Americans 65 and older
undergo nearly 20 million surgeries each year, which frequently improve and
sometimes save their lives. But the brain doesn’t always fare so well. Delirium
in the immediate post-operative period is alarmingly frequent. More prolonged dysfunction
is not rare. And there’s a substantial increase in subsequent dementia.
Clinicians have noted
the association between surgery and cognitive compromise for decades, but only
recently have researchers started paying serious attention. “This is really a
bedside to bench story,” said Howard Fillit, director of the Alzheimer’s Drug
The Foundation was a
co-sponsor—the other was the New York Academy of Sciences—of what was perhaps
the first conference
devoted to surgery and cognition, held recently at the Academy.
“It’s a topic of tremendous
importance,” said Sharon Inouye, professor of medicine at Harvard Medical
School. Surgeries on older people increased by one-third from 2000 to 2010. Serious
complications ensue 10–25 percent of the time, and “delirium is, according to
some studies, the most frequent and devastating of these,” she said.
Besides delirium—acute confusion with
disruption in attention and other cognitive functions —surgery can be followed
by more sustained post-operative cognitive decline (POCD), and dementia months
or years later. “The interrelationship between these three conditions remains
unclear, and it’s crucial to gain understanding to prevent and manage them,”
Focus on deliriumPost-operative delirium occurs in 15–53 percent of older patients, depending on factors like age, comorbidity (the presence of additional disorders and diseases), and the specifics of the surgery and anesthesia. It is associated with increased risk of institutionalization and of death.
relationship with dementia is bi-directional. Pre-existing dementia or mild
cognitive impairment are leading risk factors for delirium, and dementia rates increase,
as much as 12-fold according to limited research, after a delirium episode.
“It’s not just
dementia,” Inouye said. “The risk of decline in cognitive score is strongly
suggested in various studies.”
Cognitive function after
surgery typically follows a trajectory: an immediate dip, then gradual recovery.
In one study of 225 cardiac surgery patients, those who hadn’t had delirium
improved to above baseline function. Patients whose delirium lasted 3 days or
longer still hadn’t recovered fully a year later, and those with briefer
delirium fell between.
Aging after Elective Surgery (SAGES) study, which Inouye directs, followed
556 post-surgery patients for up to 36 months. Those without delirium were
still above baseline cognitive function 3 years later; while the 24 percent who
had had an episode declined gradually over this period, to a degree equivalent
to mild cognitive impairment.
The implications of
such studies are important, she said, in that "delirium is potentially
preventable." One important step would be identifying people at heightened
risk. Inouye said an analysis of SAGES data found that Alzheimer's disease
biomarkers such as APOE4 failed to predict delirium. But neuroimaging of 136 SAGES
patients suggested an association with pre-existing structural disconnection between
hemispheres and in frontal-thalamic networks involved in memory and limbic
Inouye pointed out that
while epidemiological associations and studies such as SAGES are highly
suggestive, they don't establish causality between delirium, post-surgical
cognitive decline, and dementia.
Miles Berger, of Duke
University, elaborated on this theme. "There are two ways to interpret
data showing that long-term decline is worse in patients who had cognitive
impairment soon after surgery. The alternative hypothesis is that some had
pre-existing Alzheimer's pathology or a lack of cognitive reserve, and anesthesia
and surgery unmasked it: They constitute a stress test for the aging
"Reverse causality" is possible, he
said: "motor dysfunction in an early, preclinical phase of Alzheimer's
could lead to falls needing surgery." Several large studies suggest that people
with Alzheimer's disease (AD) have higher surgery rates.
research showing post-operative changes in biomarkers of processes underlying
AD: a three-fold increase in CSF tau protein and in the tau/amyloid-beta ratio—
into the range seen in AD—in the 24-hour period surrounding surgery.
"It was unclear
whether this was caused by the surgery, the anesthesia, or both," but the
fact that changes were the same with deep intracranial and peripheral central
nervous system surgery pointed toward anesthesia.
Berger said, "it's uncertain how long these changes persist, and what they
mean functionally. They could be just an acute phase reaction."
A subsequent study, now
in progress, might clarify some questions. Berger and colleagues are following
these biomarkers and cognitive indices in 100 patients from before to a year
after various surgical procedures. They also will do neuroimaging to compare
connectivity in the surgery group and controls will also be done, he said.
cognitive effects of anesthesia from surgery is difficult, other presenters
agreed. Joshua Mincer, of the Icahn School of Medicine at Mt. Sinai, described
an ongoing study that may advance that effort.
Investigators are using
fMRI to track resting state brain activity and cognitive scores in healthy elders
before and up to a year after two hours of general anesthesia without surgery.
In particular, they are assessing “dimensionality,” a measure of the complexity
of resting state network activity, during the trajectory of recovery. Preliminary
findings have not yet been published.
Seeking insights to protect the brain
Michael S. Avidan, professor of anesthesiology
at Washington University in St. Louis, described research using EEG to investigate
(and perhaps mitigate) anesthesia’s effect on the brain.
A number of studies
have linked EEG patterns during anesthesia with post-operative delirium. In
particular, “burst suppression,” in which periods of flattened activity
alternate with bursts of electrical discharge, has been associated with up to a
fourfold increase in delirium.
In a meta-analysis of
four studies, using EEG to guide anesthesia administration, cutting back when
burst suppression occurred, reduced delirium incidence. Avidan described an
ongoing randomized controlled trial of EEG-guided anesthesia titration, ultimately
enrolling 1200 patients, to explore the question further.
“Is burst suppression a
murderer, a mediator, or a mirror of brain vulnerability? We need to sort this
out,” Avidan said. “If people are vulnerable, we need to intervene, while in
healthy people [anesthesia depth] may not matter.”
EEG monitoring in the
post-operative period might help distinguish delirium characterized by
somnolence—a common, easily misdiagnosed form—from other conditions, such as
sustained non-convulsive seizure, that require different treatment. “Continuous
EEG can be an important adjunct to clinical assessment,” he said.
While evidence of
association between surgery, anesthesia, delirium and lasting cognitive compromise
has accumulated, the pathophysiology linking them is speculative. Edward R.
Marcantonio, professor of medicine at Harvard Medical School, discussed a leading
According to this
hypothesis, “surgery, a major inflammatory event in the periphery, releases
cytokines, which can cross the blood-brain barrier and activate microglia,
setting up a process of neuroinflammation that leads to neuronal insult, even
death. This can resolve quickly [as in the case of delirium], or persist,
resulting in post-operative cognitive decline, even dementia.”
several studies that support this hypothesis. Data from SAGES compared
inflammatory biomarkers in elderly patients who did and did not develop
post-surgical delirium. “There were two significant results,” he said: IL-6 was
similar in both patient groups initially, but rose substantially in those who
developed delirium; IL-2 was elevated throughout in this group. The latter
cytokine, which regulates blood-brain barrier permeability, may be a marker of delirium
risk, he said.
Another study found that
C-reactive protein, a marker of active inflammation, was higher before and rose
dramatically after surgery in patients who developed delirium. “Those in the
highest CRP quartile had the most severe, prolonged [episodes],” he said.
“Delirium may be
associated with a heightened inflammatory response to stress, and patients at
risk may have higher levels of inflammation even before surgery.” A
meta-analysis of animal studies linked inflammation after surgery to reduced
cognitive performance, he said.
The ultimate goal is clinical
translation, Marcantonio said. “Hopefully we can integrate biomarkers to
identify individuals at risk of delirium and long-term [post-operative] cognitive
dysfunction, and develop intervention strategies that protect the brain.”