See Article, p 1501
Postoperative cognitive dysfunction (POCD) has been reported to occur with widely varying frequency, especially in older adults in the weeks to months following surgery.1 Prospective studies with nonsurgical control groups suggest that the incidence of POCD is actually much lower than originally documented and that lingering effects are either minor or nonexistent.2–4 In fact, in a cohort of over 10,000 patients followed over an average of 13 years, age-related cognitive decline following hospital admissions for either nonsurgical reasons or stroke was greater than cognitive decline following major surgery.5 Nevertheless, anesthetic exposure6 and neuroinflammatory processes7 continue to be frequently investigated as mechanisms for POCD. Several large-scale prospective cohorts,8 multicenter randomized studies,9 and meta-analyses10 suggest that, at a minimum, anesthetic exposure by itself does not account for all, or even the majority, of POCDs. Surgeries including cardiopulmonary bypass (CPB), associated with a profound inflammatory response, do not confer risk for worse cognitive outcomes than those without CPB11; and studies testing prevention of neuroinflammation using glucocorticoids have not demonstrated effect either.7
While clarity continues to be sought on the role of anesthetics and neuroinflammation in the genesis of POCD, there is consensus that advanced age, especially with preexisting cognitive impairment and other medical and neurologic comorbidities frequently associated with aging, increases the risk for POCD.12,13 Risk factors that normally predispose an elderly individual to cognitive impairment, such as ApoE allelic expression, reduced cerebrovascular reserve, or increased vascular burden (ie, presence of factors known to impair vascular structure and function, eg, atherosclerosis, diabetes, hypertension, smoking, obesity, hypercholesterolemia, and lack of physical activity as discussed in the following), may exacerbate the POCD risk. Coincident cerebral hypoxia is a mechanism common to many medical comorbidities of aging and has been implicated as a risk factor for cognitive decline outside the surgical arena. We propose that cerebral hypoxia from any source should be considered as an important mechanism contributing to POCD.
PERIOPERATIVE HYPOXIA AND POCD
Hypoxia has been classified into general categories arising from low oxygen uptake (hypoxemic), ischemic, or anemic mechanisms. Each category has been independently linked to cognitive decline in diseases common in the elderly, with accumulating evidence that aging may exacerbate hypoxic stress. Furthermore, major surgery, especially in older adults, involves procedures that decrease oxygen supply, including fluid overload, acute anemia, hypoperfusion, hypoventilation, and atelectasis. Postoperatively, sleep-disordered breathing (present in patients with14 and without15 a history of obstructive sleep apnea [OSA]) and narcotics (commonly prescribed for postoperative pain control16) likely contribute to postoperative hypoxemia.
Intraoperative hypoxemia and postoperative hypoxemia occur with a frequency previously unrecognized. Ehrenfeld et al17 found that 6.8% of patients experienced an intraoperative hypoxemic event, with a hypoxemic event lasting at least 2 minutes occurring in 3.5% of patients. More recently, Sun et al18 published the results of a prospective, blinded observational study in which pulse oximetry was recorded continuously in 1500 patients (mean age = 64 years) for 3 consecutive days postoperatively. Twenty-one percent experienced hypoxemia for at least 10 min/h, 8% experienced hypoxemia for at least 20 min/h, and 8% experienced severe hypoxemia (arterial hemoglobin oxygen saturation [Sao2] <85%). Prolonged hypoxemic episodes were also common, with 37% experiencing at least 1 episode lasting 1 hour minimum, 11% experienced at least 1 episode lasting 6 hours or more, and 3% experienced severe hypoxemia (Sao2 <80%) lasting 30 minutes or longer. Similar results have been reported by others.19
Regardless of anesthetic approach (general versus regional) and surgical approach (off-CPB versus on-CPB), patients are subject to the same milieu of factors contributing to postoperative hypoxemia or hypoxia that may precede cerebral hypoxia. In fact, cerebral hypoxia has been associated with POCD following hip arthroplasty,20 abdominal surgery,21 and cardiac surgery.15,22
Hypoxemic hypoxia (HH), due to low oxygen uptake by the pulmonary circulation, is often present before surgery due to pathophysiological conditions. Clinically, HH is observed during respiratory failure, as experienced in chronic obstructive pulmonary disease (COPD), interstitial lung disease, OSA, and increased interstitial fluid, or pulmonary edema secondary to heart failure (HF), and pulmonary embolism.
The severity of respiratory disease, such as COPD or OSA, consistently correlates with poor performance on assessments of executive function, processing speed, and attention.23 In a multicenter study of individuals over the age of 65 suffering from COPD, cognitive and motor impairments were inversely correlated with resting Sao2.24 Hypoxemia during sleep also plays a major role in cognition.25 Treatment of hypoxemia suggests that at least some cognitive function is recoverable,25 as observed in children26 and adults with OSA.
HF, in addition to hypoperfusion, may also cause HH secondary to an increased arteriolar-alveolar oxygen gradient with pulmonary edema and is associated with higher risk for cognitive decline.27 The Cardiovascular Health Study found that global cognition declined more rapidly following incident HF than in age-matched controls without HF.28 The REasons for Geographic and Racial Differences in Stroke (REGARDS) study, a longitudinal study of racial and geographic disparities in incident HF, also reported that the rate of cognitive failure accelerated following incident HF. Acute decompensated HF, often accompanied by both pulmonary edema and hypoperfusion, is associated with acute decline in cognitive performance compared to those with stable HF.29 Rarely does HF exist in individuals without attendant atherosclerotic disease; therefore, both ischemia and HH likely contribute to cognitive decline.
Ischemic hypoxia, or ischemia, refers to low tissue oxygenation as a result of reduced blood flow and is the category most well recognized as being associated with cognitive failure. In the surgical arena, ischemia occurs secondary to acute and chronic embolic events or hypoperfusion. Embolic, ischemic, and hemorrhagic strokes have been widely recognized as important contributors to cognitive decline and dementia.30 Resulting cognitive and behavioral impairments may be circumscribed or diffused, as even focal brain damage may disrupt widespread functional networks. The most frequently impaired cognitive domains (and their associated brain regions) following a stroke include executive functions (prefrontal cortex, parietal cortex, and underlying white matter), episodic memory (medial temporal lobe and subcortical structures), language/aphasia (dominant [usually left] cerebral hemisphere), attention/hemispatial neglect (brainstem, midbrain, prefrontal cortex, parietal cortex, and underlying white matter), and visuospatial/visuoconstructional abilities (parietal cortex and nondominant [usually right] cerebral hemisphere).31,32 Risk factors for cognitive impairment after stroke include older age, prior ischemic lesions, stroke severity (ie, volume of tissue damaged), location of the stroke, and prestroke cognitive impairment.31–34 Gradual improvement occurs over time and is most notable in younger patients and within the first 6 months poststroke, although many continue to demonstrate residual cognitive impairment years after stroke.32
Patients who suffer from a transient ischemic attack (TIA) also demonstrate a range of cognitive deficits that are observed for months and years beyond the resolution of their focal TIA symptoms.35 Individuals with a history of stroke and/or TIAs are at increased risk for future progressive cognitive decline.35 Approximately 10% of stroke patients develop some form of dementia in the first year after stroke, which increases to over 30% with recurrent stroke.36 Multiple strokes may lead to multi-infarct dementia, characterized by progressive, stepwise decline in cognitive function.
