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Special Articles  |   September 2008
We Care, Therefore We Are: Anesthesia-related Morbidity and Mortality: The 46th Rovenstine Lecture
Author Affiliations & Notes
  • James Edward Cottrell, M.D.
    *
  • * Professor of Anesthesiology.
Article Information
Special Articles / Central and Peripheral Nervous Systems / Geriatric Anesthesia
Special Articles   |   September 2008
We Care, Therefore We Are: Anesthesia-related Morbidity and Mortality: The 46th Rovenstine Lecture
Anesthesiology 9 2008, Vol.109, 377-388. doi:10.1097/ALN.0b013e31818344da
Anesthesiology 9 2008, Vol.109, 377-388. doi:10.1097/ALN.0b013e31818344da
EMERY Andrew Rovenstine, M.D. (Professor, Department of Anesthesiology, New York University, New York; 1895–1960), was a giant in the founding of our specialty, and I feel greatly honored to have been selected to deliver this Rovenstine Memorial Lecture. The closest I came to Dr. Rovenstine was the privilege of occupying his former office at the old Bellevue Hospital in 1974. The textbooks he left behind, with underlined passages and notes written in the margins, were fascinating, and I have made them available through the Wood Library Museum of Anesthesiology.
The message I want to bring to you today is the message that I have brought to this society since way back when I became the American Society of Anesthesiologists' Vice President of Scientific Affairs: To make the future of our specialty shine, we need to grab hold of the questions about anesthesiology that our patients and recent research have brought to the forefront. Whether you are a clinician, a clinician researcher, a nonclinician researcher, or a potential patient (as we all are), we need to show how much we care by supporting efforts to answer questions that address our patients' fears. When their fears become our research focus, public advocacy will convert our poor showing in National Institutes of Health (NIH) research funding into a scientific powerhouse.1 
Responses like “no time,”“no money,”“medical students with previous research experience choose other specialties,”“department chairs don't have sufficient research background,” or “we've solved all of our major problems” are not acceptable, and they are, in fact, not true. For example, take “we've solved all of our major problems.” What about mortality? We have made substantial progress in the sense that we are anesthetizing sicker patients who undergo more complex procedures without an increase in mortality, but mortality from anesthesia has not decreased significantly since the 1960s.2 What about “medical students who do research don't go into anesthesiology”? Our residents have done research, and like residents who match into other highly desired specialties—such as dermatology, plastic and reconstructive surgery, orthopedics, and radiology—they use their qualifications to gain admission to a specialty that receives little NIH funding.1 What about the qualifications of anesthesia chairs? I am confident that our chairpersons compare favorably to chairs in specialties that receive the lion's share of funding.
Most of all, we need to reject the rejoinder that anesthesiology receives little research funding because it is a specialty without a disease. As my friend Jeff Balser, M.D., Ph.D. (Professor, Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee), says, “Every disease in every patient who is going to be anesthetized is ‘our' disease.” In addition to diseases that are known to affect anesthetic management—such as coronary artery disease, chronic lung disease, and renal failure—there may be many that we are yet to discover. What about conditions that are exacerbated by anesthetics? These may include fetal apoptosis (brain cell suicide), Alzheimer disease (AD), Parkinson disease, Huntington disease, and asymptomatic cognitive dysfunction that becomes symptomatic as postoperative cognitive dysfunction (POCD). These are the diseases whose connection to anesthesia can connect us to grant proposals that—if properly formulated—NIH cannot refuse.
So today I want to talk about some of the morbidities that we need to investigate most urgently. We will review characteristics of the young brain, discuss anesthetic effects on the young brain—effects that are being delineated today—and talk about characteristics of the old brain and anesthetic effects on the older brain. In doing so, we will consider the controversy over which is worse—deep anesthesia or light anesthesia—and talk about factors that probably aggravate cognitive dysfunction. Then we will consider the apparent lack of difference between regional versus  general anesthesia, some of the confounding factors in that discussion, and some potential alleviating procedures, such as the use of continuous peripheral nerve catheters instead of deep sedation after regional anesthesia.
We will also look at the neurodegenerative diseases. What happens when patients with AD have anesthesia and surgery? Do anesthetics hasten the progression of cognitive dysfunction? In light of that risk, I will review some of the agents and techniques that have shown protective potential in laboratories. Preconditioning is one such technique. Could we deliver a nondamaging stressor 24–48 h before surgery—a stressor that would generate a protective cascade, protective against an ischemic cascade? And what about neurogenesis? Can we stimulate the production of new brain cells that would repair damage not prevented by preconditioning? These prospects have left the arena of science fiction, but their clinical utility remains unknown.
Last but not least, I want to add a lagniappe  —“a little something extra” (for those of you who are not from Louisiana or Mississippi)—and tell you about work being done at my institution that involves memory, targeted prevention and erasure of memory, and the potential that research might have for treating phantom pain, preventing memory of intraoperative awareness, and treating posttraumatic distress syndrome. Then I will conclude with a vision of how we can make ourselves and our specialty more profoundly appreciated by the press, the public, our patients, and funding agencies!
The Young Brain
The developing nervous system is highly susceptible to neurotoxic insults during rapid synaptogenesis, during the brain growth spurt, before neurons have migrated to their final destination and fully differentiated.3 In human newborns, the brain has a full complement of 40–50 billion neurons.4 However, in utero  , for every neuron that survives, 1–2 neurons undergo apoptosis and die.5 The signal for initiating those cell suicides is normally a lack of synaptic feedback due to failure to form synaptic connections, such that rates of cell death average approximately 8,000 neurons per second during the last 11 weeks of gestation. This suggests that neurons have a ready capacity to trigger cell death quickly in response to a lack of stimulation, or in response to a neurotoxic insult. With that response potential in mind, let's look at some of the evidence about adverse effects of anesthetics in children and newborns.6 
In 1953, James Eckenhoff, M.D. (Professor, Department of Anesthesiology, University of Pennsylvania, Philadelphia, Pennsylvania; 1915–1996), looked at personality changes in children after anesthesia and surgery.7 They developed more temper tantrums, more phobias, and more bed-wetting. Those changes were most frequent (38%) in the youngest children (younger than 4 yr) and least frequent (8%) in the oldest children (older than 8 yr). Unsatisfactory anesthetic induction was a prominent risk factor. So way back in 1953, there was an indication that anesthesia might have an adverse effect on young children.
One of the first animal models to test the effect of anesthesia on fetuses was developed while I was at New York University. Jack Chalon, M.D. (Professor, Department of Anesthesiology, New York University, New York), exposed pregnant mice to halothane and found that their offspring performed significantly more slowly than those of control mice.8 Unfortunately, early reports indicating a potential problem did not receive the attention they deserved. That changed in 2003 with the publication of Jevtovic-Todorovic et al.  's “Early Exposure to Common Anesthetic Agents Causes Widespread Neurodegeneration in the Developing Rat Brain and Persistent Learning Deficits”—a title that says it all.9 Several studies have augmented those findings,10–13 including a recent investigation by Fredriksson et al.  14 They injected mice with propofol, ketamine, thiopental, propofol with thiopental, ketamine with thiopental, or high-dose propofol during the critical stage of mouse development (10 days old) and found increases in brain cell death and significant reductions in functional performance. Now the laboratory evidence is sufficient to heighten concern about anesthetizing pregnant women during their third trimester, about anesthesia in our neonatal and pediatric patients, and about sedation in the neonatal intensive care unit. What are the proposed mechanisms for this neurotoxicity in laboratory animals? Do anesthetics trigger the same mechanisms in human fetuses and neonates?15,16 And if they do, can we prevent or reduce that effect?
