(BQ) Part 5 book Millers textbook has contents: Geriatric anesthesia, anesthesia for trauma, anesthesia and prehospital emergency and trauma care, anesthesia for eye surgery, anesthesia for ear, nose, and throat surgery, administration of anesthesia by robots,... and another contents.
Chapter 80 Geriatric Anesthesia FREDERICK SIEBER • RONALD PAULDINE Key Points • An important principle of aging is a progressive loss of functional reserve in all organ systems, with considerable variation from person to person • Older patients are more sensitive to anesthetic drugs Less medication is usually required to achieve a desired clinical effect, and drug effects are often prolonged Hemodynamic responses to intravenous anesthetics may be exaggerated because of interactions with the aging heart and vasculature • The incidence of postoperative delirium is substantially more frequent in patients with preoperative dementia • The ability to predict patients at high risk for postoperative delirium has enabled proactive interventions to prevent or attenuate the severity or duration of postoperative delirium The cornerstone of management of delirium is the recognition and treatment of any predisposing or precipitating factors for delirium • Postoperative cognitive dysfunction (POCD) in older patients occurs in the first days to weeks after surgery POCD is well documented, and early POCD is reversible • Perioperative management of depression is a lower priority than management of the patient’s more acute medical illnesses • Although advance directives can be helpful in perioperative decision making, accurate documentation of advance care planning is often lacking for many older patients • In older patients perioperative complications lead to poor outcome The most important risk factors for perioperative complications in older patients are age, the patient’s physiologic status and coexisting disease (American Society of Anesthesiologists class), whether the surgery is elective or urgent, and the type of procedure • The success of surgical intervention in geriatric patients depends partly on whether patients can return to their previous level of activity and independence • Recognizing acute illness and exacerbation of chronic disease in older adults can be challenging Not infrequently, acute illness may have an atypical presentation Defining and implementing optimal perioperative care for older adults is of increasing importance to all stakeholders in health care, including consumers, insurers, and government agencies Health care reform legislation has focused an increasing emphasis on cost containment, value, and rigorous assessment of meaningful outcomes for older patients The demographic considerations are sobering The U.S Census 2010 data revealed the number of persons older than 65 years of age in the United States had increased to 40.4 million, with 21.7 million 65 to 74 years old, and 13.1 million 75 to 84 years of age, with 5.5 million over the age of 85 years The average life expectancy was 78.2 years It is estimated that by 2030, 20% of U.S citizens will be older than 65 years By 2034, baby boomers in the United States will all be over 70 years of age By 2050 those over 85 years of age will represent 14% of the population over 65 years.1 Worldwide, nearly billion people will be over 60 years of age.2 Older individuals frequently access health care In 2003, older patients represented roughly 12% of the U.S population, accounted for one third of all hospitalizations and 43.6% of inpatient hospital charges.3 Patients 65 years of age and older have surgery at a rate to times that of younger patients and tend to have longer hospital stays.4 2407 2408 PART V: Adult Subspecialty Management CORE CONCEPTS IN THE ANESTHETIC MANAGEMENT OF THE OLDER PATIENT Two important principles must be kept in mind when discussing the physiology of aging First, aging is associated with a progressive loss of functional reserve in all organ systems Second, the extent and onset of these changes vary from person to person In most older patients, physiologic compensation for age-related changes is adequate and underlying limitation in physiologic reserve may become evident only during times of physiologic stress, including exercise, illness, and surgery Anticipating the interaction of underlying disease, limited end-organ reserve, and the stress of the perioperative period should aid the perioperative physician in providing the best care possible MECHANISMS OF AGING Aging is a universal and progressive physiologic process characterized by declining end-organ reserve, decreased functional capacity, increasing imbalance of homeostatic mechanisms, and an increasing incidence of pathologic processes.5 Aging is now viewed as an extremely complex multifactorial process with interaction of various pathways to differing degrees and effect.6 Theories of aging may be grouped into broad categories including evolutionary and physiologic mechanisms These may also be defined according to the “programmed” or biologic clock theory, in which genetic mechanisms program declining function, and “error” theories, in which environmental damage to processes lead to impaired function and progressive decline These processes of aging overlap and may be further defined by the organizational level of an organism in which a given process occurs Changes at one level influence processes at another level Molecular effects will influence cellular function, which in turn causes alterations in major organ systems and may ultimately exert evolutionary pressure by influencing survival and reproduction Theories of aging have been reviewed.5,7 These are summarized in Table 80-1 CENTRAL NERVOUS SYSTEM With aging, several important processes occur that are of interest to the anesthesiologist.8 These changes may be further modified by other underlying pathologic or agerelated processes.9 Memory decline occurs in more than 40% of persons over 60 years of age but is not a universal finding.10 Importantly, age-related memory decline can dramatically affect performance of the activities of daily living (ADL) Structurally, a decrease occurs in the volume of both gray matter and white matter in the central nervous system (CNS).11 Regions of the brain are affected in a selective and differential manner The decrease in gray matter volume is likely secondary to neuronal shrinkage as opposed to neuronal loss A small overall loss occurs of neurons from the neocortex.8 This decrease in neuron number is not as massive as older studies had indicated Some neocortical areas not lose any neurons with aging There may be 15% loss, however, of white matter with aging.8 These structural changes result in gyral atrophy and increased ventricular size Shrinkage in the