Chapter 12 – Stress Response to Surgery in the Elderly




Chapter 12 Stress Response to Surgery in the Elderly


Nazish K. Hashmi and Mihai V. Podgoreanu



Key Points





  • Major surgery is a global healthcare burden and is further compounded by unprecedented population aging, a major risk factor for perioperative organ injury and poor long-term outcomes.



  • Surgical trauma triggers a robust stress response, the characteristics of which are generally altered with aging, becoming the primary mechanism driving further injury and perioperative organ dysfunction in older adults.



  • A new field of geroscience has identified seven pillars of aging that distinguish the key processes to understanding and treating biologic aging, principal among which is adaptation to stress.



  • With aging, the allostatic response becomes impaired, and there may be an exaggerated or inadequate peak response, as well as a sluggish return to baseline.



  • Aging increases vulnerability to surgical stress, ischemia-reperfusion injury, and critical illness that is related to decreases in physical resilience characterized by immunosenescence, loss of mitochondrial function and nutrient sensing, and impaired recovery following surgical stressors.



  • Increasing evidence suggests that prehabilitation, healthy diet, nutrition, and exercise for seniors in anticipation of surgical stressors are effective interventions to promote physical resilience.



  • Provocative tests or biomarkers to predict increased vulnerability or, conversely, physical resilience are poorly developed, and our understanding of which patient subgroups may experience substantial benefit from interventions remains limited. Furthermore, pharmacologic resilience enhancers or boosters are currently not available.



  • The influence of age as a modifier of subsequent insults and “second hits” (e.g., postoperative infection) and its impact on outcome trajectories are extremely complex. The intestinal microbiota decreases in abundance and function following surgical trauma, and a virulent and resistant pathobiome emerges, rendering the stressed host more vulnerable to infection.



  • Postoperative pain trajectories differ by age and are amenable to interventions aimed at elderly patients.



Major Surgery in an Aging Population: A Global Healthcare Burden


The life expectancy for the US population in 2014 had increased to 78.8 years as death rates declined for children and young adults [1]. The number of adults aged 65 or older was estimated to be 46.2 million, which is 28 percent (or 10 million) more than in 2004 [2]. This number is expected to grow from 13 percent of the total population to over 20 percent in 2030, with adults older than age 85 expected to triple in the next four decades to 19 million [3]. Major surgery is a global healthcare burden, with around 244 million procedures performed annually, up to 4 percent of patients suffering perioperative deaths, up to 15 percent having serious postoperative morbidity, and 5 to 15 percent being readmitted within 30 days [4,5].


The implication of an aging population in the perioperative setting is obvious: the elderly comprises more than 40 percent of all surgical patients in the United States [6]. With the growing popularity of transcatheter aortic valve replacement (TAVR) and other minimally invasive procedures for malignancies, we can only expect to see a further increase in the number of elderly surgical patients. Among the very elderly, there is a threefold increased risk of death, including anesthesia-related deaths [7]; more than 40 percent will experience significant postoperative complications requiring extended intensive care unit (ICU) stays [8,9], with over 50 percent of patients older than age 65 [10] and 22 percent older than age 85 [11] receiving ICU care; and there will be an exponential increase in the use of state-of-the-art life support technologies. In octogenarians, planned surgical admissions to the ICU are associated with 12 and 25 percent ICU and hospital mortality, respectively. However, unplanned surgical admissions to the ICU are associated with a higher 1-year mortality of 67 percent [12]. Even more important, many elderly ICU survivors continue to display excess mortality and a high incidence of post-ICU syndrome following hospital discharge [11,13,14] such that only one-quarter of patients aged 80 and older return to their baseline level of physical function at 1 year [15].



General Characteristics of the Surgical Stress Response


The systemic host response to major surgery can be conceptualized as an acute “controlled trauma.” It is an evolutionarily conserved, complex series of neuroendocrine, metabolic, coagulation, inflammatory, and immune system events that maximize an organism’s ability to heal. This stereotyped multilevel stress response is modified by two categories of influences: host (endogenous) factors, such as age, gender, prior health status, and the genome, and procedural (exogenous) factors, including type, duration, and invasiveness of surgery, anesthetic management, fluid administration, and need for extracorporeal circulation and perioperative analgesia. The interactions between endogenous and exogenous factors ultimately contribute to variability in postoperative outcomes and recovery trajectories [1621] (Figure 12.1). As it will be discussed in greater detail in this chapter, aging is a particular concern because many older surgical patients present with multiple comorbidities, are frail, and have decreased reserves and resilience to cope with surgical stress [2224].





