EDITORIAL

Surgery and Anesthesia: Healing the Body but

Harming the Brain?
Gregory Crosby, MD, and Deborah J. Culley, MD

F rom the origins of surgical anesthesia in the 1840s

through the late 1990s, the prevailing view has been
that the brain emerged unscathed from the assault of
surgery and the pharmacologic coma that we call general
is no consensus on the cause and, therefore, on whether the
anesthesiologist can prevent or mitigate it. Indeed, because
it is not a clinical diagnosis and the criteria used to define
it are not uniform, there is debate about whether it even
anesthesia. Since then, the literature has been awash with exists as a unique entity. Evered et al.3 suggest in this issue
studies suggesting that is not always the case and that of the Journal that POCD is, in fact, perhaps not a new or
sometimes, in an effort to heal the body, we might be harming distinct entity because the incidence in older patients is
the brain. However, when, why, and how this happens is a similar after procedures of very different invasiveness/
matter of considerable debate. That debate is winding up complexity (coronary artery bypass, elective hip replace-
rather than down and is unlikely to be resolved anytime soon. ment, and coronary angiography). Hence, they suggest that
In the spirit of fueling, if not resolving, the debate, the section the surgical experience just unmasks brain compromise
on Neuroscience in Anesthesiology and Perioperative Medi- that was already present preoperatively.
cine in this issue of Anesthesia & Analgesia pulls together a Delirium, on the other hand, is a common and well-
collection— consisting of original work, reviews, a meeting defined clinical syndrome. As reviewed in this issue of the
summary, and an opinion piece—that speaks to various Journal by Rudolph and Marcantonio4 and by Hughes and
aspects of this subject. There is something here for everyone Pandharipande,5 delirium occurs in up to 50%– 80% of elderly
interested in the topic, and even for those who might just be surgical patients, the criteria and tools to diagnose it are
curious, but before you dive into the specific articles, we agreed upon, and it presages poor short- and long-term
thought it would be useful to put them in the context of outcomes. Importantly, there is evidence that medication
current themes/hypotheses about adverse perioperative cog- choices, depth of anesthesia, and treatment of pain can affect
nitive outcomes. delirium risk.4 –7 Nonetheless, the anesthesia community has
The first theme has to do with the nature of the surgery been somewhat inattentive to delirium, perhaps because it is
or medication-induced brain dysfunction and whether it is erroneously believed to be a transient and unimportant con-
clinically important. The brain, for all its complexity, has dition. Nothing could be farther from the truth, and the
only so many ways to malfunction. Excluding stroke and reviews by Rudolph and Marcantonio4 and by Hughes and
seizures, which typically result from major physiologic or Pandharipande5 make it clear that there are opportunities to
pathologic events, perioperative brain dysfunction mani- improve cognitive outcomes for patients at risk for delirium
fests mainly as abnormalities in cognition/thinking. Post- with seemingly small changes in patient management.
operative cognitive dysfunction (POCD), a mild but possibly The cognitive consequences of surgical and anesthetic
long-lasting cognitive fogginess that is “diagnosed” only by events in young children are the most enigmatic. That is
neurocognitive testing, is probably most familiar to the because unlike the elderly—in whom cognitive syndromes
anesthesia community. Within the first week after surgery, (delirium and POCD) were identified first and animal
30%–50% of patients have POCD, with no difference by studies looking at potential mechanisms followed—the
age, and at 3 months after surgery about 10%–15% do, but sequence is reversed on the question of whether sedative
at this point the problem is limited to the elderly.1,2 There and anesthetic agents are neurotoxic in young children.
That worrisome story started with animal work and, be-
From the Harvard Medical School, Department of Anesthesiology, Peri- cause results of epidemiological studies examining an
operative, and Pain Medicine, Brigham and Women’s Hospital, Boston,
Massachusetts. association between anesthesia and surgery during early
Accepted for publication February 16, 2011. childhood and learning disabilities later in life are few and
Funding: NIH GM088817 (to GC) and GM077057 (to DJC). conflicting,8,9 it is not clear that there is a clinical correlate.
The authors declare no conflicts of interest. In essence, in the elderly we started with a victim (delirium,
Reprints will not be available from the authors. POCD) and are looking for a weapon, whereas in children
Address correspondence to Gregory Crosby, MD, Department of Anes- we started with a weapon (anesthetic/sedative drug-
thesiology, Harvard Medical School, Brigham & Women’s Hospital, 75 induced neurodegeneration in animals) and are searching
Francis Street, Boston, MA 02115. Address e-mail to gcrosby@zeus.bwh.
harvard.edu. for a victim (clinical problem).
Copyright © 2011 International Anesthesia Research Society Another major theme relates to the putative causes of
DOI: 10.1213/ANE.0b013e3182160431 adverse cognitive outcomes. There are 3 general theories:

May 2011 • Volume 112 • Number 5 www.anesthesia-analgesia.org 999

 EDITORIAL

medications, surgery, and the patient. Evidence that our young patients. And it is not just about age alone. This is
drugs are responsible is most consistent for developmental illustrated by articles in this issue of the Journal by Leung et
neurotoxicity. A major and consistent feature of the pathol- al.22 and by Jankowski et al.23 showing, respectively, that
ogy in the developing animal brain following exposure to a preoperative frailty and cognitive impairment are indepen-
variety of common sedative and anesthetic agents is cell dent risk factors for development of delirium postopera-
and synapse loss.10 –12 This has been convincingly demon- tively. Likewise, the report of Evered et al.,3 which shows a
strated in cell culture models, rodents, and primates, even similar incidence of POCD in older patients after proce-
when systemic physiology is well controlled, implying that dures of very different invasiveness, points away from the
it is a direct effect of the medications. Learning and social surgical and anesthetic details and toward the intrinsic
deficits in adulthood have also been identified in animals characteristics of the patient. This could have profound
exposed to sedative/anesthetic medications in the neonatal implications. If much of the cognitive dysfunction observed
period.10,13 As such, anesthetic-induced neurodegeneration after surgery in elders is simply unmasking a preexisting
is the prevailing theory driving concerns about general problem such as mild cognitive impairment, which afflicts
anesthesia in young children. However, even this is not about 1 in 5 community-dwelling elders,24 our terminology
straightforward; exposure to sedative/anesthetic medica- would have to change. POCD might be a misnomer be-
tions after the peak of synaptogenesis increases synapse cause the condition may be neither “post” nor “operative.”
numbers14 and, in in vitro work using human neuronlike “Illness-related cognitive dysfunction” may be a more
cells and published in this issue of the Journal, Lin et al. accurate descriptor. More importantly, our focus would
challenge the idea that volatile agents injure neurons in logically shift to identifying in advance those at risk. This is
humans.15 There is also major disagreement about the at the heart of a provocative Open Mind piece by Silbert et
ability of medications to cause long-lasting changes in the al.25 in this issue. They essentially propose that we use
old brain. In the mature brain, anesthetic-induced neuro- surgical preadmission test centers to screen patients for
apoptosis appears to be a minor event, but accumulation of mild cognitive impairment or dementia much as we do for
the neurotoxic proteins amyloid ␤ and phosphorylated ␶, cardiovascular disease in at-risk groups. One approach
both of which are implicated in the pathogenesis of Alzhei- would be to add cognitive evaluation to the routine preop-
mer disease, has been observed.16,17 Likewise, persistent erative assessment of elders, a course that would make
cognitive deficits have been reported in old animals after good sense given the frequency and seriousness of periop-
exposure to some common anesthetic agents.18 However, erative cognitive morbidity in elders but that is not fool-
as is well summarized by Eckenhoff in his report of the proof.26 Another might be to take the lead on utilizing
Second International Perioperative Neurotoxicity Work- biomarkers to more accurately and reliably diagnose cog-
shop in this issue of the Journal, there is still considerable nitive compromise27 so we can make better-informed clini-
controversy about whether anesthetic agents contribute to cal management decisions perioperatively. Regardless of
development of POCD and dementia.19 In contrast, as what one thinks of these specific ideas, there is no disputing
reviewed here by Rudolph and Marcantonio4 and by the general concept that with elders it is essential to
Hughes and Padharipande,5 evidence is reasonably good explicitly consider the functional state of the brain both
that both specific sedative agents and depth of anesthesia before and after surgery.
can contribute to delirium. As the articles in the collection of this month’s issue of
The surgical theory of causation involves inflammation. the Journal illustrate, there has been a remarkable transfor-
This idea is obviously more appealing to anesthesiologists mation over the past 10 to 15 years in how we view the
than accepting that our drugs are harmful. Moreover, there brain’s response to the duress of surgical illness, sedation,
is ample evidence that under other circumstances, inflam- and general anesthesia. The specter of cognitive dysfunc-
mation can adversely affect cognitive performance (con- tion after noncentral nervous system surgery is alarming to
sider the subtle cognitive cloudiness that one often feels patients, families, and anesthesiologists alike, but it is also
during a viral illness) and lead eventually to neurodegen- a strong motivator for learning more and doing better so
eration.20 Thus far, however, a relationship between that our work to heal the body does not harm the brain.
surgery and subsequent cognitive dysfunction has been Please read, enjoy, and be stimulated by the articles in this
demonstrated experimentally mostly in young animals and month’s collection to do just that.
over the short term, and the clinical story is circumstantial.
Nor does the inflammation hypothesis exclude anesthetic
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