subcortical white matter and hippocampus may be accelerated by hypertension and vascular disease Whether the aging process alters the number of synapses present in the cortex is controversial Data from nonhuman primates suggest significant regional reductions with aging in the neurotransmitters dopamine, acetylcholine, norepinephrine, and serotonin.12 Levels of glutamate, the primary neurotransmitter in the cortex, TABLE 80-1 CLASSIFICATION AND BRIEF DESCRIPTION OF THEORIES OF AGING Biologic Level and Theory Evolutionary Mutation accumulation Disposable soma Antagonistic pleiotropy Molecular Gene regulation Codon restriction Error catastrophe Somatic mutation Dysdifferentiation Cellular Senescence-telomere theory Free radical Wear-and-tear Apoptosis System Neuroendocrine Immunologic Rate-of-living Description Mutations that affect health at older ages are not selected against Somatic cells are maintained only to ensure continued reproductive success; after reproduction, soma becomes disposable Genes beneficial at younger age become deleterious at older age Aging is caused by changes in the expression of genes regulating both development and aging Fidelity and accuracy of mRNA is impaired as a result of inability to decode codons in mRNA Decline in fidelity of gene expression with aging results in increased fraction of abnormal proteins Molecular damage accumulates primarily to DNA and genetic material Gradual accumulation of random molecular damage impairs regulation of gene expression Phenotypes of aging are caused by an increase in frequency of senescent cells as a result of telomere loss or cell stress Damage caused by free radical production from oxidative metabolism Accumulation of normal injury Programmed cell death Alterations in neuroendocrine control of homeostasis leads to physiologic change Decline in immune function leads to altered incidence of infection and autoimmunity Assumes a fixed amount of metabolic potential for every living organism (live fast, die young) Modified from Weinert BT, Timiras PS: Invited review: theories of aging J Appl Physiol 95:1707, 2003 With permission Chapter 80: Geriatric Anesthesia are not affected Coupling of cerebral electrical activity, cerebral metabolic rate, and cerebral blood flow remains intact in older individuals Although biochemical and anatomic changes have been described in the aging brain, the exact mechanisms causing changes in functional reserve are unclear Decreases in brain reserve manifest by decreases in functional ADL, increased sensitivity to anesthetic medications, increased risk for perioperative delirium, and increased risk for postoperative cognitive dysfunction (POCD) Neuraxial changes include a reduction of the area of the epidural space, increased permeability of the dura, and decreased volume of cerebrospinal fluid The diameter and number of myelinated fibers in the dorsal and ventral nerve roots are decreased in older individuals In peripheral nerves, inter–Schwann cell distance is decreased, as is conduction velocity These changes tend to make older individuals more sensitive to neuraxial and peripheral nerve blocks.13 CARDIOVASCULAR CHANGES Primary changes in the vasculature, or arterial aging, cause important secondary changes in the heart and other end organs including the brain and kidney The process of vascular aging is accelerated by the presence of primary cardiovascular disease, including hypertension and atherosclerosis, as well as other risk factors such as diabetes, tobacco abuse, and obesity Primary changes in cardiac function also occur with advancing age Morphologic changes include decreased myocyte number, thickening of the left ventricular wall, and decreases in both conduction fiber density and the number of sinus node cells.14 Functionally, these changes translate to decreased contractility, increased myocardial stiffness and ventricular filling pressures, and decreased β-adrenergic sensitivity.14 Breakdown of elastin in the proximal thoracic aorta and proximal branches of the great vessels leads to progressive central aortic dilatation, increased thickness of the arterial wall, and increased vascular stiffness with advancing age.15 Alterations in nitric oxide–induced vasodilatation also contribute.16 Functionally, these changes are readily observed in terms of an elevated mean arterial pressure and increased pulse pressure.17,18 Increased vascular stiffness leads to important secondary responses in the heart Functionally, the vascular system acts as both a cushion and a conduit to ensure the mechanically efficient and smooth delivery of blood to the periphery In youth, the cardiac pump and the blood vessels are optimally coupled to maximize efficiency.19 With increased resistance in the blood vessels, the velocity of conduction of pulse waves down the vascular tree increases Increased pulse wave velocity results in earlier reflection of pulse waves from the periphery In younger humans, wave reflection occurs later as a result of slower propagation such that reflected waves reach the heart after aortic valve closure This timing preserves pressure in the compliant central aorta, promoting coronary blood flow during diastole In the setting of increased pulse wave velocity with wave reflection occurring earlier, reflected pulse waves reach the heart during the latter phases of ejection, resulting in an increased cardiac 2409 load.18 Alterations in left ventricular afterload lead to left ventricular wall thickening, hypertrophy, and impaired diastolic filling.20 Decreased ventricular compliance and increased afterload combine to cause compensatory prolongation of myocardial contraction This occurs at the expense of decreased early diastolic filling time Under these conditions the contribution of atrial contraction to late ventricular filling becomes more important and explains why cardiac rhythm other than sinus is often poorly tolerated in older adults and why older patients are often preload sensitive Peripheral blood pressure measurements probably not accurately represent central aortic pressures In youth, pulse pressure amplification occurs as pulse waves travel down the vascular tree This is observed as an increase in systolic pressure of 10 to 15 mm Hg between the central aorta and the periphery, with a slight decrease in diastolic and mean pressures With aging, this is lost, which results in an augmentation of central aortic pressure (Fig 80-1) Several methods have been described to estimate changes in aortic stiffness These include noninvasive technologies to measure aortic pulse pressure, pulse wave velocity, and aortic augmentation index.21 Increased vascular stiffness as assessed by these methods is associated with adverse cardiovascular events.22,23 Differential responses