Olney et al.  have proposed that anesthetic drug effects on fetal and neonatal γ-aminobutyric acid and N  -methyl-d-aspartic acid receptors cause translocation of a Bcl-2–associated protein to mitochondrial membranes, leading to an apoptotic cascade.15 If we can interfere with the apoptotic cascade in abnormally inhibited neurons, we might be able to prevent anesthetic-induced neuronal apoptosis. Some ways to do that have been found in laboratory animals. Using the early postnatal rat model in which Jevtovic-Todorovic et al.  found that anesthesia generates neural apoptosis and long-term learning deficits, Yon et al.  17 found that melatonin reduced that damage in the most vulnerable brain regions: “Melatonin-induced neuroprotection was mediated, at least in part, via  inhibition of the mitochondria-dependent apoptotic pathway since melatonin caused an up-regulation of the antiapoptotic protein, bcl-XL, reduction in anesthesia-induced cytochrome C release into the cytoplasm and a decrease in anesthesia-induced activation of caspase-3.” An analogous effect of melatonin has been found in fetal sheep.18 Augmentation of another endogenously generated substance with neuroprotective potential, erythropoietin,19,20 has also shown promise against N  -methyl-d-aspartic acid receptor antagonist neurotoxicity in rat21 and mouse22 neonates and in hypoxic-ischemic injured neonatal rats.23 Perhaps the problem can even be alleviated by anesthetic choice in pregnant females. Ma et al.  24 have presented evidence that “xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain.” What about hypothermia? A human trial looking at whole body hypothermia (72 h at 33.5°C) in neonates with hypoxic ischemia encephalopathy found a decrease in death or moderate to severe disability from 62% down to 44%.25,26 
So what can we say about anesthesia and the young brain? What recommendations can we take home? We have been warned about this potential problem since 1953, and those warnings have been supported by substantial laboratory evidence published over the past 5 yr. I recommend that until and unless we establish that human fetuses and newborns do not suffer anesthetic neurotoxicity, we should minimize or avoid late third-trimester anesthesia, delay elective surgery in preterm and early postnatal infants, avoid nitrous oxide and ketamine because they seem to be the most toxic anesthetics,6 and limit surgical procedure times whenever possible. Meanwhile, we need to continue to look for ways to reduce fetal and newborn anesthetic toxicity in the laboratory, especially in nonhuman primates. We have made progress in defining the potential problem and possible solutions, but I think this question is so serious that it presents our specialty with an enormous obligation and opportunity to find answers.
The Older Brain
The older brain is different, but like the very young brain, it is fragile. Some people define the older brain as over 50 yr. Some define it as over 60. I define it as over 70, and in another 5 yr I hope to have gained the wisdom to define it as over 75—unless I decide to run for President, in which case it will be over 80! Okay, let's look at the not-entirely-happy reality.
The older brain has less cognitive reserve—less resilience to neuropathologic damage.27 It also has declining anesthetic requirements—lower minimum alveolar concentration, lower minimum intraarterial concentration. There are many potential mechanisms that might underlie these age-related differences in cognitive reserve and anesthetic requirements. Oxidative phosphorylation may not work as well. We have picked up some genetic mutations—mutations that can alter outcomes. There are also genetic alleles that were silent when we were young, but manifest themselves (have phenotypic effects) as we age. And then there is free radical buildup with reduced levels of free radical scavengers such as vitamin C, melatonin, and vitamin E.
How do we look for deterioration after anesthesia and surgery? We try to measure decrement in memory or concentration, sometimes not detectable until weeks after anesthesia, with a duration of several weeks to permanent. A diagnosis of POCD is only warranted if we have evidence from a battery of before-and-after neuropsychological tests.
POCD after Noncardiac Surgery
The first major report of cognitive dysfunction after anesthesia was published in 1955 by P. D. Bedford, M.D. (Cowley Road Hospital, Oxford, United Kingdom; died 1962).28 He reviewed 1,193 (presumably noncardiac) patients older than 50 yr who had received general anesthesia. Mental deterioration in 10% of patients seemed to be long term or permanent—a figure that concurs with recent findings. The author concluded that cognitive decline was related to anesthetic agents and hypotension. He recommended that “Operations on elderly people should be confined to unequivocally necessary cases” and that “postoperative medication should not be a routine matter.” The next major study to report POCD skips ahead 43 yr to 1998—the first International Study of Postoperative Cognitive Dysfunction.29 In noncardiac patients older than 59 yr, the incidence of cognitive dysfunction 1 week after surgery was 22% higher than in age-matched controls and 7% higher 3 months after surgery (P  < 0.004 for both), with 10% of patients (91 of 910) evidencing POCD (identical to Bedford's finding at a longer postoperative interval). Increasing age, duration of anesthesia, lesser education, a second operation, postoperative infection, and respiratory complications were risk factors for early POCD. However, under a circumstance of significantly reduced statistical power due to a 22% loss to follow-up at 3 months, only age and benzodiazepine use before surgery remained statistically significant independent risk factors for late POCD. Hypoxemia and hypotension were not significant early or late risk factors.
Let's consider the most recent study. Twelve and seven tenths of a percent of elderly (aged >59 yr), noncardiac patients had POCD 3 months after surgery30 —again, within the confidence interval of Bedford's 1955 report. Corroborating earlier work,31 this study also found a substantial relation between POCD and death within 1 yr of surgery (fig. 1).
Fig. 1. Relation between the presence of postoperative cognitive dysfunction (POCD) and the percentage of patients who died in the first year after surgery. This figure includes only patients who survived to test at the 3-month (late) test time. The figure includes the following four groups: none (patients who did not experience POCD at either of the testing times), hospital discharge (patients who had POCD only at hospital discharge), 3 months (patients who had POCD only at the late [3 months postoperative] testing session), and hospital discharge + 3 months (patients who had POCD at both hospital discharge and the late testing sessions). * Hospital discharge + 3 month group was significantly different than the other three groups,  P  = 0.02.  30 
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Fig. 1. Relation between the presence of postoperative cognitive dysfunction (POCD) and the percentage of patients who died in the first year after surgery. This figure includes only patients who survived to test at the 3-month (late) test time. The figure includes the following four groups: none (patients who did not experience POCD at either of the testing times), hospital discharge (patients who had POCD only at hospital discharge), 3 months (patients who had POCD only at the late [3 months postoperative] testing session), and hospital discharge + 3 months (patients who had POCD at both hospital discharge and the late testing sessions). * Hospital discharge + 3 month group was significantly different than the other three groups,  P  = 0.02.  30 
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Independent risk factors for sustained POCD among the elderly included greater age, less education, POCD at hospital discharge, and a history of stroke without residual damage. Consistent with many investigations, more education may indicate greater presurgical cognitive reserve, just as previous stroke may indicate presurgical reduction of cognitive reserve.32,33 Notably, this most recent study did not find duration of anesthesia to be a risk factor. However, sample size of elderly patients at the 3-month measurement was even smaller (308 with 39 POCD patients, 13%) than in the International Study of POCD (901 with 91 POCD patients, 10%).