All surgeries involve some risk of cerebral ischemia (ie, “silent” stroke; not accompanied by any observable stroke symptoms and detected only on postoperative diffusion-weighted imaging [DWI] and magnetic resonance imaging [MRI]) or clinical stroke (ie, acute brain lesion with clinical manifestation lasting >24 hours).37 Generally, silent strokes are more common than clinical strokes38; and risk is higher in cardiac surgery and in aged individuals. Stroke in nonsurgical populations and perioperative stroke share common patterns of resulting cognitive dysfunction, yet cerebral ischemia is not generally considered in the conceptualization of POCD.39 This is particularly surprising, because postoperative MRI studies have demonstrated incidence rates of new ischemic lesions after both cardiac and noncardiac surgeries ranging from <1% to 17%.37,40,41 A slight increase in perioperative stroke has been reported from 2003 to 2014,42 which may be partially due to more careful perioperative surveillance. While stroke or TIA was diagnosed after surgical aortic valve replacement in only 7% of patients by the routine clinical care team, 19% were diagnosed when a formal stroke–assessment protocol was in place.40
In most studies of POCD, DWI scans are obtained several days after surgery, increasing the likelihood that “acute” lesions reflect irreversibly damaged tissue.43 In large prospective studies, perioperative silent stroke on DWI was observed in 7%–10% following noncardiac, noncarotid artery surgery.38 Silent ischemic lesions are even more common following cardiac surgery and procedures that involve instrumentation of the cerebral vessels or aorta.44 After surgical aortic valve replacement, 61% exhibited silent infarcts on postoperative DWI.40 Patients experiencing clinically “silent” ischemic events may be at greater risk for future cognitive decline. Cognitive decline 1 year after surgery was identified in 42% of surgical patients with perioperative silent stroke versus 29% without.38
Because silent lesions are not accompanied by overt stroke symptoms, the extent to which they contribute to POCD is debatable.40 Studies showing no relation between new ischemic lesions and POCD typically include relatively small samples and report relatively small total lesion volumes (eg, <1000 mm3).45,46 However, a larger study showed that those with POCD had more and larger acute ischemic lesions on DWI 5 days after surgery, suggesting a threshold effect with poor cognitive outcomes observed only after the burden of multiple infarcts and/or a single large infarct reaches a tipping point.2
Anemic hypoxia results from reduced oxygen carrying capacity of red blood cells. Inadequate oxygen transport may result from low hematocrit, low hemoglobin concentration, or reduced ability of hemoglobin to bind oxygen (sickle cell anemia, carbon monoxide poisoning). Acute anemia elicits cognitive impairment even in healthy individuals.47 Anemia that accompanies HF,48 COPD,49 and lung cancer50 has been associated with cognitive impairment, although the rate of anemia in chronic kidney disease may not contribute to cognitive decline.51 Chronic anemia has been associated with impaired cognitive performance, even in otherwise healthy adolescents52 and adults.53 Furthermore, worsening white matter lesions54 during chronic anemia are associated with an increased incidence of cognitive impairment in older adults.55,56 Finally, anemia prolongs cognitive recovery after stroke,57 and erythropoietin (EPO) therapy may improve cognitive performance.58
Surgical candidates frequently present with anemia associated with chronic diseases, and major surgery in all arenas often results in acute and severe anemia. Several studies have demonstrated correlations between lower preoperative hemoglobin levels and adverse postoperative cerebral outcomes.59 Mathew et al60 found that aged subjects randomized to a transfusion hematocrit threshold of 18% experienced a greater degree of cognitive impairment that those randomized to 27%. Finally, the time course of recovery from perioperative anemia61 mimics recovery from POCD.
Finally, hypoxic challenges do not end in the operating room; they do not necessarily end in the recovery room, and they may often extend well beyond hospital discharge. Hypoxia is at the epicenter of the dysfunction of every organ in the perioperative period62 and with aging,63 and thus, cerebral hypoxia may indeed contribute to POCD.
MECHANISMS OF COGNITIVE DECLINE ASSOCIATED WITH CHRONIC AND ACUTE HYPOXIA OR HYPOXEMIA
Outside of the surgical arena, diseases associated with acute and chronic cerebral or systemic hypoxia, such as stroke, TIA, cerebrovascular disease, COPD, OSA, lung cancer, congestive HF, renal failure, and lack of aerobic fitness, are all associated with cognitive impairment.63,64 Acute cognitive dysfunction also occurs in patients in the intensive care setting who have not undergone surgery or anesthesia.5
Cellular Hypoxic Response
Protective responses to hypoxia are controlled at the cellular level by hypoxia-inducible factors (HIFs)65 (Figure 1). Hypoxia immediately stabilizes the various isoforms of hypoxia-inducible factor alpha (HIF-α; HIF-1α, HIF-2α, and HIF-3α) to regulate acute and chronic responses to hypoxia. HIF-α controls expression of over 600 genes66 including EPO and vascular endothelial growth factor (VEGF), metabolic switching proteins like glucose transporter-1 and lactate dehydrogenase-A, vasoactive nitric oxide, and reactive oxygen species (ROS) generating nicotinamide adenine dinucleotide phosphate oxidase (NOX).
Although their roles overlap to some degree, the expression ratio of the isoforms modulates acute or chronic hypoxic outcomes to match oxygen supply with metabolic needs. For example, elevated HIF-1α:HIF-2α expression within carotid bodies is an integral component of the hypertensive response to chronic intermittent hypoxia, causing elevated sympathetic excitatory transmission,67 whereas HIF-2α is the primary modulator of EPO within astrocytes and is integral to maintaining memory.68 Mitochondrial function under hypoxia is mediated by the various HIF-α isoforms, and dysfunction (ie, impaired membrane potential, lower number, and aberrant morphology) is implicated in a number of diseases and cognitive failure.69 Cognitive failure associated with hypoxia may be overcome by mimicking the effects of HIF-α, such as by administration of EPO.58
Effect of Cerebrovascular Impairment
The cerebrovascular response to hypoxemia is vasodilation to increase cerebral blood flow (CBF) and oxygen delivery.70 In the case of anemia, the marked increase in CBF is driven primarily by cerebral oxygen demand.71 This global response appears to be largely intact with aging.72–74 Evidence abounds that limitations in regional cerebrovascular reserve75 could potentially contribute to cerebral hypoxia and/or ischemia under multiple scenarios to include severe anemia,76,77 hypotension, low cardiac output, and intra- and extracranial cerebrovascular occlusive disease.78 Conversely, intentional isovolemic hemodilution in the management of acute ischemic stroke does not appear to worsen or improve outcomes.79
Progressive cognitive decline is observed as a consequence of chronic cerebral hypoperfusion, even in the absence of acute stroke/TIA.30,31 The effect of chronic diseases of the vasculature (eg, small vessel disease, carotid disease, atherosclerosis, endothelial dysfunction, deficient cerebral autoregulation,80 amyloidosis,81 and integrity of the blood brain barrier [BBB]82) on the brain is observed in reliable neuroimaging (MRI) markers, including small punctate lesions, microbleeds, and white matter hyperintensities (WMH, also called leukoaraiosis and lacunes).82 Zhong et al83 found that increased severity of carotid disease was associated with higher risk of cognitive impairment during a 10-year follow-up. WMH and lacunes (small subcortical cavities arising from arterial disease) have been associated with general cognitive impairment and decline in information processing speed and executive function82,84 and WMH with increased risk for mild cognitive impairment and dementia.82,85
Similarly, deficient hemoglobin saturation or diminished release of oxygen at tissue sites due to anemia contributes to poor cognitive outcomes.47 In fact, multiple hypoxic sources can coexist as evidenced by an elevated risk of developing WMH due to anemia,55,86 which is exacerbated by coexistent hypertension.77,86 Furthermore, the age-dependent elevation of cortical HIF (in spite of preserved tissue oxygenation) in a chronically hypertensive rat model of acute isovolemic hemodilution suggests that hypertension and anemia interact to cause a failure of oxygen delivery equated with cellular hypoxic states.77
The terms “vascular cognitive impairment,” “vascular dementia,” and “Binswanger disease” are all used to denote progressive decline in cognition from chronic vascular disease.87,88 These disorders are similar to Alzheimer disease (AD) in that cognitive impairment progresses slowly over time. However, these disorders differ from AD in that the cognitive impairment profile is notable for deficits in processing speed and executive function, as opposed to episodic memory impairment and the loss of recognition memory observed in AD.