Figure 12.1 Variability in patient responses to perioperative stressors is driven by endogenous and exogenous factors.


(Source: Modified from Podgoreanu et al. [11].)

Classically described by Sir David Cuthbertson, the immune, inflammatory, and metabolic responses to traumatic injury characteristically display three distinct phases – ebb, flow, and recuperation – which were subsequently extrapolated to surgery and the perioperative setting [19,25,26]. During the ebb phase, an intense vasoconstrictive response shunts blood and substrate toward vital organs, geared toward the organism’s survival by reducing posttraumatic energy depletion. This leads to the flow phase, a hypermetabolic state accompanied by increases in physiologic parameters such as cardiac output, minute ventilation, and oxygen consumption, aimed at providing substrate and energy for reparative mechanisms. As recovery occurs, the recuperation phase of the stress response aims to downregulate previously revved-up physiologic processes and return the organism to its preinjury state [17].


It is now appreciated that early drivers of the surgical stress response are sterile local tissue injury, inflammation, afferent nerve cell stimuli, neuroendocrine responses, and endothelial dysfunction, leading to a succession of rapidly cascading events from a local to a systemic phenomenon [27] (Figure 12.2). Damage signals generated from local tissue injury are detected by pattern-recognition receptors on resident and nonresident immune cells, resulting in activation of effector systems, including key proinflammatory cytokines, complex interactions with complement, and acute coagulopathy and hyperfibrinolysis. The primary goal of the acute immune response is wound healing and prevention of pathogen invasion through a restorative process that involves coagulation, inflammation, proliferation, and remodeling. Each phase of repair is complexly orchestrated by immune cells, cytokines, chemokines, changes in gene transcription, and posttranslational modifications.





Figure 12.2 Brief overview of the surgical stress response showing the complex interplay between the central nervous system (CNS) and the mediators released at the time of local tissue injury, resulting in an inflammatory response (HPA = hypothalamic-pituitary axis).


At the same time, local tissue trauma with peripheral nerve injury, activation of nociceptors, and pain during major surgery induce afferent mediators and neurotransmitters to the spinal cord and central nervous system (CNS), activating the hypothalamic-pituitary-adrenal (HPA) axis and the nucleus tractus solitarius and ultimately exacerbating the stressed clinical phenotype in surgical patients through release of stress hormones, altered circadian entrainment, and neuroinflammation. The magnitude of the systemic response is proportional to the degree of surgical insult, with cardiac surgery being an extreme example where the consequences of surgical trauma are compounded by ischemia-reperfusion and physiologic responses to cardiopulmonary bypass [27]. While normally self-limiting and resolving, the stress response to surgical injury can in some instances “overshoot” and exceed the body’s internal tolerances, becoming the primary mechanism driving further perioperative organ injury such as cognitive and cardiac dysfunction, endothelial activation, vascular instability, systemic inflammation, coagulopathy, and possibly immunosuppression with increased risk of infection [2628].


In surgical patients, acute sterile stressors are often followed by secondary insults that may be either sterile or pathogen induced (such as postoperative infection). Consequently, the so-called two-hit model of inflammatory insult has become the commonly accepted paradigm for stressful injury. The components of host response from the initial surgical insult are more clearly defined than those resulting from secondary events. What has become clear is that the cognate signals from either sterile surgical injury or pathogen-induced sources converge on the same recognition/response pathways. Interestingly, while host responses to the initial sterile hit of surgery are modified primarily by the magnitude of the insult and patient-specific (endogenous) factors, including age, exogenous factors such as postoperative management and pathogen virulence more prominently influence the overall responsiveness to secondary insults [29].



Aging Modifies the Host Response to Surgical Injury



Inflammation and Immune System


There is increasing evidence that specific cellular and molecular changes are direct contributors to all manifestations of aging, including altered responses to surgical stress. A dizzying composite of phenotypes of aging include changes in mitochondrial, nuclear, and ribosomal DNA; genomic and chromatin instability; increasing levels of oxidative stress (particularly mitochondrial damage); increasing systemic inflammation, paradoxically concomitant with declining immunocompetence; increasing glycation of proteins, which potentiates inflammation; increasing cellular senescence and loss of telomeres; dysregulation of apoptosis (programmed cell death is over- or underrecruited); impaired protein turnover and reduced removal of damaged and glycated proteins (impaired autophagy); endocrine dyscrasia; and altered stem cell repair and rejuvenation [30].