POCD after Cardiac Surgery
What about POCD in coronary artery bypass patients? Most of us have heard friends or relatives say something like “since he had open-heart surgery he's not the same, he can't think as well, he's not as happy.” The New York Times  brought attention to this problem with an article titled “Saving the Heart Can Sometimes Mean Losing the Memory.”34 They explained the basics of extracorporeal circulation and discussed reasons for memory loss, focusing on a patient who had gone back to work and found that he had difficulty with his job—a patient who could not perform functions that he had performed for many years. That article raised a great deal of concern, setting the stage for an article published a year later in the New England Journal of Medicine  by Newman et al.  35 They found POCD in 53% of coronary artery bypass graft (CABG) patients at discharge and in 36% of patients 6 weeks later. That percentage went down to 24% at 6 months after surgery, but came back up to 42% at 5 yr after surgery—a pattern of early improvement followed by subsequent decline that was predicted by POCD at discharge.35 
The factors that cause decline in cognitive capacity among non-CABG patients also affect CABG patients. However, some of those risk factors, such as duration of exposure to anesthetics, may be masked by damage done to CABG patients by increased liability to cerebral emboli, cerebral ischemia during reperfusion, and overwarming36 at the end of the procedure.
Does off-pump versus  on-pump make a difference? A small study found no difference,37 but a large study of more than 16,000 patients found a greater incidence of delirium in patients exposed to on-pump cardiopulmonary bypass, with duration of surgery (and so anesthesia) as a significant risk factor (fig. 2).38 Although these patients were not followed up for POCD, a relation between delirium and POCD should not be discounted,39,40 such that off-pump patients may be at lesser risk for POCD.
Fig. 2. Prevalence of postoperative delirium according to the type of cardiac surgical procedure. BH = beating heart surgery; CABG–CPB = coronary artery bypass grafting with cardiopulmonary bypass; CPB = cardiopulmonary bypass; Valve = valvular surgery with or without coronary artery bypass grafting with cardiopulmonary bypass. #  P  < 0.0001  versus  CABG–CPB and Valve-CPB. §  P  < 0.0001  versus  CABG-CPB  .38 
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Fig. 2. Prevalence of postoperative delirium according to the type of cardiac surgical procedure. BH = beating heart surgery; CABG–CPB = coronary artery bypass grafting with cardiopulmonary bypass; CPB = cardiopulmonary bypass; Valve = valvular surgery with or without coronary artery bypass grafting with cardiopulmonary bypass. #  P  < 0.0001  versus  CABG–CPB and Valve-CPB. §  P  < 0.0001  versus  CABG-CPB  .38 
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Aggravating Factors
What factors aggravate the development of POCD in the elderly? Inflammation caused by surgical trauma is an early candidate. We know about the up-regulation of interleukin 1, and this in turn can affect the anesthetic receptors.41 The ensuing cascade of events ultimately affects the anesthetic γ-aminobutyric acid and N  -methyl-d-aspartic acid receptors and increases production of β-amyloid, and we know that β-amyloid, even in nondemented patients, can cause cognitive problems if there is enough of it.41 
Genetic predispositions are another aggravating factor. For example, Mathew et al.  42 have shown the contribution of P-selectin and C-reactive protein alleles in modulating susceptibility to cognitive decline caused by inflammation after cardiac surgery (fig. 3).
Fig. 3. Incidence of postoperative cognitive deficit by C-reactive protein (CRP) 1059G/C and P-selectin (SELP) 1087G/A genotypes. The incidence of cognitive deficit was 16.7% in carriers of minor alleles at both of these loci compared with 42.9% in patients homozygous for the major allele. n = 386.  42 
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Fig. 3. Incidence of postoperative cognitive deficit by C-reactive protein (CRP) 1059G/C and P-selectin (SELP) 1087G/A genotypes. The incidence of cognitive deficit was 16.7% in carriers of minor alleles at both of these loci compared with 42.9% in patients homozygous for the major allele. n = 386.  42 
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Are anesthetics aggravating factors? Culley et al.  43 found that spatial memory is impaired for 2 weeks after 2 h of 1.2% isoflurane and 70% nitrous oxide in aged rats. What about nitrous oxide alone? In a more recent investigation, Culley et al.  44 found that aged rats exposed to 70% nitrous oxide for 4 h took more time to complete a maze test and made fewer correct choices before making their first error compared with control rats over the following 2 weeks. In a separate group of rats, they found that the same nitrous oxide exposure profoundly, but transiently, reduced the activity of cortical methionine synthase—an enzyme whose depletion produces a myelopathy that is implicated in dementia and may be related to accumulation of homocysteine (a cytotoxic amino acid normally remethylated to methionine, an essential amino acid, by methionine synthase).
Evidence from Monk and coauthors' (2005) study indicated that cumulative deep hypnotic time is associated with more POCD,31 but a recent study by Farag et al.  45 looked at lighter anesthesia (Bispectral Index 50) versus  deeper anesthesia (Bispectral Index 39) and found that deeper levels of anesthesia were associated with better cognitive function 4–6 weeks postoperatively. How could that be? As Lenz et al.  46 and others have shown, equilibrated anesthetic does not mean equal anesthesia. Using glucose utilization as a measure of metabolic rate, we can see (table 1) that anesthetics affect different brain subregions to a greater or lesser extent—with most areas showing a reduction in metabolism, some areas showing no change in metabolism, and a few areas in which metabolism actually increases during anesthesia.
Table 1. Local Cerebral Glucose Utilization (μmol · 100 g · min−1± SD) during 1 and 2 MAC of Isoflurane and Sevoflurane Anesthesia in Subregions of Rat Mesencephalon, Diencephalon, and Telencephalon 
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Table 1. Local Cerebral Glucose Utilization (μmol · 100 g · min−1± SD) during 1 and 2 MAC of Isoflurane and Sevoflurane Anesthesia in Subregions of Rat Mesencephalon, Diencephalon, and Telencephalon 
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So if synaptic feedback is key to preventing the apoptotic cascade, neurons capable of generating action potentials (nonanesthetized) that do not receive sufficient input from connecting neurons (anesthetized) to generate summed signals that are large enough to trigger depolarization might be at greater risk than neurons that are in a state of stable quiescence (fig. 4), and the ratio of nonanesthetized to anesthetized neurons should be higher in less deeply anesthetized patients.