More recent conceptualizations of dementia recognize the complexity of neurodegenerative neuropathology and include a prominent role for vascular pathology/cerebral ischemia.89 Current research suggests that cerebrovascular pathology has a dose-dependent effect on cognition,82,84,90,91 independent of other pathologies.92 These observations have led to the development of the concept of “vascular burden,” a general term that refers to the cumulative effect of vascular disorders and risk factors including stroke, hypertension, white matter disease, diabetes mellitus, obesity,30,31,36 as well as vascular reactivity93 on the degree of cognitive impairment and age-related brain atrophy.84,94 Consequently, investigators have focused on understanding the role of cerebrovascular pathologies in AD and have discovered that cerebrovascular disease reduces the threshold of AD-specific pathologic burden of cortical pathology (eg, cortical amyloid plaques and cortical atrophy) needed to produce cognitive impairment.84,95
Even in the surgical arena, recent studies underscore the relevance of vascular burden for understanding POCD. Accumulating evidence shows that presurgical neuroimaging markers of general vascular health,96 cerebral ischemia,97 and presurgical cognitive status are all strong predictors of POCD.97,98 A recent systematic review of 15 neuroimaging (MRI) studies44 reported that POCD was more frequently associated with presurgical imaging markers of cerebrovascular ischemia (WMH) than neuroimaging markers of neurodegenerative changes (ie, global and regional brain volumes). Therefore, mechanisms that hinder cerebral vascularization may be of particular interest in future investigations of POCD.
Cerebral white matter is critical to rapid signaling among both close and distant neuronal circuits. Disturbances indicated by WMH disrupt neuronal transmission and functional network connectivity, leading to widespread cerebral dysfunction and cognitive impairment.99 For instance, in patients with chronic ischemia due to carotid artery stenosis but without overt indicators of clinical stroke, MRI network analyses show imaging patterns associated with cognitive impairment in the form of impaired cerebral connectivity100 and altered resting state blood oxygen level–dependent (BOLD) signal.101
Neurons have a high metabolic rate, resulting in a need for rapid and precise regulation of CBF102 and making them particularly vulnerable to damage from both acute and chronic hypoxia. Oligodendrocytes, glial cells that compose the cerebral white matter, may be even more sensitive than neurons.103 Acute and complete oxygen deprivation to cerebral tissue downstream of an ischemic insult, such as a major clinical stroke, can result in relatively focal cell death (infarct) within minutes, leading to disruption of focal and widespread cognitive and sensorimotor functions, dependant on the infarct size and location.102 Astrocytes modulate synapses, neurovascular coupling, and transport of molecules across the BBB and are highly sensitive to hypoxia, altering glucose uptake and BBB integrity to fulfill energetic needs of neurons.102,104
Regional responses to cerebral hypoxia often differ. The severity of OSA has been correlated with hypoperfusion of lateral cortical regions in elderly patients but hyperperfusion of medial and subcortical regions105 that may be a contributing factor in the loss of cortical and hippocampal gray matter associated with cognitive dysfunction in OSA.106 Additionally, sleep-disordered breathing damages cerebellar and hypothalamic controls of sympathetic tone107 and is associated with diminished working memory.108 In HF, low CBF is observed in the posterior hippocampal regions,109 resulting in depressed mood and impairment of delayed and immediate recall.109,110
Elevated ROS from hypoxia induces cytokine transcription and elevates intracellular calcium.69,111,112 These molecules modulate the composition and number of postsynaptic excitatory and inhibitory receptors,107 leading to more frequent excitatory postsynaptic potentials and altered synaptic connectivity. Excitotoxicity induces the neuronal loss associated with cognitive dysfunction observed in hypoxia.108,112 Excitotoxicity is reported in the brainstem, cerebellar Purkinje neurons, and memory centers of the central nervous system (CNS) during hypoxia.107 Cholinergic neurons (integral to many cognitive pathways) appear to be particularly vulnerable to excitotoxicity as fewer are evident in the forebrain of young adult male rats following as little as 14 days of chronic intermittent hypoxia and their loss contributes to impairments in spatial working memory.113
Many studies demonstrate that hypoxia induces inflammation both systemically and centrally.114,115 Neuroinflammation arising from hypoxia is initiated by HIF-α,116 may be of neuronal or glial origin, and is correlated with cognitive impairment.111,117 Cognitive effects are attenuated by administration of EPO.118 Neuroinflammation is often proposed as a central culprit in the onset of POCD.7 These overlaps provide further evidence that cerebral hypoxia may be at the epicenter of mechanisms of POCD.
INTERACTION BETWEEN AGING AND HYPOXIA
Older adults are particularly vulnerable to perioperative hypoxia as aging is the leading risk factor for POCD13 and older adults are at highest risk of needing surgical intervention. Dysregulation is observed in cerebrovascular reactivity,119 oxygen delivery,120–122 neural connectivity,82 neuroinflammation,123 and responsiveness to hypoxia124 during aging (Figure 2). Current literature suggests that protective molecular processes fail to respond to hypoxic conditions during aging and may exacerbate negative cognitive outcomes.
Aging Impairs Oxygenation
Of primary concern is the contribution of hypertension, loss of myogenic tone, accumulated plaque deposition, and deficient response to vasopressin or nitric oxide to reduced cerebrovascular reactivity and reserve119 during aging, in spite of the fact that cerebral metabolic rate of O2 (CMRO2) remains constant over the lifespan.125 Low cerebral oxygenation and worsening cerebral hypoxia is evident even in older adults without diagnosed hypoxia and is associated with memory impairment.126 Furthermore, unlike young adults, lower CBF is associated with inattention in older individuals.120 Indeed, low-resting CBF in older adults is associated with higher WMH volume127 and is a strong predictor of the number of newly developed cortical WMH observed 18 months later.128 The loss of cerebrovascular reserve in the elderly may thus impair their ability to recover from perioperative hypoxic stresses.