The relationship between age-related immune competence and confounding illness is more complex than commonly appreciated [31,32]. Epidemiologic data suggest that aging centrally involves changes in both innate and adaptive immunity (in the direction of declining adaptive immunity and compensatory upregulation of innate immunity), combined with increasing systemic inflammation. This proinflammatory heightened innate immune responsiveness in older subjects [33], often in the absence of an inflammatory threat – dubbed inflamm-aging – is characteristically more systemic, chronic, and often asymptomatic [30]. The aging population exhibits increased cytokine markers of low-grade inflammation (e.g., interleukin 6 [IL-6]), and this is associated with increased risk for the development of both infection [34] and other stressful events [35]. Elderly subjects challenged with lipopolysaccharides (LPS) also exhibit a more prolonged febrile response and hypotension [33,36,37] and have prolonged and enhanced cytokine responses during pneumococcal pneumonia [38]. Recently, inflammasome activation has also been mechanistically implicated in inflamm-aging [39]. As a component of the innate immune system, inflammasomes are intracellular structures triggered by the presence of pathogens or cellular stress and are responsible for the maturation of inflammatory cytokines IL-1β and IL-18. Specifically, in individuals 85 years of age and older, elevated and persistent expression of particular inflammasome gene modules correlates with the occurrence of hypertension, arterial stiffness, chronic increases in levels of inflammatory cytokines, metabolic dysfunction, oxidative stress, and all-cause mortality [39]. Although some theories of aging suggest that innate immune response capacity is sustained, at least in part, by the accumulated influences of noxious challenges, such as oxidative stress [40], there may be other interacting factors that promote proinflammatory competence during aging. For instance, the diminution of autonomic variability, in particular of vagal activity, that accompanies advancing age [41] may promote enhanced tumor necrosis factor α (TNF-α) activity during initial stress. By contrast, physical conditioning enhances parasympathetic system signaling and provides a survival advantage to physically fit elderly patients during acute inflammatory stress by attenuating cytokine excesses [29]. Furthermore, age-related imbalances in the composition of gut microbes (the gut microbiome) appear to drive increased intestinal permeability, age-associated inflammation, and decreased macrophage function [42]. With increasing evidence supporting the central role of the microbiome and dysbiosis in outcomes and recovery following surgical stress, sepsis, and critical illness [43], the implications of aging in increasing translocation of microbial pathogens from the intestine to the systemic circulation following shock, ischemia-reperfusion, and hemorrhage cannot be overemphasized [44]. In this regard, the main goal of early enteral nutrition in the postoperative course and critical illness is to promote nonnutritional benefits such as gut integrity and modulation of immunity (immunonutrition) and only later on to address maintenance of lean muscle mass and avoidance of malnutrition. Given our better understanding of the gut microbiome and its implications for surgical stress response and outcomes, the role of perioperative probiotics and other acute nutritional interventions (such as fecal transplantation) to help preserve of restore beneficial intestinal microbial communities is an active area of investigation [44,45]. Meta-analyses found an approximately 40 percent reduction in operative site infections and postoperative sepsis with systematic probiotic use, as well as a consistent reduction in the incidence of multiple-organ-dysfunction syndrome after trauma, but convincing evidence for their therapeutic efficacy is lacking [46].


The process of immunosenescence, or age-related defects in the human immune system, appears to affect principally the adaptive immune response [32,33]. There is a gradual loss of T-cell repertoire from naive CD8 T cells and a reduced response to neoantigens in elderly subjects. Concomitantly, there is a gradual shift from a type 1 cytokine response (IL-2, interferon-gamma [IFN-γ], and TNF-α) toward a type 2 response (IL-4, IL-6, IL-10, and IL-15) that further impairs cell-mediated immunity [29]. The net result is reduced pathogen recognition, chemotaxis, and phagocytosis with an inadequate T-cell antibody response and cytotoxicity.