to drugs with regard to central aortic pressure and peripheral arterial pressure may have important implications for treatment of cardiovascular disease.21 Changes in the autonomic system with aging include a decrease in response to β-receptor stimulation and an increase in sympathetic nervous system activity.24 Decreased β-receptor responsiveness is secondary to both decreased receptor affinity and alterations in signal transduction.25 Decreased β-receptor responsiveness assumes functional importance when increased flow demands are placed on the heart Normally β-receptor–mediated mechanisms act to increase heart rate, venous return, and systolic arterial pressure while preserving preload reserve In contrast, the attenuated β-receptor response in older individuals during exercise and stress is associated with decreased maximal heart rate and decreased peak ejection fraction This causes the increased peripheral flow demand to be met primarily by preload reserve, making the heart more susceptible to cardiac failure.14 Sympathetic nervous system activity increases with aging Although changes in β-receptor responsiveness are well defined, it is controversial whether the aging process alters the α-receptor response Increased resting sympathetic nervous system activity may contribute to increases in systemic vascular resistance and mechanical stiffening of the peripheral vasculature.14 This explains in part the exquisite sensitivity of many older patients to interventions that decrease sympathetic tone Clinically, these autonomic changes lead to a greater likelihood of adverse intraoperative hemodynamic events and decreased ability to meet the metabolic demands of surgery Although the age-related changes in cardiovascular physiology are generally well tolerated, several pathophysiologic states deserve mention Impairment of diastolic relaxation leads to diastolic dysfunction in the aging heart In its severest form, diastolic dysfunction may manifest as diastolic heart failure, now referred to 2410 PART V: Adult Subspecialty Management Older patient Pressure Pressure Augmented pressure Radial artery waveform Central aortic waveform Reflected wave point Time Young patient Pressure Pressure Radial artery waveform Reflected wave point Central aortic waveform Time Figure 80-1. Illustration of the influence of increased vascular stiffness on peripheral (radial) and central (aortic) derived pressures Note the similarity of peripheral radial pressures in individuals with normal (lower left panel) and increased (upper left panel) vascular stiffness In young individuals with normal vascular stiffness, central aortic pressures are lower than radial pressures (lower panels) In contrast, in older individuals with increased vascular stiffness, central aortic pressures are increased and can approach or equal peripheral pressures as a result of wave reflection and central wave augmentation during systole (top panels) (Redrawn from Barodka VM, Joshi BL, Berkowitz DE, et al: Implications of vascular aging [Review article], Anesth Analg 112:1048-1060, 2011 With permission) as heart failure with preserved ejection fraction (HFpEF) Predisposing disease states for HFpEF include hypertension with left ventricular hypertrophy, ischemic heart disease, hypertrophic cardiomyopathies, and valvular heart disease HFpEF is twice as prevalent in females.26 Population-based studies suggest that diastolic dysfunction is common and associated with an increase in allcause mortality.27 Furthermore, in patients with clinically evident heart failure, ejection fraction is preserved in over half, with 40% manifesting overt HFpEF Mortality in the cohort with preserved ejection fraction is similar to that in patients with reduced ejection fraction (HFrEF).28 The pathophysiologic process includes decreased left ventricular compliance during diastole, resulting in greatly increased left ventricular diastolic pressure with retrograde conduction to the pulmonary circulation, which causes pulmonary venous congestion and pulmonary edema HFpEF is often related to systemic blood pressure Chapter 80: Geriatric Anesthesia and does not necessarily imply volume overload Diagnosis can be difficult because the clinical picture appears identical to that of left ventricular systolic failure Making the correct diagnosis is important because interventions commonly employed in systolic failure—such as diuretics and inotropes—may exacerbate diastolic dysfunction.29 Echocardiography is the diagnostic modality of choice Classically, echocardiography will demonstrate preserved or hyperdynamic left ventricular systolic function and characteristic changes of flow velocity at the mitral valve Left ventricular systolic dysfunction and diastolic dysfunction often coexist Pulmonary arterial pressures increase in aging, and HFpEF may be a contributing factor.30 Aortic valve sclerosis and mitral annular calcification are common echocardiographic findings in older adults These represent non–flow-limiting calcifications around the aortic and mitral valves, respectively Aortic valve sclerosis is common in older individuals and is associated with an increase in the risk for adverse cardiovascular and coronary events.31 RESPIRATORY CHANGES Alterations in control of respiration, lung structure, mechanics, and pulmonary blood flow place older adults at increased risk for perioperative pulmonary complications Ventilatory responses to hypoxia, hypercapnia, and mechanical stress are impaired secondary to reduced CNS activity.32 In addition, the respiratory depressant effects of benzodiazepines, opioids, and volatile anesthetics are exaggerated.32,33 These changes compromise the usual protective responses against hypoxemia after anesthesia and surgery in older patients Structural changes in the lung with aging include the loss of elastic recoil after reorganization of collagen and elastin in lung parenchyma This combined with altered surfactant production leads to an increase in lung compliance Increased compliance leads to limited maximal expiratory flow and a decreased ventilatory response to exercise.34 Loss of elastic elements within the lung is associated with enlargement of the respiratory bronchioles and alveolar ducts and a tendency for early collapse of the small airways on exhalation, leading to an increased risk for air trapping and hyperinflation Progressive loss of alveolar surface area occurs secondary to increases in size of the interalveolar pores of Kohn The functional results of these pulmonary changes are increased anatomic dead space, decreased diffusing capacity, and increased closing capacity, all leading to impaired gas exchange Changes in chest wall compliance result in greater elastic load during inspiration, with an increased work