Preclinical studies indicate that the oxygen pressure within cerebral tissue declines in middle age and continues into old age.129 The oxygen pressure set point in the CNS has a narrow range and extremes lead to vascular dysregulation. Temporary fluctuations in tissue oxygenation early in adulthood have been linked to rapid subsequent vascular dysregulation (eg, hypertension) and working memory impairment that is not evident until later in life.130,131
In addition to hypoperfusion, aging is associated with more frequent bouts of anemia as nutritional intake declines, gastrointestinal tract disorders and pharmaceutical intake increase, and hormone levels change.122 Although Price121 found no difference in circulating EPO in nonanemic individuals of any age, EPO concentration was lower in elderly, but not in young, anemic patients. Other studies suggest that EPO production slows with age and coincides with lower cerebral metabolism.122 Additionally, aged spontaneously hypertensive rats experienced greater memory impairment and evidence of cellular hypoxia (elevated HIF expression) after anemia caused by isovolemic hemodilution, which is not evident in their younger adult counterparts.77
Aging Impairs the Hypoxic Response
Elegant studies performed by the LaManna Laboratory demonstrate that the normal cortical response to hypoxia stabilizes HIF-α leading to increased capillary density, blood flow, and glycolysis (Figure 1).132 Unfortunately, a blunted or, in some cases, nonexistent response to hypoxia mediated by HIF-α is observed in the aged brain.66,124,133 Aged rats exhibit low VEGF in carotid bodies under normal oxygen conditions and an attenuated response to 12 hours of 12% oxygen for 12 days than young rats do.133 Cortical vascularization and expression of HIF-controlled proteins (eg, EPO, inducible nitric oxide synthase, and heme oxygenase-1) following hypoxia are lacking in aged models66,133 in combination with fewer and smaller mitochondria in carotid bodies.133 Furthermore, prolyl hydroxylases that regulate HIF-α expression also lose responsivity during aging.134 Therefore, the primary adaptive hypoxia pathway may be particularly susceptible to acute and chronic hypoxic insults during aging. Investigations using aged preclinical models to investigate HIF-α mechanisms in specific brain regions and cell types are scarce and represent an area of active inquiry.
Aging Induces Inflammation and Impairs Neurotransmission
Aged rodent and postmortem human brain samples exhibit low-grade inflammation and aberrant glial morphology.123,135 Recent studies suggest that glial cells are particularly vulnerable to aging and hypoxia104 and that typical neuroprotective glial activities136 are diminished while reactive and senescent phenotypes flourish in aged brains.137,138 Damage to oligodendrocytes and astrocytes affects both dendritic spine stability and diffuse connectivity. Impaired astrocytic support combined with reduced cardiovascular reserve, vascularization, and hypoxic responsiveness renders aged neurons more vulnerable to hypoxic insults than young neurons, as evidenced by diminished excitatory output, smaller postsynaptic density, and lower tissue volume in aged hippocampi.137,139
MANAGEMENT OF HYPOXIA-RELATED POCD
Thankfully, long-term cognitive impairment after surgery appears to be a very infrequent phenomenon, with most resolving within weeks to months. Ischemic-hypoxic events may pose the greatest risk for long-term effects, while lingering anemia and cardiorespiratory failure in recovery may also contribute. Management of hypoxia-related POCD starts with recognition of the contribution of hypoxia to cognitive performance and identification of those at risk. While aging has been recognized as a major risk factor, older patients with superimposed cerebrovascular disease, chronic anemia, and preexisting cardiorespiratory failure comprise subgroups at the highest levels of risk. Those at the highest levels of risk may be further stratified by preoperative cognitive evaluation, as preoperative cognitive status in and of itself appears to be a risk factor for further decline.140
Management of patients at risk for hypoxia-related POCD should start with prevention via optimization of preexisting disease that carries the hypoxic burden. The strong relationship between cognitive performance, cardiovascular fitness,141 and cardiovascular disease in the general population142 clearly demonstrates their interdependence. Prerehabilitation programs have shown benefit in reducing overall and pulmonary morbidity and may, therefore, impact hypoxia-related cognitive performance after surgery.143 Patients at risk with preexisting anemia may benefit from preoperative supplementation and possibly EPO.58,144
Intraoperative efforts should obviously focus on prevention of hypoxemia and heightened attention to the predisposition of certain high-risk groups such as those with morbid obesity and those undergoing lung transplantation. Intraoperative use of cerebral oximetry has yet to clearly demonstrate benefit in prevention of POCD.145 We remain without high-quality guidance as to a patient-specific transfusion trigger to guide us either intraoperatively or postoperatively for organ protection, brain or otherwise. Advances in the approach to the heavily calcified aorta146 and use of intraarterial emboli trapping devices to date have not been as effective as originally hoped in altering the frequency of perioperative stroke and POCD,147 likely due to the fact that stroke risk continues beyond the critical period of aortic manipulation.
Postoperatively, it can be assumed that physicians already attempt to optimize cardiopulmonary function and carefully balance the risks and benefits of transfusion in their patients. In the management of anemia, perhaps more aggressive approaches to iron replacement and the use of EPO should be considered to speed up the recovery of erythrocyte volume. Enhanced attention to the impact of narcotic use on pulmonary function in those with respiratory compromise from multiple etiologies may include more aggressive and prolonged respiratory monitoring, administration of supplemental oxygen, and advancement of lower or nonnarcotic approaches to pain control.148 Earlier and more accurate diagnosis of perioperative stroke may be enhanced by anesthetic techniques that allow for immediate postoperative assessment,149 implementation of more frequent and rigorous stroke assessment protocols,40 and judicious application of advances in interventional strategies.150
There is voluminous evidence that short- to intermediate-term age–related changes in cognition occur in the perioperative arena. However, the evidence connecting those changes to modern anesthetic use is tenuous. Aging is accompanied by hypoxic conditions that have been firmly established as risk factors for cognitive dysfunction outside the surgical arena. Surgery, as well as critical illness, may elevate hypoxic exposure through hypoperfusion, hypoventilation, pulmonary edema, and blood loss. Given these parallels, it is, therefore, conceivable that hypoxia, in its many forms, contributes importantly to POCD and may share similar mechanisms with hypoxia-related cognitive failure in the general population. Future studies fully elucidating the role of hypoxia in age-related memory loss in chronic and acute settings may also clarify the role of hypoxia in POCD.
Name: Brina Snyder, PhD.
Contribution: This author helped conceive the topic, draft the original outline, manage collaboration, and write and organize the manuscript.
Name: Stephanie M. Simone, BS.
Contribution: This author helped write the ischemic hypoxia sections and collaborate on organization of the manuscript.
Name: Tania Giovannetti, PhD.
Contribution: This author helped write the ischemic hypoxia section, provide insight on mechanistic review sections, and collaborate on organization of the manuscript.
Name: Thomas F. Floyd, MD.
Contribution: This author helped conceive the main topic, supervise the progress, and write and organize the manuscript.
This manuscript was handled by: Robert Whittington, MD.
1. Fink HA, Hemmy LS, MacDonald R, et al. Intermediate- and long-term cognitive outcomes after cardiovascular procedures in older adults: a systematic review. Ann Intern Med. 2015;163:107–117.
2. Giovannetti T, Price CC, Fanning M, et al.; DENOVO Investigators. Cognition and cerebral infarction in older adults after surgical aortic valve replacement. Ann Thorac Surg. 2019;107:787–794.
3. Dokkedal U, Hansen TG, Rasmussen LS, Mengel-From J, Christensen K. Cognitive functioning after surgery in middle-aged and elderly Danish twins. Anesthesiology. 2016;124:312–321.