Fig. 4. Neurons in nonanesthetized cortical subregions (  red  and  black  ) may be in a sort of reverse penumbra. That is, a penumbra where the cluster in the center is OK because each neuron is connected to potentially active neurons and they can maintain sufficient activity through a local-talk network to ward off apoptosis (the default program), but farther away from the core, approaching fully anesthetized subregions (  green  ), there will be nonanesthetized neurons that do not receive enough talk to have anything to say in response. Neurons that do not receive sufficient input (  black  , with dendrites connecting to anesthetized neurons) would be in a state of nonanesthetized inactivity, which may be physiologically worse than being anesthetized during a period of inactivity because, unlike anesthetized neurons, they retain the capacity to transcribe and translate enzymes needed to undergo apoptosis (apoptosis is an active process, requiring substantial metabolic activity). Indeed, a state of prolonged nonanesthetized inactivity may be analogous to the state of a neuron in a developing fetus that fails to grow sufficient functional dendritic and axonal connections, and so undergoes apoptosis.  6 
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Fig. 4. Neurons in nonanesthetized cortical subregions (  red  and  black  ) may be in a sort of reverse penumbra. That is, a penumbra where the cluster in the center is OK because each neuron is connected to potentially active neurons and they can maintain sufficient activity through a local-talk network to ward off apoptosis (the default program), but farther away from the core, approaching fully anesthetized subregions (  green  ), there will be nonanesthetized neurons that do not receive enough talk to have anything to say in response. Neurons that do not receive sufficient input (  black  , with dendrites connecting to anesthetized neurons) would be in a state of nonanesthetized inactivity, which may be physiologically worse than being anesthetized during a period of inactivity because, unlike anesthetized neurons, they retain the capacity to transcribe and translate enzymes needed to undergo apoptosis (apoptosis is an active process, requiring substantial metabolic activity). Indeed, a state of prolonged nonanesthetized inactivity may be analogous to the state of a neuron in a developing fetus that fails to grow sufficient functional dendritic and axonal connections, and so undergoes apoptosis.  6 
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In this conjectured brain scenario, a nonanesthetized neuron whose dendrites are surrounded by anesthetized neurons is in solitary confinement. Eventually, it may kill itself. The nonfunctional fetal neuron and the nonanesthetized adult neuron may undergo apoptosis for the same reason—insufficient functioning connections—but in the case of the fetal neuron, that is because it  has not made enough functional connections, whereas for the nonanesthetized neuron, too many of its anesthetized neighbors have become nonfunctional. Whether a neuron finds itself in solitary confinement because it fails to make enough connections (fetal neuron), or because it is stuck in a neighborhood from which most of its neighbors seem to have left (nonanesthetized neuron in an otherwise anesthetized brain region), the effect may be the same. Much is at stake here, and there is much to learn. As put by Farag et al.  ,45 “Our observations highlight the need for further studies to better understand the contribution of perioperative management to POCD.”
Perhaps this perspective is also relevant to the frequently observed lack of difference in POCD, or the weakness of the difference in POCD, between patients who receive general anesthesia and patients who receive regional anesthesia with sedation.47 That is, perhaps perioperative sedation associated with regional anesthesia generates areas of nonanesthetized neurons surrounded by anesthetized neurons, setting up a proapoptotic condition that is analogous to the effect of general anesthesia. Ancelin et al.  48 found that “Adding sedation to peridural anesthesia led to a decline in verbal secondary memory,” and Jankowski et al.  49 at the Mayo Clinic found that replacing postoperative sedation with continuous peripheral nerve catheters was associated with a 58% decline in the incidence of postoperative delirium. Again, there are empirical39 and neuropathologic40 reasons to suspect a link between delirium and POCD, and there is evidence that patients with the apolipoprotein ϵ4allele experience postoperative delirium at more than twice the rate of patients without apolipoprotein ϵ4.50 
What about the effects of anesthetics on the neurodegenerative diseases? Hydrophobic cavities keep sticky proteins from becoming irreversibly glued together. Unfortunately, molecules of inhalational anesthetics can fill those cavities and reduce the amount of energy required to maintain protein assembly (fig. 5).51 
Fig. 5. Anesthesia-facilitated disinhibition of protein binding helps monomers aggregate into oligomers, and if those monomers are amyloid β, the resulting oligomerization can lead to protofibrils that are small enough to diffuse into neurons and large enough to be neurotoxic. Adapted with permission; from Carnini  et al.  51 
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Fig. 5. Anesthesia-facilitated disinhibition of protein binding helps monomers aggregate into oligomers, and if those monomers are amyloid β, the resulting oligomerization can lead to protofibrils that are small enough to diffuse into neurons and large enough to be neurotoxic. Adapted with permission; from Carnini  et al.  51 
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This anesthesia-facilitated disinhibition of protein binding helps monomers to aggregate into oligomers, and if those monomers are amyloid β, the resulting oligomerization can lead to protofibrils that are small enough to diffuse into neurons and large enough to be neurotoxic. Amyloid β oligomers seem to contribute to the neurodegeneration characterized by Alzheimer in the early 20th century. Thirteen million Americans are projected to have AD by the middle of the 21st century. Many of them will need to be anesthetized, and many of them will have been anesthetized before they became demented.
The role of inhalational anesthetics in the above scenario has been verified in vitro  by a decade of work from Eckenhoff et al.  , now supported in vivo  by a transgenic mouse model.52 In addition to the amyloid β–anesthesia connection, Xie et al.  40,53,54 have used human neuroglioma cell cultures to add anesthesia-induced apoptosis as a factor contributing to AD, and Jevtovic-Todorovic and Carter55 have reported that old rat brains are equally (nitrous oxide) or more sensitive (ketamine) to anesthetic neurotoxicity than young rat brains.
Do the rodent and cell culture findings apply to humans? Results from retrospective studies are unsettling. Examining records of 9,170 veterans, Lee et al.  56 compared the risk of developing AD within 5–6 yr of cardiac surgery (CABG) during inhalational anesthesia versus  the risk of developing AD within 5–6 yr of percutaneous transluminal coronary angioplasty, the latter seldom requiring general anesthesia. After adjustment for age, duration of hospital stay, comorbidity, and number of procedures, the CABG patients developed AD at nearly twice the rate of percutaneous transluminal coronary angioplasty patients (hazard ratio = 1.71; P  < 0.04). Yes, CABG patients faced more predisposing factors than percutaneous transluminal coronary angioplasty patients, including embolic ischemia, but given in vitro  evidence supporting mechanisms for a causal link between anesthesia and AD, it would be reckless to dismiss prolonged inhalational anesthesia as an independent contributing factor to the finding of Lee et al. 