of breathing Loss of height and calcification of the vertebral column and rib cage leads to a typical barrel chest appearance with diaphragmatic flattening The flattened diaphragm is mechanically less efficient, and function is further impaired by a significant loss of muscle mass associated with aging Although alterations in lung volumes occur with aging, total lung capacity is relatively unchanged Residual volume increases by 5% to 10% per decade 2411 TABLE 80-2 NORMAL VALUES FOR ARTERIAL PARTIAL PRESSURE OF OXYGEN Age (yr) Mean and Range (mm Hg) 20-29 30-39 40-49 50-59 60-69 94 (84-104) 91 (81-101) 88 (78-98) 84 (74-94) 81 (71-91) From Nunn J: Nunn’s applied respiratory physiology, ed 4, Oxford, Butterworth-Heinemann, 1995, p 269 Therefore, vital capacity decreases Closing capacity—the volume at which small dependent airways start to close— increases with age Although functional residual capacity is unchanged or slightly increased, closing capacity is unaffected by body position Change in the relationship between functional residual capacity and closing capacity causes an increased ventilation-perfusion mismatch and represents the most important mechanism for the increase in the alveolar-arterial gradient for oxygen observed in aging.35 In younger individuals, closing capacity is less than functional residual capacity At 44 years of age, closing capacity equals functional residual capacity in the supine position, and at 66 years of age, in the upright position.35 When closing capacity encroaches on tidal breathing, ventilation-perfusion mismatch occurs When functional residual capacity is below closing capacity, shunt will increase and arterial oxygenation will fall This effect is observed in the decreased resting arterial oxygen (O2) tension with aging and impairs the effectiveness of breathing O2 before induction of general anesthesia (Table 80-2) Another effect of increasing closing capacity in concert with depletion of muscle mass is a progressive decrease in forced expiratory volume in second (FEV1) by 6% to 8% per decade Increases in pulmonary vascular resistance and pulmonary artery pressure occur with age and may be secondary to decreases in the cross-sectional area of the pulmonary capillary bed.36 Hypoxic pulmonary vasoconstriction is blunted in older adults and may cause difficulty with one-lung ventilation Older patients may have an increased sensitivity for bronchoconstriction and a diminished response to treatment with inhaled β-agonists.37 Alterations in immune responses in older adults may lead to an increased susceptibility to environmental exposure and lung injury.38 RENAL AND VOLUME REGULATION Structural and functional changes occur in the kidney as part of normal aging Nephrosclerosis is observed with increasing age but may not correlate with decreases in glomerular filtration rate (GFR).39 Renal blood flow decreases approximately 10% per decade after 40 years of age, with a decline in GFR of mL/min/1.73 m2 from a baseline of 140 mL/min/1.73 m2.40 With normal aging, serum creatinine remains relatively unchanged in the face of a progressive decrease in creatinine clearance This occurs because muscle mass also decreases with aging Therefore, serum creatinine is a poor predictor of renal function in older individuals.40,41 2412 PART V: Adult Subspecialty Management This concept is important in proper dosage adjustment for medications excreted by the kidneys Functional changes in the kidneys with aging include alterations in response to abnormal electrolyte concentrations and the ability to concentrate and dilute urine.42 Renal capacity to conserve sodium is decreased Overall, the older patient has a tendency to lose sodium in the setting of inadequate salt intake This paired with a decreased thirst response may place the older patient at risk for dehydration and sodium depletion The older patient also has a diminished ability to respond properly to an increased salt load, as evidenced by increased sodium retention and expansion of the extracellular volume during the perioperative period This change assumes importance under conditions of limited fluid intake HEPATIC CHANGES Liver volume decreases approximately 20% to 40% with aging Hepatic blood flow decreases approximately 10% per decade.43 A variable decrease occurs in the liver’s intrinsic capacity to metabolize drugs Effects on phase I reactions predominate Decreases in hepatic blood flow may decrease maintenance dose requirements in drugs that are rapidly metabolized The pharmacokinetics of drugs that are slowly metabolized are more affected by innate liver capacity than blood flow.44 COGNITIVE ISSUES IN OLDER ADULTS DEMENTIA Dementia is common in the geriatric population In the population 65 years of age and older, 5% to 8% of people experience dementia For those 75 years of age and older, 18% to 20% suffer dementia For individuals over 85 years of age, more than one third may have dementia.45 Dementia has many causes, with Alzheimer disease accounting for the majority of cases The main perioperative management issues concerning the demented patient include detection, informed consent, possible anesthetic interactions causing delayed emergence, postoperative delirium, pain management, and increased mortality Many instruments of varying length are available to test for cognitive impairment.46 However, accurate diagnosis of dementia is not always easy For dementia screening, the AD8, an 8-item questionnaire that distinguishes between people who have dementia and people who not, is a quick and reliable instrument.47 For preoperative evaluation of baseline cognitive status, rather than detection of dementia, the Short Blessed Test allows for quick screening.48 In addition, insight may be gained by speaking with the patient’s family concerning baseline function and ADL Some of the instruments for testing cognition may be used to help guide the physician in determining the patient’s capacity to consent.49 The patient with dementia may display one of a number of psychiatric symptoms, including agitation, depression, and sleep disturbances.50 Many of the drugs used to manage dementia and its symptoms interact with general anesthetics,51 causing delayed emergence It is unclear whether use of the bispectral index (BIS) monitor (see also Chapter 50) or other processed electroencephalography methods for guidance of drug administration is helpful because dementia does alter baseline BIS values.52 When determining an anesthetic plan, no anesthetic technique or drug has been shown to be superior in older patients However, patient cooperation may be an issue with regional anesthesia (see also Chapters 56 and 57) Dementia is critical in risk stratification for postoperative delirium The incidence of postoperative