Two recent studies shed some new light on the role of immune responsiveness in predicting recovery after surgery. By cataloging the detailed phenotypic and functional immune responses to surgical trauma in individual immune cell types using mass cytometry, Gaudilliere et al. identified a uniform surgical immune signature as well as novel predictors of specific aspects of surgical recovery such as functional impairment and pain [47]. Specifically, cell signaling responses, but not cell counts, were linked to recovery. Furthermore, the correlated signaling responses occurred most notably in CD14+ monocytes and dendritic cells, with signaling induced by toll-like receptor 4 (TLR4) activation demonstrating a very strong predictive ability for individual postoperative recovery trajectories. In a follow-up study from the same group, the authors demonstrated that the preoperative “immune phenotype” of individual patients, assessed in vitro as the strength of LPS-induced signaling in CD14+ monocytes in samples collected before surgery, also predicts the speed of postoperative recovery in some domains [48].



Coagulation System


An increasingly procoagulant and prothrombotic milieu arises with aging. Surgical tissue injury results in the release of tissue factor (TF), which, in turn, results in activation of the coagulation cascade via the extrinsic pathway. This leads to clot formation via thrombin generation and fibrin deposition. Uncontrolled activation of tissue factor can result in perioperative coagulopathy [49] There is an age-related increase in plasma concentrations of many coagulation factors. An element of this heightened procoagulant status may reflect the ongoing inflammatory processes mentioned earlier, given some markers, notably factor VIII and fibrinogen. The hemostasis factor affected most by age is the increase in von Willebrand factor. Furthermore, thrombin generation and platelet activation both increase with aging [50]. Increased platelet activation results in upregulation of specific binding to leukocytes that promote a proinflammatory state and inhibit resolution of inflammation. Thus in older people there is an increase in platelet P-selectin expression, proinflammatory leukocyte phenotypes, and platelet-leukocyte interactions [51] that have significant influences in mediating organ injury following surgical stress. This increase in leukocytes bound to platelets has been attributed to a decrease in the biologic activity of nitric oxide and cyclic guanosine monophosphate (cGMP) in platelets [52]. Plasminogen activator inhibitor 1 (PAI-1) is a principal inhibitor of fibrinolysis and is induced in thrombotic, fibrotic, and cardiovascular diseases, which, in turn, primarily afflict the older population. PAI-1 expression is elevated in aged individuals and is significantly upregulated in a variety of pathologies associated with the process of aging, including myocardial and cerebral infarction, atherosclerosis, cardiac and lung fibrosis, metabolic syndromes, cancer, and inflammatory responses. Thus PAI-1 may play a critical role in the development of aging-associated pathologic changes. Intriguingly, PAI-1 is also recognized as a marker and mediator of senescence and a key member of a group of proteins collectively known as the senescence-messaging secretome [53].


Hyperfibrinolysis also can occur as a result of surgical stress and is seen in trauma and cardiac and major spine surgery. Hyperfibrinolysis can result in the need for massive transfusion and may lead to prolonged ICU and hospital lengths of stay and even death [54]. In contrast, postoperative immobility and the systemic inflammation accompanying surgical stress response can lead to an increased risk of postoperative thromboembolism in older adults in the setting of acquired thrombophilia associated with aging [55].



Neuroendocrine-Metabolic Systems


The endocrine response to surgery includes secretion of growth hormone, adrenocorticotropic hormone (ACTH), prolactin, and vasopressin from the pituitary; increased cortisol, catecholamines, and aldosterone from the adrenals; and increased glucagon release and decreased insulin release from the pancreas. There is also a decrease in testosterone, estrogen, and triiodothyronine following surgery. The complex interplay between these hormones induces a catabolic state characterized by insulin resistance, hyperglycemia, lipolysis, and skeletal muscle wasting resulting in a negative nitrogen balance. The magnitude of these catabolic changes is likely not very different in the elderly compared with young adults, but elderly patients have reduced muscle mass at the outset and are more prone to protein catabolism [56]. Skeletal muscle wasting can result in frailty and delayed return to baseline functional status [57], need for discharge to intermediate care institutions such as nursing facilities, and worst of all, death.


Though, effect of age on responses to the initial surgical insult are somewhat described in the literature, our understanding of the influence of age as a modifier of subsequent insults and second hits (e.g., postoperative infection) and its impact on outcome trajectories remains extremely limited. Most models of infection pathogenesis, including postoperative infection, do not incorporate host stress. It is now well established that following acute insults to the host such as surgery, trauma, myocardial infarction, or burn surgery, the intestinal microbiota decreases in abundance and function, and a virulent and resistant pathobiome emerges, rendering the stressed host more vulnerable to infection [58]. This is particularly complex because the intervention or treatment-related effects appear to interact with endogenous determinants such as age in the context of prolonged postoperative stress and systemic inflammatory response. Age-related diminutions of immune and endocrine functions [59] and autonomic signal attenuation all may contribute to adverse outcomes among elderly patients. There is currently limited insight across the age spectrum as to how prominently these endogenous factors contribute to loss of adaptability during prolonged stress [29].