Bohnen et al.  57 performed a case-controlled retrospective study of 252 AD patients. Unfortunately, 199 of the 252 controls (non-AD patients) had previous exposure to general anesthesia, which greatly dilutes their statistical power to evidence an effect of anesthesia relative to AD patients. Nevertheless, Bohnen et al.  found non–statistically significant effects in the direction of a link between AD and general anesthesia on each of three independent variables: cumulative exposure to anesthesia, exposure to six or more episodes of general anesthesia (odds ratio = 1.44), and cumulative exposure to 600 min or more of general anesthesia (odds ratio = 1.63). Gasparini et al.  58 also performed a retrospective case-controlled study of AD patients. In their study, the controls were Parkinson disease patients and patients with other neurologic diseases, but a link between general anesthesia and other neurologic diseases has been hypothesized,51 such that lack of a difference in anesthetic exposure between AD patients and patients with Parkinson disease or other neurologic diseases does not imply a lack of a deleterious effect of anesthetic exposure.
Although a connection between anesthetics and AD has received more attention than a possible relation between anesthesia and Parkinson or Huntington disease, two investigations suggest that further research is warranted. Peretz et al.  59 have found evidence that supports an increased risk of Parkinson disease among anesthesiologists as compared with internists, and Wei et al.  60,61 have found in vitro  laboratory evidence that isoflurane may exacerbate Huntington disease.
So there is evidence that anesthetics are a particular problem for older patients, but before we make recommendations more firm than Bedford's admonition from 1953 that “Operations on elderly people should be confined to unequivocally necessary cases,”28 we need to know more about genetic profiles to know which older patients are most at risk. My purpose today is to stimulate our research community to ask more questions and do more research more quickly.
Potential Alleviating Factors
How might we reduce the risk of apoptosis in the very young and those with POCD, or worse, in older patients? Is there evidence that some anesthetics are more deleterious than others? Lee et al.  62 presented data at the 2007 American Society of Anesthesiologists Annual Meeting indicating that “In aged rats, propofol anesthesia is devoid of the persistent memory effects observed with other general anesthetic agents in this model. Thus, it appears that general anesthesia-induced memory impairment may be a function of the agent rather than the anesthetic state itself.” In a rat cardiopulmonary bypass model, isoflurane with 60% xenon has been shown to prevent the decrement in neurocognitive function caused by bypass during isoflurane alone.63 So the protective potential of xenon is being evaluated in humans, and preliminary results are encouraging.64 
My department's laboratory has investigated the effects of lidocaine during global ischemia in rats. We found that neuron death in the hippocampus is substantially reduced in animals that have received clinically relevant doses of lidocaine. Function was also better retained after global ischemia in animals that received lidocaine.65 Looking at CABG patients, Wang et al.  66 found that lidocaine (1.5-mg/kg bolus followed by a 4-mg/min infusion during operation and 4 mg/kg in the priming solution of cardiopulmonary bypass) reduced POCD measured 9 days after surgery. Looking at a larger number of CABG patients, Mitchell et al.  67 also found reduced POCD in patients who received lidocaine— from 75% to 40% at 10 days (P  < 0.025), from 75% to 46% at 10 weeks (P  < 0.05), and from 48% to 28% at 6 months (not statistically significant).
What about melatonin and statins in the elderly? A review by Cheng et al.  68 of the beneficial effects of melatonin in experimental models of AD is encouraging, but the jury has looked hard for evidence that statin therapy prevents or ameliorates AD, with little to show.69,70 Nevertheless, because there are other important reasons for the elderly to take statins, we can expect to need to anesthetize many AD patients who are using statins. If the evidence from stroke patients applies, statin therapy should not be withdrawn without specific indication for withdrawal.71 
Preconditioning
Although fetuses and the elderly are particularly sensitive to ischemia, hypoperfusion, and hypoxia, “Nietzsche's Toxicology: whatever doesn't kill you might make you stronger”72 could lead to improved clinical management of patients with fragile brains. For example, prodromal temporary ischemic attacks protect people's brains during subsequent ischemia by inducing cerebral preconditioning.73–75 That finding enhances the intriguing possibility that prophylactic cerebral protection could be initiated before surgery.
In 1964, Dahl and Balfour76 published evidence of “prolonged anoxic survival due to anoxia preexposure.” This phenomenon was eventually replicated in a model of cerebral ischemia,77 and induction of endogenous proteins of repair and the genes that code for them are now well documented. Although improved understanding of preconditioning has removed much of the paradox from such findings,78 it still seems ironic that “Mild, non-lesioning transient hypoxia in the newborn rat induces delayed brain neurogenesis associated with improved memory scores”!79 
Our laboratory recently added sevoflurane as a potential preconditioner (fig. 6),80 and the in vitro  finding of Wang et al.  81 that “preconditioning-induced neuroprotection by volatile anesthetics is not agent-specific” indicates that “mechanisms involved in inducing anesthesia [per se  ] may contribute to the induction of preconditioning.” If a limited dose of anesthesia triggers the same protective mechanisms as a limited bout of hypoxia, how much anesthesia can we give before what would have been a protective effect becomes a deleterious effect?
Fig. 6. CA1 pyramidal neurons after global cerebral ischemia. Representative hematoxylin and eosin–stained cryostat sections (16 μm) from the CA1 pyramidal cell layer of the experimental groups 6 weeks after the global cerebral ischemia are shown at approximately 250× magnification (  A    D  ). (  A  ) Tissue from naive rats not subjected to ischemia. (  B  ) Tissue from rats subjected to 10 min of global ischemia without preconditioning. (  C  ) Tissue from rats preconditioned with 2% sevoflurane (Sevo) for 1 h before ischemia. (  D  ) Tissue from rats preconditioned with 4% sevoflurane for 1 h before ischemia. The data were quantitated by counting the number of intact CA1 neurons per 475 μm length of stratum pyramidale in each hemisphere at the same level of coronal section using light microscopy (250× magnification); the observer was blind to the experimental treatment (  E  and  F  ). The numbers were averaged across both hemispheres to yield a single value for each rat and expressed as number/mm (mean ± SD). There were significantly more intact CA1 pyramidal cells with sevoflurane treatment compared with the untreated ischemic group (untr) (  P  < 0.01) at both 1 week (  E  ) and 6 weeks (  F  ) after ischemia.  80 
Image Not Available
Fig. 6. CA1 pyramidal neurons after global cerebral ischemia. Representative hematoxylin and eosin–stained cryostat sections (16 μm) from the CA1 pyramidal cell layer of the experimental groups 6 weeks after the global cerebral ischemia are shown at approximately 250× magnification (  A    D  ). (  A  ) Tissue from naive rats not subjected to ischemia. (  B  ) Tissue from rats subjected to 10 min of global ischemia without preconditioning. (  C  ) Tissue from rats preconditioned with 2% sevoflurane (Sevo) for 1 h before ischemia. (  D  ) Tissue from rats preconditioned with 4% sevoflurane for 1 h before ischemia. The data were quantitated by counting the number of intact CA1 neurons per 475 μm length of stratum pyramidale in each hemisphere at the same level of coronal section using light microscopy (250× magnification); the observer was blind to the experimental treatment (  E  and  F  ). The numbers were averaged across both hemispheres to yield a single value for each rat and expressed as number/mm (mean ± SD). There were significantly more intact CA1 pyramidal cells with sevoflurane treatment compared with the untreated ischemic group (untr) (  P  < 0.01) at both 1 week (  E  ) and 6 weeks (  F  ) after ischemia.  80 
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Clinically acceptable means of accomplishing cerebral preconditioning are being sought. In addition to volatile anesthetics, laboratory results suggest promise for pretreatment with the antibiotic erythromycin6 —but the most impressive human trial of a preconditioning/neurogenic agent published to date uses erythropoietin82 (see Grasso19 and Hasselblatt et al.  20 for review). Limiting their study to ischemic stroke patients whose treatment could begin within 8 h of the onset of symptoms, Ehrenreich et al.  82 found that intravenous injection of recombinant erythropoietin once daily for 3 days led to 60- to 100-fold increases of erythropoietin in the central nervous system, reduced serum concentrations of the glial marker of cerebral injury S100β, reduced infarct size, and improved recovery. If these results hold up in the multicenter, randomized, controlled trial that is currently under way, there is reason to hope that erythropoietin would be even more effective as a prophylactic protectant—because we could harness erythropoietin's preconditioning effects by initiating administration 24–48 h before surgery, deliver it during surgery, and maintain administration in the intensive care unit.