delirium is substantially more frequent in individuals with preoperative dementia than in those without.53 Pain management in the patient with dementia is challenging for several reasons (see also Chapter 98) Pain assessment can be difficult.54 Despite use of the best available pain assessment instruments, decreased pain scores and opioid administration occur postoperatively in patients with dementia.55 Pain management can be more nursing intensive because patient-controlled analgesia often is not an option in these patients Furthermore, the clinician must maintain a delicate balance between opioid CNS effects and the role of poorly treated pain in precipitating delirium.56,57 Dementia has many associated comorbidities, including vascular disease, diabetes, alcoholism, and neurodegenerative disease (e.g., Parkinson, Huntington) Dementia is associated with a 2.18 (1.10 to 4.32) relative risk for developing a patient-related adverse event during an unplanned acute hospital admission.53,58 Longterm postoperative mortality is related to the presence of dementia,59 with the severity of cognitive impairment being associated with higher mortality.60 Whether general anesthesia accelerates the progression of senile dementia is controversial.61,62 Certainly, much evidence exists both in vitro and in animal models suggesting that inhaled anesthetics enhance amyloid β oligomerization,63 increase plaque density in transgenic mice (human APP gene),64 induce caspase-3 activation (one of the final steps of apoptosis), and increase amyloid β protein (Aβ) levels in cell culture.65 However, in humans, recent retrospective data suggest that long-term cognitive decline is neither independently attributable to surgery (and anesthesia) or illness, nor have surgery (and anesthesia) or illness been associated with accelerated progression of dementia.66,67 Unfortunately, no prospective human data convincingly answer this question Thus, the relationship between anesthetic exposure and accelerated progression of dementia remains unclear; “Available human studies on anesthesia and Alzheimer disease are inconclusive because they are under-powered or confounded by coincident illness, independent risk factors for dementia and, of course, surgery.”68 DELIRIUM The overall prevalence of delirium in older patients after surgery has been estimated to be 10%.69 The incidence of postoperative delirium in older patients varies widely depending on the type of surgery, underlying comorbidities, and intensive care unit (ICU) stay For Chapter 80: Geriatric Anesthesia instance, cardiac surgery and hip fracture repair may have an increased incidence over that of other procedures.69 Delirium occurs in 60% to 80% of patients in the ICU.70 Postoperative delirium has profound financial implications Delirium is associated with prolonged hospital stay, increased incidence of nursing home placement, and an increased incidence of postoperative complications.71 Overall to million older patients per year sustain delirium during their hospital stay, involving more than 17.5 million inpatient days.70 The total direct 1-year health costs attributable to delirium range from $143 billion to $152 billion nationally.72 Adding to these costs, the occurrence of postoperative delirium is associated with an accelerated trajectory of cognitive decline in patients with underlying dementia.73 Delirium and POCD are not the same Postoperative delirium is an acute confusional state with alterations in attention and consciousness On the other hand, POCD is a decline in a variety of neuropsychological domains (e.g., memory, executive function, speed of processing) Delirium is a syndrome characterized by acute onset of variable and fluctuating changes in level of consciousness accompanied by a range of other mental symptoms By convention, the presence or absence of delirium is based on application of diagnostic criteria articulated in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV): “The essential feature of a delirium is a disturbance in consciousness that is accompanied by a change in cognition that cannot be better accounted for by a preexisting or evolving dementia”74 (Box 80-1) Postoperative delirium may have several presentations with the hyperactive (“wild man”), hypoactive (“out of it”), and mixed (hypoactive alternating with hyperactive) presentations accounting for 1%, 68%, and 31% of cases, respectively.75 Several instruments are available to diagnose delirium The Confusion Assessment Method (CAM)76 is the most widely used instrument in North America The CAM is a bedside rating scale developed to assist clinicians not trained in psychiatry in the rapid and accurate diagnosis BOX 80-1 Diagnostic and Statistical Manual of Mental Disorders IV Diagnostic Criteria for 293.0 Delirium A Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention B A change in cognition (e.g., memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia C The disturbance develops over a short time (usually hours to days) and tends to fluctuate during the course of the day D There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiologic consequences of a general medical condition From American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed, Text Revision (DSM-IV-TR), Washington, DC, 2000, American Psychiatric Publishing 2413 of delirium in clinical settings The CAM is designed to be administered by any clinician, including physicians or nurses, and may be administered by trained lay interviewers Geriatricians, nurses, and trained lay interviewers perform as well as psychiatrists in rating the CAM.77 The sensitivity of the CAM against the gold standard of psychiatric diagnosis is 94% to 100%, with specificity 90% to 95%.76 The CAM-ICU has been adapted for measuring delirium in ventilated patients in the ICU.78 Many possible pathophysiologic mechanisms can account for delirium Delirium may be associated with inflammatory mediators or alterations in one of several neurotransmitter systems.79 Although we not yet fully understand the basic mechanisms of delirium, in the geriatrics paradigm, delirium epitomizes an atypical presentation of disease80 in which acute illness is manifested in the most vulnerable organ system, or “the weakest link”—in this case, the brain This theory holds that the normal aging process can be characterized as homeostenosis, the progressive constriction of each organ system’s ability to respond to stress.81 In addition, the aging brain is more likely to be affected by diseases and drugs that cloud the sensorium The sum of these effects leads some older adults to be teetering on the brink of neurodysfunction Add any stressor, and these individuals develop acute worsening of their mental status Based on the concept