4. Avidan MS, Evers AS. The fallacy of persistent postoperative cognitive decline. Anesthesiology. 2016;124:255–258.
5. Krause BM, Sabia S, Manning HJ, Singh-Manoux A, Sanders RD. Association between major surgical admissions and the cognitive trajectory: 19-year follow-up of Whitehall II cohort study. BMJ. 2019;366:l4466.
6. Avidan MS, Searleman AC, Storandt MLong-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness. Anesthesiology. 2009;111:964–970.
7. Safavynia SA, Goldstein PA. The role of neuroinflammation in postoperative cognitive dysfunction: moving from hypothesis to treatment. Front Psychiatry. 2018;9:752.
8. Sprung J, Schulte PJ, Knopman DSCognitive function after surgery with regional or general anesthesia: a population-based study. Alzheimers Dement. 2019;15:1243–1252.
9. Rasmussen LS, Johnson T, Kuipers HM, et al.; ISPOCD2(International Study of Postoperative Cognitive Dysfunction) Investigators. Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiol Scand. 2003;47:260–266.
10. Miller D, Lewis SR, Pritchard MW, et al. Intravenous versus inhalational maintenance of anaesthesia for postoperative cognitive outcomes in elderly people undergoing non-cardiac surgery. Cochrane Database Syst Rev. 2018;8:CD012317.
11. Selnes OA, Gottesman RF, Grega MA, Baumgartner WA, Zeger SL, McKhann GM. Cognitive and neurologic outcomes after coronary-artery bypass surgery. N Engl J Med. 2012;366:250–257.
12. Schulte PJ, Roberts RO, Knopman DS, et al. Association between exposure to anaesthesia and surgery and long-term cognitive trajectories in older adults: report from the Mayo Clinic Study of Aging. Br J Anaesth. 2018;121:398–405.
13. Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998;351:857–861.
14. Chung F, Liao P, Yegneswaran B, Shapiro CM, Kang W. Postoperative changes in sleep-disordered breathing and sleep architecture in patients with obstructive sleep apnea. Anesthesiology. 2014;120:287–298.
15. Chung F, Liao P, Yang Y, et al. Postoperative sleep-disordered breathing in patients without preoperative sleep apnea. Anesth Analg. 2015;120:1214–1224.
16. Wang Y, Sands LP, Vaurio L, Mullen EA, Leung JM. The effects of postoperative pain and its management on postoperative cognitive dysfunction. Am J Geriatr Psychiatry. 2007;15:50–59.
17. Ehrenfeld JM, Funk LM, Van Schalkwyk J, Merry AF, Sandberg WS, Gawande A. The incidence of hypoxemia during surgery: evidence from two institutions. Can J Anaesth. 2010;57:888–897.
18. Sun Z, Sessler DI, Dalton JE, et al. Postoperative hypoxemia is common and persistent: a prospective blinded observational study. Anesth Analg. 2015;121:709–715.
19. Moller JT, Johannessen NW, Espersen K, et al. Randomized evaluation of pulse oximetry in 20,802 patients: II. Perioperative events and postoperative complications. Anesthesiology. 1993;78:445–453.
20. Lin R, Zhang F, Xue Q, Yu B. Accuracy of regional cerebral oxygen saturation in predicting postoperative cognitive dysfunction after total hip arthroplasty: regional cerebral oxygen saturation predicts POCD. J Arthroplasty. 2013;28:494–497.
21. Casati A, Fanelli G, Pietropaoli P, et al.; Collaborative Italian Study Group on Anaesthesia in Elderly Patients. Monitoring cerebral oxygen saturation in elderly patients undergoing general abdominal surgery: a prospective cohort study. Eur J Anaesthesiol. 2007;24:59–65.
22. Browne SM, Halligan PW, Wade DT, Taggart DP. Postoperative hypoxia is a contributory factor to cognitive impairment after cardiac surgery. J Thorac Cardiovasc Surg. 2003;126:1061–1064.
23. Areza-Fegyveres R, Kairalla RA, Carvalho CRR, Nitrini R. Cognition and chronic hypoxia in pulmonary diseases. Dement Neuropsychol. 2010;4:14–22.
24. Grant I, Heaton RK, McSweeny AJ, Adams KM, Timms RM. Neuropsychologic findings in hypoxemic chronic obstructive pulmonary disease. Arch Intern Med. 1982;142:1470–1476.
25. Gagnon K, Baril AA, Gagnon JFCognitive impairment in obstructive sleep apnea. Pathol Biol (Paris). 2014;62:233–240.
26. Kheirandish-Gozal L, Philby MF, Alonso-Álvarez ML, Terán-Santos J, Gozal D. Biomarkers of Alzheimer disease in children with obstructive sleep apnea: effect of adenotonsillectomy. Sleep. 2016;39:1225–1232.
27. Cannon JA, Moffitt P, Perez-Moreno ACCognitive impairment and heart failure: systematic review and meta-analysis. J Card Fail. 2017;23:464–475.
28. Hammond CA, Blades NJ, Chaudhry SILong-term cognitive decline after newly diagnosed heart failure: longitudinal analysis in the CHS (cardiovascular health study). Circ Heart Fail. 2018;11:e004476.
29. Kindermann I, Fischer D, Karbach JCognitive function in patients with decompensated heart failure: the Cognitive Impairment in Heart Failure (CogImpair-HF) study. Eur J Heart Fail. 2012;14:404–413.
30. Sahathevan R, Brodtmann A, Donnan GA. Dementia, stroke, and vascular risk factors; a review. Int J Stroke. 2012;7:61–73.
31. Lo Coco D, Lopez G, Corrao S. Cognitive impairment and stroke in elderly patients. Vasc Health Risk Manag. 2016;12:105–116.
32. Jokinen H, Melkas S, Ylikoski R, et al. Post-stroke cognitive impairment is common even after successful clinical recovery. Eur J Neurol. 2015;22:1288–1294.
33. Nys GM, van Zandvoort MJ, de Kort PL, Jansen BP, de Haan EH, Kappelle LJ. Cognitive disorders in acute stroke: prevalence and clinical determinants. Cerebrovasc Dis. 2007;23:408–416.
34. Klimkowicz-Mrowiec A, Dziedzic T, Słowik A, Szczudlik A. Predictors of poststroke dementia: results of a hospital-based study in Poland. Dement Geriatr Cogn Disord. 2006;21:328–334.
35. van Rooij FG, Kessels RP, Richard E, De Leeuw FE, van Dijk EJ. Cognitive impairment in transient ischemic attack patients: a systematic review. Cerebrovasc Dis. 2016;42:1–9.
36. Pendlebury ST. Dementia in patients hospitalized with stroke: rates, time course, and clinico-pathologic factors. Int J Stroke. 2012;7:570–581.
37. Mashour GA, Shanks AM, Kheterpal S. Perioperative stroke and associated mortality after noncardiac, nonneurologic surgery. Anesthesiology. 2011;114:1289–1296.
38. NeuroVISION InvestigatorsPerioperative covert stroke in patients undergoing non-cardiac surgery (NeuroVISION): a prospective cohort study. Lancet. 2019;394:1022–1029.
39. van Dijk D, Keizer AM, Diephuis JC, Durand C, Vos LJ, Hijman R. Neurocognitive dysfunction after coronary artery bypass surgery: a systematic review. J Thorac Cardiovasc Surg. 2000;120:632–639.
