Disease (νόσος) is not only suffering (πάθος): it is also toil (πόνος).
Introduction
Reacting when facing a threat to homeostasis is a common and primeval pattern of behavior in living beings, that involves a number of complex endocrine and metabolic functions. The reaction to surgical stress is an example of this primordial behaviour. Stress response is also the pathway along which both aging and illnesses occur.
Surgery for which older patients are scheduled can be more or less invasive and more or less demanding in terms of energy expenditure, thus causing stressing effects that go beyond that of the underlying surgical condition. On the other hand, aging processes, the way in which functional reserves are affected by aging, and the number and severity of associated conditions substantially modulate the effectiveness of the individual response to surgical aggression. When intense and prolonged external stressors superimpose on a state of vulnerability induced by aging processes and comorbidity, severe post-operative complications may originate, such as myocardial ischemia, post-operative delirium, respiratory insufficiency, deep metabolic alterations, intense deconditioning and consequent functional impairment.
As a consequence of both the stress intensity and duration and the effectiveness of defensive reaction, different trajectories are possible.
Stress response: stages and determinants
The concept of stress as general adaptation syndrome (GAS) was defined by Seyle in the last century (Seyle 1936). Since its definition, the conceptual model of stress as GAS has provided a paradigm for interpreting and understanding this complex defensive reaction under multiple aspects.
Essentially, in an attempt to counteract aggression, the organism starts providing extraordinary performance, continues opposing strong resistance and, when the aggression persists for too long, ends up self-harming.
Stages of stress
Independently from the nature of the stressor applied, Seyle individuated a typical sequence in biological answers to stress: alarm, resistance and exhaustion. Important endocrine mechanisms are involved.
Alarm
During the “alarm” stage, the stressor is recognized as a threat. Stress hormones are produced in response, such as adrenaline, noradrenaline and cortisol. This enables the body to perform extraordinary activities, but at the cost of heavy energy consumption and consequent tissue damage.
Resistance
Resistance stage is characterized by the need to repairing the tissue damage; with this aim, catecholamine release is reduced and other hormonal responses are elicited involving adrenocorticotropic (ACTH) and growth hormones (GH), but this makes defence mechanisms less effective.
Exhaustion
If the stressor persists, the body continues to fight, but at reduced intensity. Under the influence of insulin and glucagon, energetic substrates are ineffectively utilized or destroyed. At the same time, the tissue damage induced by the stressor elicits a strong inflammatory response, which further increases catabolic processes. As the stress continues, the body loses its ability to fight because the adaptive mechanisms are all exhausted; at this stage, the situation risks becoming irreversible.
Determinants of Stress
The intensity and effectiveness of stress response are widely influenced by both the characteristics of stressor stimuli and those of the individual to which the stress is applied.
Type of Tissue Damage
The first determinant of the reaction is the type of tissue damage produced by the stressor itself. In reference to surgical stress, the invasiveness of the procedure, its duration and the consequent inflammatory response are the most important; laparoscopic versus open surgery evokes a lighter stress, a long-lasting procedure is heavier than a shorter one, coronary artery bypass with extracorporeal circulation is accompanied by a more intense inflammatory response when compared to off-pump procedures.
In addition, pain stimuli reaching the hypothalamus are another important source of stress; this underlines the important role exerted by anesthesia techniques in reducing the endocrine and metabolic response to surgical aggression.
Individual Resistance to Stress
The second determinant of the stress reaction is represented by effectiveness and duration of the individual response to aggression, which is influenced by functional reserves and possible associated conditions. As aging affects both, stress response in the elderly has reduced effectiveness when compared with that observed in younger subjects. Furthermore, as this reduction is proportional to the degree in which reserves are narrowed, comorbid and frail older subjects can oppose aggression with only a poor adaptive response.
Frailty (see Chapter 2) and malnutrition (see Chapter 13) have been shown in many studies to dramatically reduce the capacity to cope with surgical stress.