Geroscience Concepts Applied to Surgical Stress Response


With the underlying rationale that aging itself is the predominant risk factor for most diseases and conditions that limit health life expectancy or “healthspan,” a new field of geroscience is seeking to understand the integrated aging-related changes in biologic systems and develop novel multidisease preventative and therapeutic approaches. Kennedy et al. have recently described seven highly intertwined processes driving aging (hence termed the pillars of aging) – including adaptation to stress, epigenetics, inflammation, macromolecular damage, metabolism, proteostasis, and stem cells and regeneration [60]. Importantly, understanding the interplay among these seven pillars is critical and should inform our approaches to study perioperative stress responses and how they may underlie surgical resilience across organ systems. Several key concepts pertaining to aging as a modifier of surgical stress response will be outlined next – these include allostasis and allostatic load, hormesis, frailty, and resilience.



Allostasis, Allostatic Load, and Surgical Stress Response


Allostasis, a concept introduced by Sterling and Eyer in 1988, describes the effect of stressors on an organism. It refers to the organism’s ability to respond to stressors or external stimuli with continuous change in an effort to maintain dynamic equilibrium. The goal of allostasis is preservation of somatic stability. When stress is perceived by the organism, it results in the activation of the hypothalamic-pituitary-adrenal (HPA) axis with a resulting increase in serum cortisol, norepinephrine, and epinephrine. When the stressor dissipates, this response is turned off, and the serum cortisol and other stress hormones return to baseline in an efficient manner. As the organism ages, the allostatic response becomes impaired, and there may be an exaggerated or inadequate peak response, as well as a sluggish return to baseline [61,62]. Repeated and prolonged exposure of the organism to these mediators can have deleterious effects, resulting in a buildup of wear and tear, a term described as allostatic load. The allostatic load therefore is the price the organism pays for adaptation to physiologic stressors [63]. The original primary mediators of allostatic load are catecholamines, cortisol, and dihydroepiandrosterone sulfate (DHEA-S). Other hormones and proteins were later included to assess allostatic load, such as insulin-like growth factor 1 (IGF-1), IL-6, serotonin, and C-reactive protein (CRP) [64,65]. These primary mediators result in physiologic changes and outcomes, including elevated systolic and diastolic blood pressure, blood glucose, lipid levels, and measures of body habitus, including waist-hip ratio. These are termed secondary mediators of stress. The eventual outcome of allostatic load is an increased propensity to develop chronic diseases, including atherosclerosis and diabetes mellitus.


Four types of allostatic load have been described as being important to the well-being of the individual. First, in the case of frequent exposures to stress such as repeated episodes of uncontrolled hypertension, the susceptible elderly individual can experience adverse outcomes such as a myocardial infarction or hemorrhagic stroke. Second, when exposed to similar stressors, there is failure of adaptation of the stress response resulting in prolonged exposure to stress mediators. The third type of allostatic load revolves around the inability of the individual to terminate the allostatic response once the stressful stimulus has subsided. An example of this type of allostatic load is the decreased bone mineral density in chronically depressed women, who continue to have an elevated serum cortisol level, which, in turn, inhibits new bone formation. In the fourth type of allostatic load, there is an inadequate allostatic response that then leads to hyperactivity of inflammatory cytokines, which are typically suppressed by glucocorticoids. This typically manifests as an increased susceptibility to autoimmune and inflammatory diseases [61].


As an organism ages, changes occur in many organ systems that are linked to the development of chronic degenerative diseases. One important process is aging of the immune system, manifested as an overall increase in proinflammatory cytokines such as IL-6, TNF-α, CRP, and IL-1β, with an accompanying reduction in anti-inflammatory cytokines such as IL-10. This “inflammaging” has been implicated in the pathogenesis of diabetes, dementia, and cardiovascular diseases and is associated with a higher mortality [66]. It is interesting to note that the cytokine profile of centenarians remains similar to that of young adults, supporting the idea that “inflammaging” is associated with decreased longevity [67].