40. Messé SR, Acker MA, Kasner SE, et al.; Determining Neurologic Outcomes from Valve Operations (DeNOVO) Investigators. Stroke after aortic valve surgery: results from a prospective cohort. Circulation. 2014;129:2253–2261.
41. Indja B, Woldendorp K, Vallely MP, Grieve SM. Silent brain infarcts following cardiac procedures: a systematic review and meta-analysis. J Am Heart Assoc. 2019;8:e010920.
42. Smilowitz NR, Gupta N, Ramakrishna H, Guo Y, Berger JS, Bangalore S. Perioperative major adverse cardiovascular and cerebrovascular events associated with noncardiac surgery. JAMA Cardiol. 2017;2:181–187.
43. Bang OY, Li WY. Applications of diffusion-weighted imaging in diagnosis evaluation, and treatment of acute ischemic stroke. Precis Future Med. 2019;3:69–76.
44. Kant IMJ, de Bresser J, van Montfort SJT, Slooter AJC, Hendrikse J. MRI markers of neurodegenerative and neurovascular changes in relation to postoperative delirium and postoperative cognitive decline. Am J Geriatr Psychiatry. 2017;25:1048–1061.
45. Cook DJ, Huston J III, Trenerry MR, Brown RD Jr, Zehr KJ, Sundt TM III. Postcardiac surgical cognitive impairment in the aged using diffusion-weighted magnetic resonance imaging. Ann Thorac Surg. 2007;83:1389–1395.
46. Knipp SC, Matatko N, Wilhelm H, et al. Cognitive outcomes three years after coronary artery bypass surgery: relation to diffusion-weighted magnetic resonance imaging. Ann Thorac Surg. 2008;85:872–879.
47. Weiskopf RB, Kramer JH, Viele M, et al. Acute severe isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology. 2000;92:1646–1652.
48. Kim HB, Park B, Shim JY. Anemia in association with cognitive impairment: a systematic review and meta-analysis. J Alzheimers Dis. 2019;72:803–814.
49. Padberg I, Schneider A, Rohmann JL, Kelley SW, Grittner U, Siegerink B. Impact of COPD and anemia on motor and cognitive performance in the general older population: results from the English longitudinal study of ageing. Respir Res. 2020;21:40.
50. Mancuso A, Migliorino M, De Santis S, Saponiero A, De Marinis F. Correlation between anemia and functional/cognitive capacity in elderly lung cancer patients treated with chemotherapy. Ann Oncol. 2006;17:146–150.
51. Kurella Tamura M, Vittinghoff E, Yang JAnemia and risk for cognitive decline in chronic kidney disease. BMC Nephrol. 2016;17:13.
52. Bahrami A, Khorasanchi Z, Tayefi MAnemia is associated with cognitive impairment in adolescent girls: a cross-sectional survey. Appl Neuropsychol Child. 2020;9:165–171.
53. Agrawal S, Kumar S, Ingole VDoes anemia affects cognitive functions in neurologically intact adult patients: two year cross sectional study at rural tertiary care hospital. J Family Med Prim Care. 2019;8:3005–3008.
54. Son SJ, Lee KS, Na DLThe effect of anemia and white matter hyperintensities (WMH) on cognitive impairment in patients with amnestic mild cognitive impairment (MCI). Arch Gerontol Geriatr. 2012;55:251–256.
55. Deal JA, Carlson MC, Xue QL, Fried LP, Chaves PH. Anemia and 9-year domain-specific cognitive decline in community-dwelling older women: the Women’s Health and Aging Study II. J Am Geriatr Soc. 2009;57:1604–1611.
56. Schneider AL, Jonassaint C, Sharrett AR, et al. Hemoglobin, anemia, and cognitive function: the atherosclerosis risk in communities study. J Gerontol A Biol Sci Med Sci. 2016;71:772–779.
57. Meng F, Zhang S, Yu J, et al. Low hemoglobin levels at admission are independently associated with cognitive impairment after ischemic stroke: a multicenter, population-based study. Transl Stroke Res. 2020;11:890–899.
58. Hernández CC, Burgos CF, Gajardo AH, et al. Neuroprotective effects of erythropoietin on neurodegenerative and ischemic brain diseases: the role of erythropoietin receptor. Neural Regen Res. 2017;12:1381–1389.
59. Karkouti K, Wijeysundera DN, Beattie WS; Reducing Bleeding in Cardiac Surgery (RBC) Investigators. Risk associated with preoperative anemia in cardiac surgery: a multicenter cohort study. Circulation. 2008;117:478–484.
60. Mathew JP, Mackensen GB, Phillips-Bute B, et al.; Neurologic Outcome Research Group (NORG) of the Duke Heart Center. Effects of extreme hemodilution during cardiac surgery on cognitive function in the elderly. Anesthesiology. 2007;107:577–584.
61. Mundy GM, Birtwistle SJ, Power RA. The effect of iron supplementation on the level of haemoglobin after lower limb arthroplasty. J Bone Joint Surg Br. 2005;87:213–217.
62. Shoemaker WC, Appel PL, Kram HB. Role of oxygen debt in the development of organ failure sepsis, and death in high-risk surgical patients. Chest. 1992;102:208–215.
63. Katschinski DM. Is there a molecular connection between hypoxia and aging? Exp Gerontol. 2006;41:482–484.
64. Arjun R, Acharya S, Shender BS, Rorres C, Hrebien L, Kam M. Correlation of cognitive scores and the onset of hypoxia. Aerosp Med Hum Perform. 2019;90:429–439.
65. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148:399–408.
66. Anderson J, Sandhir R, Hamilton ES, Berman NE. Impaired expression of neuroprotective molecules in the HIF-1alpha pathway following traumatic brain injury in aged mice. J Neurotrauma. 2009;26:1557–1566.
67. Semenza GL, Prabhakar NR. Neural regulation of hypoxia-inducible factors and redox state drives the pathogenesis of hypertension in a rodent model of sleep apnea. J Appl Physiol (1985). 2015;119:1152–1156.
68. Leiton CV, Chen E, Cutrone A, et al. Astrocyte HIF-2alpha supports learning in a passive avoidance paradigm under hypoxic stress. Hypoxia (Auckl). 2018;6:35–56.
69. Herst PM, Rowe MR, Carson GM, Berridge MV. Functional mitochondria in health and disease. Front Endocrinol (Lausanne). 2017;8:296.
70. Juttukonda MR, Donahue MJ. Neuroimaging of vascular reserve in patients with cerebrovascular diseases. Neuroimage. 2019;187:192–208.
71. Waschke KF, Krieter H, Hagen G, Albrecht DM, Van Ackern K, Kuschinsky W. Lack of dependence of cerebral blood flow on blood viscosity after blood exchange with a Newtonian O2 carrier. J Cereb Blood Flow Metab. 1994;14:871–876.
72. Li M, Ratcliffe SJ, Knoll FAging: impact upon local cerebral oxygenation and blood flow with acute isovolemic hemodilution. J Neurosurg Anesthesiol. 2006;18:125–131.
73. Floyd TF, McGarvey M, Ochroch EAPerioperative changes in cerebral blood flow after cardiac surgery: influence of anemia and aging. Ann Thorac Surg. 2003;76:2037–2042.
74. McKetton L, Cohn M, Tang-Wai DFCerebrovascular resistance in healthy aging and mild cognitive impairment. Front Aging Neurosci. 2019;11:79.