Unfortunately, erythropoietin has the attribute of increasing hematocrit—a potentially deleterious effect in the context of ischemic injury and perhaps in fetuses more generally. Fortunately, nonhematopoietic analogs of erythropoietin, such as asialoerythropoietin, have been developed and are showing equivalent potency as neuroprotectants.83,84 
Neurogenesis
The old adage that neurogenesis is only for the young was shown to be wrong in rodents in 196585 and also seems to be wrong for primates.86 This raises the possibility that negative effects of surgery and anesthesia on the elderly, as well as the very young, can be compensated by therapies that strengthen the neurogenic response. Results in rats encourage the conclusion that “neural precursors resident in the brain initiate a compensatory response that results in the production of new neurons. Moreover, administration of growth factors can enhance this compensatory response …[and] we may eventually be able to manipulate these precursors to improve recovery of function”87 (see also Sherstnev et al.  88). In addition to ischemic preconditioning,89 granulocyte colony-stimulating factor and erythropoietin seem to be such manipulators90 and erythropoietin has shown protective promise against N  -methyl-d-aspartate receptor antagonist neurotoxicity in rat21 and mouse22 neonates, in hypoxic-ischemic–injured neonatal rats,23 and against amyloid-β neurotoxicity in an in vitro  AD model.91 Electrical deep brain stimulation has also been shown to elicit neurogenesis in rats92 and has shown promise in a human after traumatic brain injury.93 
Epilogue
I hope all of you have noticed that I have been talking about issues that have been in the literature since the 1950s and 1960s—effects of anesthetics on the very young, POCD in the elderly, preconditioning, and neurogenesis—and it's not just because that's when I started reading medical literature! The problems are old, but our awareness of them has enjoyed a renaissance over the past decade. Because of that newfound interest and the research it has inspired, my guess is that we will soon have anesthetic and adjuvant drugs ranked according to their deleterious effects on the very young and the very old, and that cerebral preconditioning and augmentation of endogenous processes of repair and regeneration will deliver brain protection to the young, the old, and everyone in between—before the younger among us are too far gone to benefit—and well before the 2050s and 2060s!
Lagniappe I
In 2002, colleagues at my institution (Downstate Medical Center, in Brooklyn), used an in vitro  model to contribute to the realization that an evolutionarily conserved molecule, protein kinase Mσ (PKMσ; PKM in fig. 794) may be both necessary and sufficient for the maintenance of long-term memory95 (see also Pastalkova et al.  96). That finding raises the prospect of pharmacologically manipulating PKMσ to selectively enhance or prevent memory formation, and even to extend or erase formed memories for therapeutic purposes, such as preventing recall of intraoperative awareness and treating posttraumatic stress syndrome, phantom limb pain, and perhaps even AD. Step 1 has already been taken; this group has used a PKMσ inhibitor, ZIP, to erase a long-term taste aversion memory in rats.97 Perhaps a team of anesthesiologists will take step 2. Could NIH say no to such research?
Fig. 7. Role of protein kinase M (PKM) in long-term potentiation (memory). (  A  ) Schematic drawing of protein kinase C (PKC) in its resting configuration (  left  ), activated state (  middle  ), and persistently active form (PKM) (  right  ). In its resting configuration, a pseudosubstrate sequence in the regulatory domain (R) inhibits the catalytic domain. The catalytic domain (C) is exposed  via  a conformational change upon activation by different second messengers. Proteolytic cleavage leaves the catalytic domain (PKM) constitutively active because it is not inhibited by the pseudosubstrate sequence. (  B  ) Model for induction and maintenance of long-term potentiation. During baseline conditions, glutamate (Glu) released from the presynaptic bouton binds to both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and γ-aminobutyric acid and  N  -methyl-d-aspartic acid (NMDA) receptors on the postsynaptic spine. However, the excitatory postsynaptic potential is mediated exclusively  via  AMPA receptors, as γ-aminobutyric acid and NMDA receptors are blocked by Mg2+ions. During induction of long-term potentiation, depolarization of the postsynaptic cell (by converging excitatory inputs or back-propagating action potentials) relieves the Mg2+block of the γ-aminobutyric acid and NMDA receptor channel, allowing Ca2+ions into the postsynaptic spine. The resultant Ca2+increase triggers long-term potentiation by activating protein kinases such as CaMKII and PKC. These are necessary during the induction of long-term potentiation. In parallel, atypical PKC is turned into a persistently active form  via  Ca2+-activated proteolytic cleavage (calpain). During maintenance, the AMPA receptors remain phosphorylated by persistent kinase activity (PKM), leading to increased conductance of AMPA receptor channels.  94 
Image Not Available
Fig. 7. Role of protein kinase M (PKM) in long-term potentiation (memory). (  A  ) Schematic drawing of protein kinase C (PKC) in its resting configuration (  left  ), activated state (  middle  ), and persistently active form (PKM) (  right  ). In its resting configuration, a pseudosubstrate sequence in the regulatory domain (R) inhibits the catalytic domain. The catalytic domain (C) is exposed  via  a conformational change upon activation by different second messengers. Proteolytic cleavage leaves the catalytic domain (PKM) constitutively active because it is not inhibited by the pseudosubstrate sequence. (  B  ) Model for induction and maintenance of long-term potentiation. During baseline conditions, glutamate (Glu) released from the presynaptic bouton binds to both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and γ-aminobutyric acid and  N  -methyl-d-aspartic acid (NMDA) receptors on the postsynaptic spine. However, the excitatory postsynaptic potential is mediated exclusively  via  AMPA receptors, as γ-aminobutyric acid and NMDA receptors are blocked by Mg2+ions. During induction of long-term potentiation, depolarization of the postsynaptic cell (by converging excitatory inputs or back-propagating action potentials) relieves the Mg2+block of the γ-aminobutyric acid and NMDA receptor channel, allowing Ca2+ions into the postsynaptic spine. The resultant Ca2+increase triggers long-term potentiation by activating protein kinases such as CaMKII and PKC. These are necessary during the induction of long-term potentiation. In parallel, atypical PKC is turned into a persistently active form  via  Ca2+-activated proteolytic cleavage (calpain). During maintenance, the AMPA receptors remain phosphorylated by persistent kinase activity (PKM), leading to increased conductance of AMPA receptor channels.  94 
×
Perhaps even closer to home, another team at my institution examined autopsy brain tissue from AD patients and found accumulations of PKMσ in neurofibrillary tangles of brain areas implicated in memory loss. PKMσ was not found in neurofibrillary tangles outside of the memory loss areas and was not found in any of the neurofibrillary tangles of normal age-matched controls.98 PKMσ seems to have its effect on long-term memory through persistent enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–mediated synaptic transmission. Do we need to determine the effects of anesthetics on PKMσ accumulation in neurofibrillary tangles?