Telomere length is another marker of allostatic load. Telomeres are tandemly repeating short DNA strands at the ends of eukaryotic chromosomes. Telomeres and their associated proteins are responsible for protection of the genomic DNA. At the end of each cell division, telomeres shorten in length, leaving the cell more vulnerable to genomic instability. The enzyme telomerase can add DNA repeating sequences at the end of the chromosome to compensate for attrition [68]. Shorter telomere length is associated with risk factors for cardiovascular disease and may be a predictor of mortality in patients with chronic kidney disease, Alzheimer’s disease, and stroke. Shortened telomere length is seen in people exposed to chronic stress such as caregivers [69]. In postmenopausal women caring for patients with dementia who were exposed to an acute stressor, a higher cortisol level associated with the acute stressor was associated with shorter telomeres. The long-term consequence of repeated high-stress exposure is likely accelerated cellular senescence [70].



Hormesis as a Potential Modifier of Surgical Stress Response in the Elderly


Hormesis, a term used most extensively in the fields of toxicology and radiation biology, refers to a generalized, evolutionarily conserved biphasic pattern of adaptive cellular responses to stressors whereby a beneficial effect (e.g., stress tolerance, improved “healthspan,” or longevity) results from exposure to low doses of agents or intensities of environmental factors that are otherwise toxic or lethal when given at higher concentrations or intensities. First described in 1946, hormetic responses were largely ignored in biomedical research until the discovery that transient heat stress invoked the appearance of a protected phenotype in cells, tissues, or organisms such that they were able to withstand the harmful effects induced by otherwise lethal stressors. Interest in this area was boosted to new heights with the discovery that antecedent exposure to short bouts of sublethal ischemia followed by reperfusion conferred cardioprotection in hearts subsequently exposed to lethal ischemia-reperfusion (I/R), a phenomenon termed ischemic preconditioning (IPC). Subsequent to that came the discoveries that the heart and other organs could be protected by subjecting distant organs or tissues (e.g., the small intestine, kidneys, and limbs) to IPC – which is referred to as remote, interorgan, or distant site ischemic preconditioning (RIPC) – or by using gradual and hemodynamically controlled reperfusion (multiple short bouts of I/R) to salvage previously ischemic but viable myocardium (a phenomenon designated ischemic postconditioning) [71]. More recently, the neuroprotective effects of cold-shock response have been reported. A protein released during hypothermia has been found to affect the progression of neurodegenerative disease in mice by sparing neurons from death and preserving synaptic plasticity [72]. These early findings support the concept that adaptive intrinsic pleiotropic cell survival programs can be activated by a variety of mildly noxious stimuli or pharmacologic agents to confer protection against the deleterious effects of I/R, which have tremendous translational relevance for surgical stress response and perioperative organ protection. In addition to heat and cold-shock response, examples of such conserved prosurvival and longevity hormetic inducible pathways include mitochondrial responses to increased oxidative stress, the unfolded protein response to endoplasmic reticulum stress, immunomodulation of signaling via TLR4, and metabolic control in response to diet restriction, caloric restriction, exercise, DNA repair/genetic stability in response to heat and radiation [73], and hibernation [74]. A prosurvival pathway shared by intermittent fasting, caloric restriction, exercise, and hibernation involves activation of a family of protein deacetylases called sirtuins (chief among which is sirtuin-3), which results in both antioxidant and metabolic reprogramming hormetic effects [74,75]. Consequently, candidate hormetic mimetics are key regulators of such prosurvival pathways and include stimulated DNA repair, endogenous antioxidants, restoration of protein structure and function, energy endurance, immunoregulation, and systemic and metabolic responses to ischemia. Several examples include hormetic heat mimetics (molecular chaperones such as HSP70, ethanol, and quercetin) and diet-restriction mimetics (metformin, resveratrol, and PPAR-delta agonists). Several points of intervention exist for limiting postischemic tissue injury that may be targeted by the adaptive endogenous programs invoked by conditioning stimuli. The mechanistic rationale for developing pharmacologic conditioning strategies that mimic the remarkably powerful effects of ischemic conditioning is sound. Lifestyle interventions, including exercise, caloric restriction or intermittent fasting, dietary manipulations, and consumption of alcoholic beverages and/or phytochemicals, may induce hormetic responses – and are relevant to perioperative management. One such area of controversy surrounds preoperative nutritional recommendations, particularly in elderly surgical patients. The current trend in preoperative nutrition away from preoperative fasting and toward carbohydrate loading embedded in enhanced recovery after surgery (ERAS) nutritional guidelines has to be counterbalanced against evidence that short-term dietary restriction and fasting (or pharmacological diet-restriction mimetics) preconditions against surgical stress via both upstream nutrient-sensing mechanisms and effector mechanisms implicating increased prosurvival insulin signaling and elevated endogenous hydrogen sulfite production [76].