75. Nemoto EM, Yonas H, Kuwabara HIdentification of hemodynamic compromise by cerebrovascular reserve and oxygen extraction fraction in occlusive vascular disease. J Cereb Blood Flow Metab. 2004;24:1081–1089.
76. Dexter F, Hindman BJ. Effect of haemoglobin concentration on brain oxygenation in focal stroke: a mathematical modelling study. Br J Anaesth. 1997;79:346–351.
77. Li M, Bertout JA, Ratcliffe SJ, Eckenhoff MF, Simon MC, Floyd TF. Acute anemia elicits cognitive dysfunction and evidence of cerebral cellular hypoxia in older rats with systemic hypertension. Anesthesiology. 2010;113:845–858.
78. Yonas H, Pindzola RR. Clinical application of cerebrovascular reserve assessment as a strategy for stroke prevention. Keio J Med. 2000;49(suppl 1):A4–A10.
79. Aichner FT, Fazekas F, Brainin M, Pölz W, Mamoli B, Zeiler K. Hypervolemic hemodilution in acute ischemic stroke: the Multicenter Austrian Hemodilution Stroke Trial (MAHST). Stroke. 1998;29:743–749.
80. Chang XL, Zhou HQ, Lei CY, et al. Association between asymptomatic carotid stenosis and cognitive function: a systematic review. Neurosci Biobehav Rev. 2013;37:1493–1499.
81. Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy in the elderly. Ann Neurol. 2011;70:871–880.
82. Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol. 2015;11:157–165.
83. Zhong W, Cruickshanks KJ, Schubert CR, et al. Carotid atherosclerosis and 10-year changes in cognitive function. Atherosclerosis. 2012;224:506–510.
84. DeCarli C, Villeneuve S, Maillard P, et al. Vascular burden score impacts cognition independent of amyloid PET and MRI measures of Alzheimer’s disease and vascular brain injury. J Alzheimers Dis. 2019;68:187–196.
85. Bangen KJ, Thomas KR, Weigand AJ, et al.; Alzheimer’s Disease Neuroimaging Initiative. Pattern of regional white matter hyperintensity volume in mild cognitive impairment subtypes and associations with decline in daily functioning. Neurobiol Aging. 2020;86:134–142.
86. Inzitari M, Studenski S, Rosano C, et al. Anemia is associated with the progression of white matter disease in older adults with high blood pressure: the cardiovascular health study. J Am Geriatr Soc. 2008;56:1867–1872.
87. Libon DJ, Price CC, Davis Garrett K, Giovannetti T. From Binswanger’s disease to leuokoaraiosis: what we have learned about subcortical vascular dementia. Clin Neuropsychol. 2004;18:83–100.
88. Román GC, Sachdev P, Royall DR, et al. Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci. 2004;226:81–87.
89. Gaugler J, James B, Johnson T, Marin A, Weuve J. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 2020;16:391–460.
90. Libon DJ, Price CC, Giovannetti T, et al. Linking MRI hyperintensities with patterns of neuropsychological impairment: evidence for a threshold effect. Stroke. 2008;39:806–813.
91. Allan LM, Rowan EN, Firbank MJ, et al. Long term incidence of dementia, predictors of mortality and pathological diagnosis in older stroke survivors. Brain. 2011;134:3716–3727.
92. Lo RY, Jagust WJ; Alzheimer’s Disease Neuroimaging Initiative. Vascular burden and Alzheimer disease pathologic progression. Neurology. 2012;79:1349–1355.
93. Silvestrini M, Pasqualetti P, Baruffaldi RCerebrovascular reactivity and cognitive decline in patients with Alzheimer disease. Stroke. 2006;37:1010–1015.
94. O’Brien J, Reisberg B, Erkinjuntti T. Vascular burden of the brain. Int Psychogeriatr. 2003;15(suppl 1):7–10.
95. Bangen KJ, Nation DA, Delano-Wood LAggregate effects of vascular risk factors on cerebrovascular changes in autopsy-confirmed Alzheimer’s disease. Alzheimers Dement. 2015;11:394–403.e1.
96. Chu Z, Cheng L, Tong Q. Carotid artery calcification score and its association with cognitive impairment. Clin Interv Aging. 2019;14:167–177.
97. Maekawa K, Baba T, Otomo S, Morishita S, Tamura N. Low pre-existing gray matter volume in the medial temporal lobe and white matter lesions are associated with postoperative cognitive dysfunction after cardiac surgery. PLoS One. 2014;9:e87375.
98. Price CC, Tanner JJ, Schmalfuss IA pilot study evaluating presurgery neuroanatomical biomarkers for postoperative cognitive decline after total knee arthroplasty in older adults. Anesthesiology. 2014;120:601–613.
99. Chen X, Huang L, Ye QDisrupted functional and structural connectivity within default mode network contribute to WMH-related cognitive impairment. Neuroimage Clin. 2019;24:102088.
100. Cheng HL, Lin CJ, Soong BWImpairments in cognitive function and brain connectivity in severe asymptomatic carotid stenosis. Stroke. 2012;43:2567–2573.
101. Xiao F, Wang T, Gao LFrequency-dependent changes of the resting BOLD signals predicts cognitive deficits in asymptomatic carotid artery stenosis. Front Neurosci. 2018;12:416.
102. Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron. 2017;96:17–42.
103. Pantoni L, Garcia JH, Gutierrez JA. Cerebral white matter is highly vulnerable to ischemia. Stroke. 1996;27:1641–1646.
104. Lourhmati A, Buniatian GH, Paul CAge-dependent astroglial vulnerability to hypoxia and glutamate: the role for erythropoietin. PLoS One. 2013;8:e77182.
105. Baril AA, Gagnon K, Arbour CRegional cerebral blood flow during wakeful rest in older subjects with mild to severe obstructive sleep apnea. Sleep. 2015;38:1439–1449.
106. Torelli F, Moscufo N, Garreffa GCognitive profile and brain morphological changes in obstructive sleep apnea. Neuroimage. 2011;54:787–793.
107. Harper RM, Kumar R, Ogren JA, Macey PM. Sleep-disordered breathing: effects on brain structure and function. Respir Physiol Neurobiol. 2013;188:383–391.
108. Gozal D, Daniel JM, Dohanich GP. Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat. J Neurosci. 2001;21:2442–2450.
109. Suzuki H, Matsumoto Y, Ota HHippocampal blood flow abnormality associated with depressive symptoms and cognitive impairment in patients with chronic heart failure. Circ J. 2016;80:1773–1780.
110. Frey A, Sell R, Homola GACognitive deficits and related brain lesions in patients with chronic heart failure. JACC Heart Fail. 2018;6:583–592.
111. Snyder B, Shell B, Cunningham JT, Cunningham RL. Chronic intermittent hypoxia induces oxidative stress and inflammation in brain regions associated with early-stage neurodegeneration. Physiol Rep. 2017;5:e13258.
112. Xu W, Chi L, Row BWIncreased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea. Neuroscience. 2004;126:313–323.
113. Row BW, Kheirandish L, Cheng Y, Rowell PP, Gozal D. Impaired spatial working memory and altered choline acetyltransferase (CHAT) immunoreactivity and nicotinic receptor binding in rats exposed to intermittent hypoxia during sleep. Behav Brain Res. 2007;177:308–314.