The Endocrine, Metabolic And Inflammatory Response to Surgery
The postsurgical stress response is a complex systemic reaction to surgical trauma (Bruder and Dumont 1999, Toft and Tønnesen 2008, Carli 2015, Watt et al. 2015).
Together with those mentioned above, several factors modulate this response, especially in the elderly: preoperative fasting, immobility, pain, anxiety, tissue destruction due to the procedure and fluid loss. Together, these stimuli trigger a systemic reaction caused by hormonal, immunological and metabolic mediators, and also a hemodynamic response. ACTH, catecholamines and cortisol are prominent in the hormonal response, but glucagon, GH, aldosterone and AVP are also released after surgical trauma. This hormonal release is provoked by hypothalamic–pituitary–adrenal (HPA) axis activation subsequent to the neurogenic input derived from the damaged tissues. After surgery, a catabolic and hypermetabolic state occurs, with breakdown of muscle and fat tissue, and peripheral insulin resistance.
Endocrine response
A key element in stress response is HPA axis activation. Tissue trauma has a pivotal role in this response, as the simultaneous effects of nociceptive ascendant stimuli and cytokines produced in situ induce the production of pituitary hormones. As a consequence of this neuroendocrine stimulation, plasma levels of catecholamines, glucocorticoids and GH are increased, with consequent hyperglycemia; at the same time, the production of both aldosterone and ADH also increases. The mechanism sustaining this stimulation is in part neuromediated (see Figure 31.1).
Figure 31.1 Organs and systems involved in the stress response.
Catecholamines
A relevant feature of surgical stress response is early sympathetic activation, with catecholamine release from the adrenal medulla that significantly stimulates the cardiovascular system and augments the oxygen consumption of the heart. This sympathetic activation is originated by the hypothalamus (descendant sympathetic activation).
Tachycardia, increased blood pressure and increased oxygen consumption are observed in the cardiovascular system; metabolic effects are increased hepatic gluconeogenesis and inhibition of insulin incretion. Cardiovascular diseases and anemia may be detrimental to the maintenance of proper O2 delivery to the cardiac tissue in the elderly, and may lead to arrhythmias and ischemia.
Plasma levels of noradrenaline reflect the sympathetic response to stress; however, they only provide an imprecise measure of the stress, as they reflect the equilibrium between noradrenaline secretion and reuptake.
Glucocorticoids
Under pituitary stimulation and consequent increase in ACTH secretion, increased production of glucocorticoids takes place. Cortisol is essential in modulating the hormone stress response by three different mechanisms: first, it increases the availability of circulating glucose, which is in part beneficial as it contributes to cerebral processes supply; second, it enhances catecholamine action at the cardiovascular level, increasing cardiac performance, and last, it limits the inflammatory reaction.
A correlation has been demonstrated between the surgical trauma and both the duration and levels of ACTH and cortisol production. After trauma, cortisol plasma levels increase for 2 hours in a measure that is proportional to the severity of the trauma itself.
Growth Hormone and IGF-1
Growth hormone (GH) has both catabolic and anabolic effects: it promotes hyperglycemia and lipolysis with the aim of increasing energetic resources, and it also promotes entry of both proteins and amino acids into cells, with an anabolic effect.
Its catabolic effect is increased by the action of insulin-like growth factor 1 (IGF-1). This hormone, the structure of which is similar to that of insulin, has anabolic properties; however, after trauma its activity is impaired and catabolic processes are further promoted. After surgery, GH plasma levels increase proportionally to the tissue trauma.
Insulin and glucagon
After surgery or trauma aggression, insulin production first decreases and then increases for days. In response to insulin incretion, initial hypoglycemia is observed, followed by hyperglycemia, resistance to insulin and reduced tolerance to glucose, which is, at least in part, related to increased production of glucagon, adrenaline and cortisol. Global ineffective tissue utilization of glucose is observed, probably also due to an alteration in cell insulin receptors.