that “lack of brain reserve” predisposes older patients to delirium when exposed to stress, investigators have examined which preexisting vulnerability factors predispose older patients to delirium In medical patients, Inouye and Charpentier82 developed a risk model for delirium that showed that the greater the number of preexisting vulnerability factors, the less acute are the stressors required to invoke delirium The important preexisting vulnerability factors defined in the medical model of delirium are advanced age, visual impairment (visual acuity 16), cognitive impairment (Mini–Mental State Examination score 70% or >90%) stenosis of the internal carotid artery Postoperatively, neurologic complications may occur as a result of brain ischemia, embolism, or brain hyperperfusion Yet, an improvement in brain function could occur 3006 PART VII: Postoperative Care if brain perfusion was corrected or perhaps because the carotid plaque is a source of brain emboli However, neuropsychological studies conducted in this area have produced inconsistent findings that have been highlighted in two systematic reviews.90,91 Improvement in cognitive performance after carotid endarterectomy was reported in over 50% of studies, with 43% showing no change or decline.91 REGIONAL VERSUS GENERAL ANESTHESIA If general anesthesia is an important factor leading to the development of POCD, regional anesthesia would reduce its incidence (see also Chapters 56 and 57) In the randomized studies using neuropsychological testing after surgery, no clear picture emerges during the first postoperative week Significantly better neuropsychological test performance has been reported at examination from the first hours to days with regional anesthesia12,92,93 but after the first week after surgery, no significant advantage of regional anesthesia has been detected (Table 99-3) Methodologic limitations could be an important confounding factor because in these types of studies blinding of patients and even blinding of examiners may be difficult The largest study conducted found no significant difference in POCD between general or regional anesthesia at either week (general anesthesia = 37 of 188 (19.7%), regional anesthesia = 22 of 176 (12.5%), P = 06), or months (general anesthesia = 25 of 175 (14.3%), regional anesthesia = 23 of 165 (13.9%), P = 93) after surgery.94 Regional anesthesia was unsuccessful in 24 patients allocated to regional anesthesia for whom general anesthesia was therefore necessary (see also Chapter 56) Also, 35 patients allocated to general anesthesia actually received spinal or epidural anesthesia Not all of these 59 patients TABLE 99-3 RANDOMIZED STUDIES COMPARING GENERAL AND REGIONAL ANESTHESIA USING NEUROPSYCHOLOGICAL TESTING Authors No Completed Age O’Dwyer et al153 Casati et al154 Rasmussen et al94 255 Mean 55 yr 30 340 Median 84 yr Median 71 yr Somprakit et al155 120 Williams-Russo et al22 Campbell et al156 Haan et al13 Nielson et al157 Jones et al158 Interval After Surgery Type of Surgery Results hr, 24 hr, and days and days mo Hernia repair No significant difference Hip fracture repair Mixed and days Mixed 231 Group = mean 37 yr Group = mean 67 yr Median 69 yr No significant difference No significant difference at mo using intention to treat but significant difference at wk 21% versus 13% in favor of regional when using per protocol analysis No significant difference in whole group, but older group had significantly more POCD wk and mo Knee replacement No difference between groups 157 Mean 77 yr Cataract No differences between groups 37 64 Mean 72 yr Mean 69 yr 24 hr, wk, mo days and mo mo Urology Knee replacement 129 50 controls >60 yr mo Knee or hip replacement Chung et al10 44 Mean 72 yr Urology Asbjørn et al93 Ghoneim et al159 Hughes et al12 40 105 Mean 69 yr Mean 61 yr Prostatectomy Mixed No difference No difference 30 Mean 68 yr Hip arthroplasty No difference after week Chung et al92 44 Mean 72 yr Prostate resection Bigler et al160 38 79 yr hr, 1, 3, and days and mo days and wk 1-7 days and mo 24 hr, 48 hr, and wk hr, 1, 3, and days and mo wk and mo No significant difference Improvement: No difference between groups Significant improvement in 2/5 variables in general anesthesia group, no change in regional anesthesia group (P = 03 and 04 between groups) No difference Riis et al161 30 >60 yr wk and mo Karhunen and Jöhn162 47 Mean 73 yr wk Significantly higher MMSE in regional at hr Improvement in both, with no difference between the two regimens Initial decline from baseline at days and then improved, with no group differences After wk significantly more deterioration in local anesthesia group in one of two combined scores Repair of hip fracture Hip replacement: general, epidural or combined Cataract surgery Chapter 99: Cognitive Dysfunction and Other Long-term Complications of Surgery and Anesthesia completed the study, but when excluded in a per protocol analysis, a significant difference in the incidence of POCD was found between general anesthesia in 33 of 156 (21.2%) versus regional anesthesia in 20 of 158 (12.7%) after week (P = 04); however, at months no difference was found ETIOLOGIC CONSIDERATIONS Perhaps POCD is the result of brain cell damage caused by toxic substances or hypoxia Toxic substances could be drugs such as general anesthetics or analgesics, but also the surgery-induced release of hormones or inflammatory mediators or a combination of these factors Hypoxia may result from arterial hypoxemia or low perfusion caused by low cardiac output, inappropriate blood flow distribution, thrombosis, or embolism DRUGS Anesthetic central nervous system toxicity may be a possible explanation for POCD (see also Chapter 15) General anesthesia is assumed to be a completely reversible condition Yet, this conclusion has not been conclusively proved Exposure of animals to anesthetics has resulted in the detection of several types of changes in the brain Jevtovic-Todorovic and co-workers95 demonstrated histologic changes in the brain after exposure to isoflurane, nitrous oxide (N2O), and midazolam In developing rat brain, apoptosis was found in thalamic nuclei and the parietal cortex after exposure to isoflurane and this effect was more pronounced if midazolam or N2O was added.95 Memory testing using a water maze revealed inferior performance in the anesthetized rats compared with control animals Also, infant mice showed signs of apoptosis in brain cortex after subcutaneous administration of midazolam or ketamine96 and after propofol or combinations of ketamine with propofol or thiopental.97 In adult rat brain cortex, neuronal vacuolization and neuronal degeneration with necrosis were found after N2O administration The neuronal vacuolization, however, seemed to be