Last but not least in this sampler of cutting-edge research, I hope that everybody in anesthesiology read Dr. Beverly Orser's99 marvelous article in last June's Scientific American  : “Lifting the Fog around Anesthesia.” In addition to the best graphics ever presented in an article about anesthetics, Professor Orser advanced the hypothesis that “by finding the correct target receptors for the amnesia-inducing effects of anesthesia, it may become possible to identify patients at risk for intraoperative awareness because they lack those receptors. Alternatively, drug strategies to prevent awareness or at least its recollection could also be developed.”
Lagniappe II
Okay, a little more something extra. I would like to close by telling you a story. One afternoon in 1980-something, I was waiting outside my office while medical students gathered inside for an introduction to our specialty. I overheard one of them ask, “What do anesthesiologists do?” The answer came back, “They put people to sleep.”
I walked in, introduced myself, and asked them to imagine the following:
You're lying face up on a cold steel table covered only by a sheet. People in disposable gowns appear at your side. One of them pulls your sheet off and cuts the skin over your sternum with a razor blade—right down to the bone. Then he saws through your chest, inserts a crank, and winds you open until he can grab your heart. After hooking you up to a pump, he cuts a valve out of your heart and sews in a valve from a pig. Then he puts you back together with needles and strings and staples.
How many of you could sleep through that?
They got the message that I have been hawking for a very long time: “Anesthesiologists are doctors who keep patients alive while surgeons do things that would otherwise kill them.”100 
We can show the public how much we care about what we do by advancing our specialty through research that addresses our patients' fears. When we show them how much we care, they too will know who we are.
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Fig. 1. Relation between the presence of postoperative cognitive dysfunction (POCD) and the percentage of patients who died in the first year after surgery. This figure includes only patients who survived to test at the 3-month (late) test time. The figure includes the following four groups: none (patients who did not experience POCD at either of the testing times), hospital discharge (patients who had POCD only at hospital discharge), 3 months (patients who had POCD only at the late [3 months postoperative] testing session), and hospital discharge + 3 months (patients who had POCD at both hospital discharge and the late testing sessions). * Hospital discharge + 3 month group was significantly different than the other three groups,  P  = 0.02.  30 
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Fig. 1. Relation between the presence of postoperative cognitive dysfunction (POCD) and the percentage of patients who died in the first year after surgery. This figure includes only patients who survived to test at the 3-month (late) test time. The figure includes the following four groups: none (patients who did not experience POCD at either of the testing times), hospital discharge (patients who had POCD only at hospital discharge), 3 months (patients who had POCD only at the late [3 months postoperative] testing session), and hospital discharge + 3 months (patients who had POCD at both hospital discharge and the late testing sessions). * Hospital discharge + 3 month group was significantly different than the other three groups,  P  = 0.02.  30 
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Fig. 2. Prevalence of postoperative delirium according to the type of cardiac surgical procedure. BH = beating heart surgery; CABG–CPB = coronary artery bypass grafting with cardiopulmonary bypass; CPB = cardiopulmonary bypass; Valve = valvular surgery with or without coronary artery bypass grafting with cardiopulmonary bypass. #  P  < 0.0001  versus  CABG–CPB and Valve-CPB. §  P  < 0.0001  versus  CABG-CPB  .38 
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Fig. 2. Prevalence of postoperative delirium according to the type of cardiac surgical procedure. BH = beating heart surgery; CABG–CPB = coronary artery bypass grafting with cardiopulmonary bypass; CPB = cardiopulmonary bypass; Valve = valvular surgery with or without coronary artery bypass grafting with cardiopulmonary bypass. #  P  < 0.0001  versus  CABG–CPB and Valve-CPB. §  P  < 0.0001  versus  CABG-CPB  .38 
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Fig. 3. Incidence of postoperative cognitive deficit by C-reactive protein (CRP) 1059G/C and P-selectin (SELP) 1087G/A genotypes. The incidence of cognitive deficit was 16.7% in carriers of minor alleles at both of these loci compared with 42.9% in patients homozygous for the major allele. n = 386.  42 
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Fig. 3. Incidence of postoperative cognitive deficit by C-reactive protein (CRP) 1059G/C and P-selectin (SELP) 1087G/A genotypes. The incidence of cognitive deficit was 16.7% in carriers of minor alleles at both of these loci compared with 42.9% in patients homozygous for the major allele. n = 386.  42 
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Fig. 4. Neurons in nonanesthetized cortical subregions (  red  and  black  ) may be in a sort of reverse penumbra. That is, a penumbra where the cluster in the center is OK because each neuron is connected to potentially active neurons and they can maintain sufficient activity through a local-talk network to ward off apoptosis (the default program), but farther away from the core, approaching fully anesthetized subregions (  green  ), there will be nonanesthetized neurons that do not receive enough talk to have anything to say in response. Neurons that do not receive sufficient input (  black  , with dendrites connecting to anesthetized neurons) would be in a state of nonanesthetized inactivity, which may be physiologically worse than being anesthetized during a period of inactivity because, unlike anesthetized neurons, they retain the capacity to transcribe and translate enzymes needed to undergo apoptosis (apoptosis is an active process, requiring substantial metabolic activity). Indeed, a state of prolonged nonanesthetized inactivity may be analogous to the state of a neuron in a developing fetus that fails to grow sufficient functional dendritic and axonal connections, and so undergoes apoptosis.  6 
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Fig. 4. Neurons in nonanesthetized cortical subregions (  red  and  black  ) may be in a sort of reverse penumbra. That is, a penumbra where the cluster in the center is OK because each neuron is connected to potentially active neurons and they can maintain sufficient activity through a local-talk network to ward off apoptosis (the default program), but farther away from the core, approaching fully anesthetized subregions (  green  ), there will be nonanesthetized neurons that do not receive enough talk to have anything to say in response. Neurons that do not receive sufficient input (  black  , with dendrites connecting to anesthetized neurons) would be in a state of nonanesthetized inactivity, which may be physiologically worse than being anesthetized during a period of inactivity because, unlike anesthetized neurons, they retain the capacity to transcribe and translate enzymes needed to undergo apoptosis (apoptosis is an active process, requiring substantial metabolic activity). Indeed, a state of prolonged nonanesthetized inactivity may be analogous to the state of a neuron in a developing fetus that fails to grow sufficient functional dendritic and axonal connections, and so undergoes apoptosis.  6 
