Circulation through Special Regions -characteristics and regulationMedicoseAcademics
 
5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials
5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials
5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materialsSherrylee83
 
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th Edition by ...
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th Edition by ...TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th Edition by ...
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th Edition by ...marcuskenyatta275
 
Creating Accessible Public Health Communications
Creating Accessible Public Health CommunicationsCreating Accessible Public Health Communications
Creating Accessible Public Health Communicationskatiequigley33
 
SURGICAL ANATOMY OF ORAL IMPLANTOLOGY.pptx
SURGICAL ANATOMY OF ORAL IMPLANTOLOGY.pptxSURGICAL ANATOMY OF ORAL IMPLANTOLOGY.pptx
SURGICAL ANATOMY OF ORAL IMPLANTOLOGY.pptxSuresh Kumar K
 
Is Rheumatoid Arthritis a Metabolic Disorder.pptx
Is Rheumatoid Arthritis a Metabolic Disorder.pptxIs Rheumatoid Arthritis a Metabolic Disorder.pptx
Is Rheumatoid Arthritis a Metabolic Disorder.pptxSamar Tharwat
 

Recently uploaded (20)

PREPARATION FOR EXAMINATION FON II .pptx
PREPARATION FOR EXAMINATION FON II .pptxPREPARATION FOR EXAMINATION FON II .pptx
PREPARATION FOR EXAMINATION FON II .pptx
 
Hemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.Gawad
Hemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.GawadHemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.Gawad
Hemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.Gawad
 
Case presentation on Antibody screening- how to solve 3 cell and 11 cell panel?
Case presentation on Antibody screening- how to solve 3 cell and 11 cell panel?Case presentation on Antibody screening- how to solve 3 cell and 11 cell panel?
Case presentation on Antibody screening- how to solve 3 cell and 11 cell panel?
 
The Orbit & its contents by Dr. Rabia I. Gandapore.pptx
The Orbit & its contents by Dr. Rabia I. Gandapore.pptxThe Orbit & its contents by Dr. Rabia I. Gandapore.pptx
The Orbit & its contents by Dr. Rabia I. Gandapore.pptx
 
hypo and hyper thyroidism final lecture.pptx
hypo and hyper thyroidism  final lecture.pptxhypo and hyper thyroidism  final lecture.pptx
hypo and hyper thyroidism final lecture.pptx
 
Denture base resins materials and its mechanism of action
Denture base resins materials and its mechanism of actionDenture base resins materials and its mechanism of action
Denture base resins materials and its mechanism of action
 
Tips and tricks to pass the cardiovascular station for PACES exam
Tips and tricks to pass the cardiovascular station for PACES examTips and tricks to pass the cardiovascular station for PACES exam
Tips and tricks to pass the cardiovascular station for PACES exam
 
Muscle Energy Technique (MET) with variant and techniques.
Muscle Energy Technique (MET) with variant and techniques.Muscle Energy Technique (MET) with variant and techniques.
Muscle Energy Technique (MET) with variant and techniques.
 
Renal Replacement Therapy in Acute Kidney Injury -time modality -Dr Ayman Se...
Renal Replacement Therapy in Acute Kidney Injury -time  modality -Dr Ayman Se...Renal Replacement Therapy in Acute Kidney Injury -time  modality -Dr Ayman Se...
Renal Replacement Therapy in Acute Kidney Injury -time modality -Dr Ayman Se...
 
Scleroderma: Treatment Options and a Look to the Future - Dr. Macklin
Scleroderma: Treatment Options and a Look to the Future - Dr. MacklinScleroderma: Treatment Options and a Look to the Future - Dr. Macklin
Scleroderma: Treatment Options and a Look to the Future - Dr. Macklin
 
CAS 110-63-4 BDO Liquid 1,4-Butanediol 1 4 BDO Warehouse Supply For Excellent...
CAS 110-63-4 BDO Liquid 1,4-Butanediol 1 4 BDO Warehouse Supply For Excellent...CAS 110-63-4 BDO Liquid 1,4-Butanediol 1 4 BDO Warehouse Supply For Excellent...
CAS 110-63-4 BDO Liquid 1,4-Butanediol 1 4 BDO Warehouse Supply For Excellent...
 
Failure to thrive in neonates and infants + pediatric case.pptx
Failure to thrive in neonates and infants  + pediatric case.pptxFailure to thrive in neonates and infants  + pediatric case.pptx
Failure to thrive in neonates and infants + pediatric case.pptx
 
5CL-ADB powder supplier 5cl adb 5cladba 5cl raw materials vendor on sale now
5CL-ADB powder supplier 5cl adb 5cladba 5cl raw materials vendor on sale now5CL-ADB powder supplier 5cl adb 5cladba 5cl raw materials vendor on sale now
5CL-ADB powder supplier 5cl adb 5cladba 5cl raw materials vendor on sale now
 
TEST BANK For Lewis's Medical Surgical Nursing in Canada, 4th Edition by Jane...
TEST BANK For Lewis's Medical Surgical Nursing in Canada, 4th Edition by Jane...TEST BANK For Lewis's Medical Surgical Nursing in Canada, 4th Edition by Jane...
TEST BANK For Lewis's Medical Surgical Nursing in Canada, 4th Edition by Jane...
 
Circulation through Special Regions -characteristics and regulation
Circulation through Special Regions -characteristics and regulationCirculation through Special Regions -characteristics and regulation
Circulation through Special Regions -characteristics and regulation
 
5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials
5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials
5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials
 
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th Edition by ...
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th Edition by ...TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th Edition by ...
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th Edition by ...
 
Creating Accessible Public Health Communications
Creating Accessible Public Health CommunicationsCreating Accessible Public Health Communications
Creating Accessible Public Health Communications
 
SURGICAL ANATOMY OF ORAL IMPLANTOLOGY.pptx
SURGICAL ANATOMY OF ORAL IMPLANTOLOGY.pptxSURGICAL ANATOMY OF ORAL IMPLANTOLOGY.pptx
SURGICAL ANATOMY OF ORAL IMPLANTOLOGY.pptx
 
Is Rheumatoid Arthritis a Metabolic Disorder.pptx
Is Rheumatoid Arthritis a Metabolic Disorder.pptxIs Rheumatoid Arthritis a Metabolic Disorder.pptx
Is Rheumatoid Arthritis a Metabolic Disorder.pptx
 

Terrando et al-2015-anesthesia_&_analgesia

  • 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.