reversible, with no vacuolated neurons after hours of recovery, and the addition of diazepam or isoflurane blocked the neurodegeneration.98 These findings are interesting but not provide convincing evidence for induction of persistent neuronal changes after general anesthesia in humans, where N2O is not used as the only anesthetic Apoptosis occurred in human neuroglioma cells that were exposed to isoflurane, and increased levels of amyloid precursor protein were also found.99 Abnormal processing of amyloid precursor protein with accumulation of β-amyloid protein is a feature of Alzheimer disease, and it is therefore important to determine whether general anesthetics influence the processing of this protein.Another possible effect of anesthetics could be related to long-term changes in brain receptor function A decrease in cholinergic function has been found in Alzheimer disease, and cholinesterase inhibitors may be beneficial for patients with this condition In one study, changes in cholinergic binding were found in rat 3007 brains after repeated pentobarbital anesthesia given by intraperitoneal injection.100 Anesthetics cause changes in gene expression in the brain and in the protein synthesis pattern, as detected by comparison of brain tissue protein contents in anesthetized and control animals.101-103 These findings in animals or cell cultures are difficult to apply to the clinical situation with POCD in humans Animal studies of anesthetic drug toxicity may be influenced by inadequate oxygenation, ventilation, perfusion, or temperature regulation In addition, hypoglycemia may occur in infant rodents exposed to general anesthesia The brain cell damage of anesthesia in this situation may therefore be caused by mechanisms other than drug effects, but these findings have caused much concern in relation to pediatric anesthesia It is difficult to study central nervous system toxicity consequent to anesthetic exposure Although large epidemiologic studies have not detected a major long-term effect of anesthesia on cognitive function, such research has important limitations For example, in a study of 1257 healthy subjects, 946 participants had been previously exposed to at least one general anesthetic with no significant correlation between exposure to anesthesia and performance in cognitive tests.104 However, as with the collection of any retrospective data, subjects may not recall reliably the type and number of anesthetics they have received or the exact date they received the anesthetic The importance of age at time of exposure is difficult to ascertain Better cognitive performance has been found in two studies of cardiac surgery patients receiving inhaled anesthesia compared with propofol during CPB105,106 (see also Chapter 67) However, the difference was present only within the first postoperative week and no difference was seen at months.105Apart from anesthetics, many other drugs are given in connection with surgery As an example, analgesics may have important effects on cognitive function but have not been related to cognitive decline in elderly surgical patients.107 In agreement, Johnson and associates35 found that opioid administration within the 24 hours before the test had no significant influence on performance Still, other psychoactive medication cannot be excluded as a potential influence on neuropsychological test data obtained in patients during the weeks to months after surgery HORMONES Major surgery causes an endocrine response with release of hypothalamic-pituitary-adrenal (HPA) and sympathetic nervous system hormones Cognitive impairment can occur with high levels of glucocorticoids.108,109 Cortisol is toxic to cells in the hippocampus, and this structure plays a critical role in the consolidation of short-term into long-term explicit memory and descending control of the HPA axis Perhaps repeated episodes of stress cause decreased hippocampal inhibition of the HPA axis and, thus, prolonged hyperactivation.110 This was studied in 187 patients older than 60 years of age undergoing major noncardiac surgery, and a persistent change in the cortisol secretion pattern was significantly related to POCD at week.111 3008 PART VII: Postoperative Care INFLAMMATORY MEDIATORS THROMBOSIS OR EMBOLISM Surgery can activate the immune system with release of inflammatory mediators from lymphocytes Important mediators include cytokines that are able to initiate the activation of other inflammatory mediators and affect brain function either directly or indirectly.89,112,113 A very pronounced inflammatory response is seen in connection with cardiac surgery using CPB, and significantly higher levels of the cytokines IL-1 and IL-10 in patients with POCD after such procedures.114 Also, after noncardiac surgery, POCD is associated with increased levels of inflammatory mediators115,116; this area is currently a focus of research using animal models.117,118 Cerebral infarction can be caused by an embolic or a thrombotic occlusion of a cerebral artery, and necrosis of brain tissue, including neurons and glial cells, may result Thus, tissue architecture is lost and a well-defined infarct can be identified by autopsy or brain imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) Cerebral infarcts may cause no symptoms at all, depending on the size and location, but the usual clinical presentation is a stroke Several risk factors have been identified in studies of stroke in the general population and in relation to surgery Age is an important factor, and other important risk factors include type of surgery; cardiac disease, especially atrial fibrillation; peripheral vascular disease; previous cerebrovascular attacks; and diabetes124,125 (see also Chapter 80) The incidence of major cerebral complications presenting as stroke after general surgery varies between 0.2% and 0.7% Most cerebral infarctions in the perioperative period are caused by emboli Macroemboli are more than 200 μm in diameter and typically consist of atheromatous material or thrombi These may arise from the left atrium, left ventricle, or aorta Microemboli are less than 200 μm in diameter and, as stated earlier, are common in cardiac surgery (see also Chapter 67) As opposed to macroemboli, they may often consist of air introduced into the venous circulation— for instance, through tubing used in the CPB circuit or arterial lines In addition, paradoxical embolization may occur through an open foramen ovale from the venous side because of subatmospheric pressure in veins or bone marrow if the surgical field is above heart level and venous structures are noncollapsible, as in procedures such as back surgery, craniotomy in the sitting position, and knee replacement Microemboli occur in joint replacement surgery (see also Chapter 