Metabolic response
Postaggression metabolism is characterized by ineffectiveness of energy production and exaggerated endogenous catabolism. Hyperglycemia, resistance to insulin and reduced tolerance to glucose are all observed; the final result is that circulating glucose is increased, although it cannot be utilized as energy source. After trauma or surgery, glycemia significantly increases, even after administration of a reduced glucose dosage; consequently – except for the rare situations where hypoglycemia may occur – a perioperative administration of glucose is not advisable and should only be made with monitoring of glycemia.
As a consequence of the ineffectiveness in glucide metabolism, lipolysis is stimulated. However, the futile cycling also occurring in this metabolic pathway further dissipates energy production. All in all, glucide and lipid turnover after trauma are both increased, but with poor energy production.
At this point, protein metabolism is put in place, with mobilization and increased turnover of energy substrates at the muscular level. Increased muscle catabolism is observed, with concurrent recycling of amino acids in gluconeogenesis. Liver production of nutritional proteins is reduced, whereas inflammatory protein production, such as fibrinogen and C-reactive protein, increases. Globally, as proteolysis is increased by about 50% and protein synthesis decreases by about 30%, the nitrogen balance becomes negative. In practical terms, a 20-30 g urinary excretion of nitrogen per day is observed after severe trauma. It is worthwhile to remark that a net loss of 20 g of nitrogen per day corresponds to 120 g of protein and has been estimated to correspond to a loss of 600 g of muscle tissue.
Overall, a sympathetic-mediated hyper-metabolic and catabolic status establishes, accompanied by hyperglycemia, increased protein catabolism, lipolysis, increased incretion of antidiuretic hormone with reduced urine production, vasoconstriction, tachycardia and increased oxygen consumption.
Immunological activation
Immunological activation is another hallmark of the surgical stress response, with both lymphocytosis and cytokine release of variable degree, leading to a systemic inflammatory response. It has been demonstrated that interleukin 6 (IL-6) levels correlate with the severity of the surgical trauma; other inflammatory mediators are also released, such as IL-1, IL-8, tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and others.
In the postoperative days, a reduction in the immune function may be observed; this may lead to an increased susceptibility to nosocomial infection. Consequences in the elderly can be more severe, as a condition of immune-senescence often coexists.
Surgical Stress in Older Patients
Usually, in elective and non-complicated surgeries, these hormonal responses last about 24–72 hours, and “healthy” elderly patients without major comorbidities can tolerate them and implement the required amount of energy. Therefore, in low-risk surgical procedures, consequences of the endocrine-metabolic response are not correlated with the patient’s chronological age, but can mostly be ascribed to the pre-existing metabolic status.
Conversely, in more invasive and demolitive procedures, the stress response continues for at least 7 days, with a self-maintaining systemic inflammatory state and a considerable detrimental protein catabolism; this situation can be too demanding for older, comorbid and functionally impaired subjects, and postoperative complications frequently occur.
Cardiovascular Complications
With aging, a number of pathophysiological changes occur at the cardiovascular level, such as diminished arterial and left ventricle compliance, impaired vasoconstriction, altered autonomic function, increased sensitivity to catecholamine and decreased baroreflex sensitivity. All these factors may impair the maintenance of cardiovascular homeostasis during acute surgical stress (see Chapter 1).
When occurring in such a basal situation, the increased oxygen demand consequent to prolonged sympathetic stimulation induced by lengthy surgery may not be adequately compensated. In addition, direct activation of cardiac sympathetic nerves may trigger coronary constriction, whereas circulating catecholamine may induce a state of hyper-coagulation. Postoperative parasympathetic nervous activity diminishes at the same time, mostly during the night after surgery (Tan et al. 2017).
Intraoperative acute myocardial infarction, myocardial ischemia, acute cardiac failure and other postoperative ischemic events can be triggered by this chain of events. This is also the rationale supporting optimal intraoperative analgesia and perioperative β-blocker administration (see Chapter 36).
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