114. Bartels K, Grenz A, Eltzschig HK. Hypoxia and inflammation are two sides of the same coin. Proc Natl Acad Sci U S A. 2013;110:18351–18352.
115. Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 2011;364:656–665.
116. Iyalomhe O, Swierczek S, Enwerem NThe role of hypoxia-inducible factor 1 in mild cognitive impairment. Cell Mol Neurobiol. 2017;37:969–977.
117. Li T, Chen Y, Gua C, Wu B. Elevated oxidative stress and inflammation in hypothalamic paraventricular nucleus are associated with sympathetic excitation and hypertension in rats exposed to chronic intermittent hypoxia. Front Physiol. 2018;9:840.
118. Dayyat EA, Zhang SX, Wang Y, Cheng ZJ, Gozal D. Exogenous erythropoietin administration attenuates intermittent hypoxia-induced cognitive deficits in a murine model of sleep apnea. BMC Neurosci. 2012;13:77.
119. Jefferson AL, Cambronero FE, Liu D, et al. Higher aortic stiffness is related to lower cerebral blood flow and preserved cerebrovascular reactivity in older adults. Circulation. 2018;138:1951–1962.
120. Catchlove SJ, Macpherson H, Hughes ME, Chen Y, Parrish TB, Pipingas A. An investigation of cerebral oxygen utilization, blood flow and cognition in healthy aging. PLoS One. 2018;13:e0197055.
121. Price EA. Aging and erythropoiesis: current state of knowledge. Blood Cells Mol Dis. 2008;41:158–165.
122. Stauder R, Valent P, Theurl I. Anemia at older age: etiologies, clinical implications, and management. Blood. 2018;131:505–514.
123. López-Valdés HE, Martínez-Coria H. The role of neuroinflammation in age-related dementias. Rev Invest Clin. 2016;68:40–48.
124. Benderro GF, Lamanna JC. Hypoxia-induced angiogenesis is delayed in aging mouse brain. Brain Res. 2011;1389:50–60.
125. Catchlove SJ, Parrish TB, Chen Y, Macpherson H, Hughes ME, Pipingas A. Regional cerebrovascular reactivity and cognitive performance in healthy aging. J Exp Neurosci. 2018;12:1179069518785151.
126. Carlson BW, Neelon VJ, Carlson JR, Hartman M, Bliwise DL. Cerebral oxygenation in wake and during sleep and its relationship to cognitive function in community-dwelling older adults without sleep disordered breathing. J Gerontol A Biol Sci Med Sci. 2011;66:150–156.
127. Bastos-Leite AJ, Kuijer JP, Rombouts SACerebral blood flow by using pulsed arterial spin-labeling in elderly subjects with white matter hyperintensities. AJNR Am J Neuroradiol. 2008;29:1296–1301.
128. Bernbaum M, Menon BK, Fick GReduced blood flow in normal white matter predicts development of leukoaraiosis. J Cereb Blood Flow Metab. 2015;35:1610–1615.
129. Moeini M, Lu X, Avti PKCompromised microvascular oxygen delivery increases brain tissue vulnerability with age. Sci Rep. 2018;8:8219.
130. Weaver J, Jalal FY, Yang Y, Thompson J, Rosenberg GA, Liu KJ. Tissue oxygen is reduced in white matter of spontaneously hypertensive-stroke prone rats: a longitudinal study with electron paramagnetic resonance. J Cereb Blood Flow Metab. 2014;34:890–896.
131. Robertson BA, Clements KM, Wainwright PE. The working memory capabilities of the spontaneously hypertensive rat. Physiol Behav. 2008;94:481–486.
132. LaManna JC, Chavez JC, Pichiule P. Structural and functional adaptation to hypoxia in the rat brain. J Exp Biol. 2004;207:3163–3169.
133. Di Giulio C, Bianchi G, Cacchio MOxygen and life span: chronic hypoxia as a model for studying HIF-1alpha, VEGF and NOS during aging. Respir Physiol Neurobiol. 2005;147:31–38.
134. Ndubuizu OI, Chavez JC, LaManna JC. Increased prolyl 4-hydroxylase expression and differential regulation of hypoxia-inducible factors in the aged rat brain. Am J Physiol Regul Integr Comp Physiol. 2009;297:R158–R165.
135. Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, Barres BA. Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci U S A. 2018;115:E1896–E1905.
136. Chavez JC, Baranova O, Lin J, Pichiule P. The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. J Neurosci. 2006;26:9471–9481.
137. Temido-Ferreira M, Coelho JE, Pousinha PA, Lopes LV. Novel players in the aging synapse: impact on cognition. J Caffeine Adenosine Res. 2019;9:104–127.
138. Soreq L, Rose J, Soreq E, et al.; UK Brain Expression Consortium; North American Brain Expression Consortium. Major shifts in glial regional identity are a transcriptional hallmark of human brain aging. Cell Rep. 2017;18:557–570.
139. Rozycka A, Liguz-Lecznar M. The space where aging acts: focus on the GABAergic synapse. Aging Cell. 2017;16:634–643.
140. Adogwa O, Elsamadicy AA, Sergesketter A, et al. Independent association between preoperative cognitive status and discharge location after surgery: a strategy to reduce resource use after surgery for deformity. World Neurosurg. 2018;110:e67–e72.
141. Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci. 2008;9:58–65.
142. An J, Li H, Tang Z, et al. Cognitive impairment and risk of all-cause and cardiovascular disease mortality over 20-year follow-up: results from the BLSA. J Am Heart Assoc. 2018;7:e008252.
143. Hughes MJ, Hackney RJ, Lamb PJ, Wigmore SJ, Christopher Deans DA, Skipworth RJE. Prehabilitation before major abdominal surgery: a systematic review and meta-analysis. World J Surg. 2019;43:1661–1668.
144. Smith A, Moon T, Pak T, Park B, Urman RD. Preoperative anemia treatment with intravenous iron in patients undergoing major orthopedic surgery: a systematic review. Geriatr Orthop Surg Rehabil. 2020;11:2151459320935094.
145. Yu Y, Zhang K, Zhang L, Zong H, Meng L, Han R. Cerebral near-infrared spectroscopy (NIRS) for perioperative monitoring of brain oxygenation in children and adults. Cochrane Database Syst Rev. 2018;1:CD010947.
146. Gaudino M, Benesch C, Bakaeen F, et al.; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Stroke Council; and Council on Cardiovascular and Stroke Nursing. Considerations for reduction of risk of perioperative stroke in adult patients undergoing cardiac and thoracic aortic operations: a scientific statement from the American Heart Association. Circulation. 2020;142:e193–e209.
147. Mack MJ, Acker MA, Gelijns AC, et al.; Cardiothoracic Surgical Trials Network (CTSN). Effect of cerebral embolic protection devices on CNS infarction in surgical aortic valve replacement: a randomized clinical trial. JAMA. 2017;318:536–547.
148. Lee LA, Caplan RA, Stephens LS, et al. Postoperative opioid-induced respiratory depression: a closed claims analysis. Anesthesiology. 2015;122:659–665.
149. Hyman MC, Vemulapalli S, Szeto WYConscious sedation versus general anesthesia for transcatheter aortic valve replacement: insights from the National Cardiovascular Data Registry Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Circulation. 2017;136:2132–2140.
150. Ko SB. Perioperative stroke: pathophysiology and management. Korean J Anesthesiol. 2018;71:3–11.