79) It was specifically assessed in 37 patients in whom cognitive function was studied with a battery of 13 tests at week and at months; POCD was found in 41% and 18%, respectively, but no significant association with microemboli was detected using transcranial Doppler imaging.84 HYPOXIA Brain hypoxia may lead to irreversible damage depending on the level, duration, and susceptibility Oxygen (O2) delivery to the brain depends on blood flow and arterial O2 concentration, which is primarily related to hemoglobin concentration and arterial O2 saturation Brain hypoxia may be caused by a decrease in blood flow or arterial hypoxemia In connection with anesthesia, inability to initiate ventilation in the patient or unrecognized esophageal intubation may cause profound and long-lasting hypoxemia119 and subsequently brain damage Modest perioperative decreases in arterial O2 saturation are common, but their importance is probably overemphasized when compared with the wide fluctuations in cerebral blood flow and blood hemoglobin level.120 One possible explanation for this is the ease of measuring arterial O2 saturation continuously by pulse oximetry No connection has been shown between modest arterial hypoxemia and postoperative complications, including POCD.23,121 BRAIN HYPOPERFUSION A temporary reduction of cerebral blood flow can cause neurologic or cognitive dysfunction without occlusion of cerebral vessels (see also Chapter 70) Cerebral blood flow is regulated according to brain metabolism and nearly unchanged within wide variations in blood pressure (autoregulation) mediated through changes in diameter of resistance vessels This autoregulation has a lower limit at approximately a mean arterial blood pressure of 50 mm Hg in healthy adults but is higher in hypertensive subjects.122 Below this limit, further dilatation of vessels cannot compensate and cerebral blood flow decreases Measuring cerebral blood flow or brain oxygenation during surgery is complicated The techniques used include xenon-133, near-infrared spectroscopy, transcranial Doppler imaging (which really measures velocity), and jugular bulb O2 saturation All of these techniques are associated with important limitations Brain perfusion pressure is therefore frequently used to evaluate brain perfusion in clinical practice During anesthesia, brain metabolism is reduced, and, therefore, a lower brain blood flow may be acceptable In earlier studies of cardiac surgery, prolonged episodes of hypotension were a risk factor for brain dysfunction,40,123 but subsequent studies have not been able to confirm this GENETIC ASPECTS Polymorphic genetic variation may explain individual differences in susceptibility to medication, inflammation, trauma, and other harmful factors Such genetic factors are important for the development of dementia but not uniquely determine the phenotype Apolipoprotein E (ApoE) is a protein that is important for recovery after central nervous system injuries.126 Important differences exist in the three different isoforms of ApoE—E2, E3, and E4, which are encoded by the alleles ε2, ε3, and ε4 of the ApoE gene, respectively The ε3 allele is the wild-type and present in 75% of the native European population, whereas ε2 and ε4 are less frequent.127 The ε4 allele seems to increase the risk for Alzheimer disease, and it is also associated with a poor prognosis after head injury.128-130 The possible association between the ε4 allele and POCD after cardiac surgery has been stu died, but literature presents conflicting information.131,132 Chapter 99: Cognitive Dysfunction and Other Long-term Complications of Surgery and Anesthesia The possible relationship between the ε4 allele and POCD after noncardiac surgery was studied in 976 patients 40 years of age and older; the ε4 allele was not a risk factor at week (P = 49) or months after noncardiac surgery (P = 28).133 POCD is related to the presence of the ε4 allele in patients undergoing carotid surgery.134 Other genetic factors could be important in the general surgical population—for instance, individual differences in inflammation and drug metabolism, with polymorphism of the drug metabolism system’s cytochrome P-450, are well described Very slow metabolism of certain drugs could be associated with prolonged recovery, and very fast metabolism could lead to high concentrations of intermediary degradation products.135 Both situations could result in a disturbance of receptor function, but the relationship, if any, with POCD remains to be established CLINICAL SIGNIFICANCE AND LONG-TERM CONSEQUENCES OF POSTOPERATIVE COGNITIVE DYSFUNCTION The detection of POCD and its likely causes have been discussed What effect does this dysfunction have on the patient? A frequent report is an elderly patient whose cognitive function has deteriorated profoundly after surgery, especially regarding memory The relatives describe a loss of function, lack of initiative, and lack of interest in activities that previously meant a lot to the person In a retired individual, this could be playing cards or doing crossword puzzles The deterioration may be most noticeable in patients returning to work, when usual tasks may be difficult to carry out in the same manner and at the same speed as before surgery Such difficulty also is not uncommon in middle-aged or young patients, who also may experience some degree of dysfunction in cognition One relevant question is whether POCD in fact results in impairment of function as reflected in activities of daily living In a study of elderly patients undergoing major noncardiac surgery with general anesthesia, a statistically significant correlation was found between POCD at months and a decline in activities of daily living.23 Another study of middle-aged patients, by Johnson and associates,35 found a statistically significant correlation between POCD at week and a decline in instrumental activities of daily living at week reported by relatives at months Long-term follow-up has revealed a significantly higher mortality in patients with cognitive dysfunction after noncardiac surgery.86,136 POCD also is associated with earlier retirement and need for social transfer payment.136 Dementia does not occur frequently after surgery, and whether POCD is a precursor of that condition has not been well studied Avidan and colleagues137 found no difference in the rate of cognitive decline according to exposure to surgery and anesthesia in a population undergoing repeated cognitive testing, and age-related cognitive decline may account for some of the changes reported previously The pronounced variability is also important, and some studies have found no difference in long-term POCD between patients undergoing 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