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Fig. 5. Anesthesia-facilitated disinhibition of protein binding helps monomers aggregate into oligomers, and if those monomers are amyloid β, the resulting oligomerization can lead to protofibrils that are small enough to diffuse into neurons and large enough to be neurotoxic. Adapted with permission; from Carnini  et al.  51 
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Fig. 5. Anesthesia-facilitated disinhibition of protein binding helps monomers aggregate into oligomers, and if those monomers are amyloid β, the resulting oligomerization can lead to protofibrils that are small enough to diffuse into neurons and large enough to be neurotoxic. Adapted with permission; from Carnini  et al.  51 
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Fig. 6. CA1 pyramidal neurons after global cerebral ischemia. Representative hematoxylin and eosin–stained cryostat sections (16 μm) from the CA1 pyramidal cell layer of the experimental groups 6 weeks after the global cerebral ischemia are shown at approximately 250× magnification (  A    D  ). (  A  ) Tissue from naive rats not subjected to ischemia. (  B  ) Tissue from rats subjected to 10 min of global ischemia without preconditioning. (  C  ) Tissue from rats preconditioned with 2% sevoflurane (Sevo) for 1 h before ischemia. (  D  ) Tissue from rats preconditioned with 4% sevoflurane for 1 h before ischemia. The data were quantitated by counting the number of intact CA1 neurons per 475 μm length of stratum pyramidale in each hemisphere at the same level of coronal section using light microscopy (250× magnification); the observer was blind to the experimental treatment (  E  and  F  ). The numbers were averaged across both hemispheres to yield a single value for each rat and expressed as number/mm (mean ± SD). There were significantly more intact CA1 pyramidal cells with sevoflurane treatment compared with the untreated ischemic group (untr) (  P  < 0.01) at both 1 week (  E  ) and 6 weeks (  F  ) after ischemia.  80 
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Fig. 6. CA1 pyramidal neurons after global cerebral ischemia. Representative hematoxylin and eosin–stained cryostat sections (16 μm) from the CA1 pyramidal cell layer of the experimental groups 6 weeks after the global cerebral ischemia are shown at approximately 250× magnification (  A    D  ). (  A  ) Tissue from naive rats not subjected to ischemia. (  B  ) Tissue from rats subjected to 10 min of global ischemia without preconditioning. (  C  ) Tissue from rats preconditioned with 2% sevoflurane (Sevo) for 1 h before ischemia. (  D  ) Tissue from rats preconditioned with 4% sevoflurane for 1 h before ischemia. The data were quantitated by counting the number of intact CA1 neurons per 475 μm length of stratum pyramidale in each hemisphere at the same level of coronal section using light microscopy (250× magnification); the observer was blind to the experimental treatment (  E  and  F  ). The numbers were averaged across both hemispheres to yield a single value for each rat and expressed as number/mm (mean ± SD). There were significantly more intact CA1 pyramidal cells with sevoflurane treatment compared with the untreated ischemic group (untr) (  P  < 0.01) at both 1 week (  E  ) and 6 weeks (  F  ) after ischemia.  80 
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Fig. 7. Role of protein kinase M (PKM) in long-term potentiation (memory). (  A  ) Schematic drawing of protein kinase C (PKC) in its resting configuration (  left  ), activated state (  middle  ), and persistently active form (PKM) (  right  ). In its resting configuration, a pseudosubstrate sequence in the regulatory domain (R) inhibits the catalytic domain. The catalytic domain (C) is exposed  via  a conformational change upon activation by different second messengers. Proteolytic cleavage leaves the catalytic domain (PKM) constitutively active because it is not inhibited by the pseudosubstrate sequence. (  B  ) Model for induction and maintenance of long-term potentiation. During baseline conditions, glutamate (Glu) released from the presynaptic bouton binds to both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and γ-aminobutyric acid and  N  -methyl-d-aspartic acid (NMDA) receptors on the postsynaptic spine. However, the excitatory postsynaptic potential is mediated exclusively  via  AMPA receptors, as γ-aminobutyric acid and NMDA receptors are blocked by Mg2+ions. During induction of long-term potentiation, depolarization of the postsynaptic cell (by converging excitatory inputs or back-propagating action potentials) relieves the Mg2+block of the γ-aminobutyric acid and NMDA receptor channel, allowing Ca2+ions into the postsynaptic spine. The resultant Ca2+increase triggers long-term potentiation by activating protein kinases such as CaMKII and PKC. These are necessary during the induction of long-term potentiation. In parallel, atypical PKC is turned into a persistently active form  via  Ca2+-activated proteolytic cleavage (calpain). During maintenance, the AMPA receptors remain phosphorylated by persistent kinase activity (PKM), leading to increased conductance of AMPA receptor channels.  94 
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Fig. 7. Role of protein kinase M (PKM) in long-term potentiation (memory). (  A  ) Schematic drawing of protein kinase C (PKC) in its resting configuration (  left  ), activated state (  middle  ), and persistently active form (PKM) (  right  ). In its resting configuration, a pseudosubstrate sequence in the regulatory domain (R) inhibits the catalytic domain. The catalytic domain (C) is exposed  via  a conformational change upon activation by different second messengers. Proteolytic cleavage leaves the catalytic domain (PKM) constitutively active because it is not inhibited by the pseudosubstrate sequence. (  B  ) Model for induction and maintenance of long-term potentiation. During baseline conditions, glutamate (Glu) released from the presynaptic bouton binds to both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and γ-aminobutyric acid and  N  -methyl-d-aspartic acid (NMDA) receptors on the postsynaptic spine. However, the excitatory postsynaptic potential is mediated exclusively  via  AMPA receptors, as γ-aminobutyric acid and NMDA receptors are blocked by Mg2+ions. During induction of long-term potentiation, depolarization of the postsynaptic cell (by converging excitatory inputs or back-propagating action potentials) relieves the Mg2+block of the γ-aminobutyric acid and NMDA receptor channel, allowing Ca2+ions into the postsynaptic spine. The resultant Ca2+increase triggers long-term potentiation by activating protein kinases such as CaMKII and PKC. These are necessary during the induction of long-term potentiation. In parallel, atypical PKC is turned into a persistently active form  via  Ca2+-activated proteolytic cleavage (calpain). During maintenance, the AMPA receptors remain phosphorylated by persistent kinase activity (PKM), leading to increased conductance of AMPA receptor channels.  94 
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Table 1. Local Cerebral Glucose Utilization (μmol · 100 g · min−1± SD) during 1 and 2 MAC of Isoflurane and Sevoflurane Anesthesia in Subregions of Rat Mesencephalon, Diencephalon, and Telencephalon 
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Table 1. Local Cerebral Glucose Utilization (μmol · 100 g · min−1± SD) during 1 and 2 MAC of Isoflurane and Sevoflurane Anesthesia in Subregions of Rat Mesencephalon, Diencephalon, and Telencephalon 
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