Despite promising preclinical studies, the efficacy of many hormetic interventions has proven ineffective in the presence of aging and cardiovascular risk factors and/or is adversely affected by coincident use of cardiovascular drugs, anesthetics (especially propofol), and opioids. Obstacles to its practical application in patients remain, as evidenced by the recent failures of remote ischemic preconditioning (RIPC) randomized, controlled trials to reduce mortality and morbidity in cardiac surgery [77]. Thus, uncovering the mechanisms responsible for such impaired responses to preconditioning stimuli and differentiating hormesis from toxic stress will be imperative to successful clinical application of hormetic interventions in relevant surgical patient populations, including the elderly.



Frailty as a Modifiable Predictor of Postoperative Outcomes in Older Adults


Frailty is defined as a multidimensional syndrome characterized by progressive reduction in physical reserve, energy, cognitive reserve, and an overall lack of physiologic reserve across several organ systems that results in a state of vulnerability by impairing an individual’s ability to cope with stressors. It is prevalent among the elderly and a known risk factor for falls, institutionalization, and morbidity [78]. Clinical frailty in older adults is associated with worse perioperative outcomes across many surgical subspecialties. The frail elderly patient is more likely to experience serious complications [7981], prolonged hospital stay [82], higher 30-day readmission rate following elective cardiac and noncardiac surgery [79], loss of independent activity with increased discharge to an institutional facility [83], and reduced 1-year survival [84]. Makary et al. measured frailty prospectively in patients older than age 65 presenting for elective surgery [82] and found frail patients to have more than 2.5-fold higher risk of complications compared with nonfrail patients. They were also more likely to have increased length of stay and had a higher likelihood of discharge to an assisted-living facility [82,85]. Moreover, preexisting cognitive impairment is emerging as a predictor of poor outcomes following surgical stress in seniors. In subjects older than age 65, the prevalence of dementia is estimated at 5 to 10 percent, and that of mild cognitive impairment, a frequently undetected problem, is as high as 35 to 50 percent. Importantly, preexisting cognitive impairment is a predictor and modifier of common cognitive complications of surgery – namely postoperative delirium (20–80 percent incidence) and postoperative cognitive dysfunction (12–15 percent incidence) [86]. The morbidity and higher economic burden of frailty call for a simplified preoperative assessment and adequate optimization of all elderly patients undergoing surgery (see Chapter 15). Indeed, a comprehensive geriatric assessment may be a stronger predictor of postoperative outcomes in this patient population than the time-honored American Society of Anesthesiology score [87].


To optimize the quality of care for elderly surgical patients, the American College of Surgery and the American Geriatric Society developed best practice guidelines for perioperative management of geriatric patients in 2012 [88]. These guidelines focus on problems specific to the elderly surgical patient, including frailty, cognitive dysfunction, and polypharmacy. They also include recommendations for assessment of nutritional status, social support, and decision-making capacity. The group compiled the recommendations in the form of a checklist (Table 12.1) that would enable a thorough and optimal preoperative workup and identify high-risk patients for further assessment. Surgery departments at various institutions have adopted and modified these guidelines to fit their patient populations. Wozniak et al. implemented these guidelines at the Sinai Center for Geriatric Surgery and modified them by including a hearing screen, oral screen, performance status, Charlson Comorbidity Index, pressure ulcer risk, and caregiver burden interview [89]. It was performed by an experienced nurse practitioner and added 20 minutes to their standard preoperative assessment. Other surgical specialties, including urology, have also acknowledged the surgical risk of an elderly adult and emphasized the importance of achieving good functional outcomes [90], which are incredibly important to elderly surgical patients. While no specific practice guidelines aimed at geriatric surgical patients have been issued by the American Society of Anesthesiology, there is a growing body of literature addressing some of the current controversies in this arena, including choice of anesthesia and prevention of postoperative delirium [91].


Oct 24, 2020 | Posted by in CRITICAL CARE | Comments Off on Chapter 12 – Stress Response to Surgery in the Elderly
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