Biology of the stress response

Pearls

•

The stress response is a universal, stereotypical, and integrated neurogenic, endocrine, inflammatory, and metabolic systems response with multiple feed-forward and feed-backward modulation signaling designed to maximize host survival.
•

The brain is the paramount organ of the stress response, as it determines what constitutes stress as well as the appropriate type and extent of reaction. Multiple afferent stress signals are integrated at the level of the hypothalamus, which coordinates the subsequent response.
•

Excessive or prolonged stress stimuli can precipitate a dysregulated stress response.
•

A complicated critical illness course may reflect elements of an ongoing stress response manifested as protein catabolism with poor wound healing and diffuse weakness and immunosuppression associated with hospital-acquired infections.
•

Therapeutic intervention must respect physiologic alterations necessary to accommodate the stress response. Pursuing “normal” values as physiologic target parameters may ultimately be counterproductive.

Humans demonstrate tremendous adaptability that has allowed them to inhabit and flourish in widely variable climates and environments. The resilience of human physiology has permitted the achievement of tremendous feats of endurance and survival under the most inhospitable circumstances. The biological systems that facilitate detection and response to stresses in the internal and external environments have been crucial to human success as a species. These same systems are at play in the intensive care unit (ICU) when children confront life-threatening conditions and affect how they respond to both injury and treatment. This chapter addresses the nature and function of the various physiologic systems that comprise the stress response as it applies to critical illness.

Definitions and background

For the purpose of this discussion, stress is defined as any force or influence on an organism that perturbs its usual state of equilibrium. Strain is the magnitude of deviation from baseline norms that the organism experiences in response to the inciting stressor. Resilience is the organism’s ability to adapt to or cope with the stresses and strains imposed on it. The process of host adaptation to an environmental, biological, or psychosocial insult is referred to as the stress response .

Living organisms require a relatively high degree of stability to maintain vital functions. Enzymes perform optimally at specific temperatures and hydrogen ion concentrations. Action potentials are promulgated along cell membranes based on a narrow range of ionic concentrations. Two competing principles relate to stability: homeostasis and allostasis. Homeostasis is the process of achieving stability through maintaining systemic variables within a fairly narrow dynamic range. Allostasis is the process of achieving stability through physiologic or behavioral changes. ^, Whereas normal physiology imposes homeostatic forces on our vital function to maintain constancy within an optimal range, the stress response pursues physiologic change to adapt to otherwise fatal stressors. This allostatic response is designed to be temporary so that once the stressor has resolved, the organism can return to baseline physiologic function.

To illustrate this concept, consider an appropriately engineered skyscraper built in an earthquake-prone area. Rising high above the earth and bearing thousands of tons of steel, concrete, and glass, the structure normally moves very little. However, in the event of an earthquake, the building is engineered to tolerate a significant amount of sway to avoid structural damage and collapse. The physical attributes that allow the building to bend without breaking comprise its resilience. This resilience accommodates the strain imposed by the stress of the earthquake. Likewise, the stress response in humans provides resilience to adapt to various stressors around and within us without catastrophic physiologic decompensation. Strain is evident in the physiologic changes undertaken in response to stress that allow survival.

Stress system primary elements

The stress response comprises a universal, stereotypical, and integrated set of biological activities that respond to both internal and external stimuli. The stress system has an afferent, sensory limb allowing it to detect stress signals as well as an efferent, effector limb, which brings about physiologic responses to address the stressors. Fig. 80.1 depicts the stress system as an integrated network of neurogenic, endocrine, inflammatory, and metabolic subsystems that interact through multiple feed-forward and feed-backward signaling channels. Initiation and regulation of the stress response occurs in the brain. In this regard, the brain is the paramount organ of the stress response, as it determines what constitutes stress as well as the appropriate type and extent of reaction.

Stress response

The effector stress response can be compartmentalized into central, peripheral, and cellular components. The interaction of all of these subsystems is coordinated to achieve three primary objectives: (1) maintain perfusion of the heart, brain, and other vital organs; (2) deploy energy resources from body fuel storage depots; and (3) optimize adenosine triphosphate availability to vital cells and tissues at the expense of nonessential tissues.

Central activation and integration

A multitude of signals may activate a stress response, including physical, physiologic, biochemical, and sensory stimuli, as well as psychological distress. ^, Common stressors in critical illness include hypoperfusion, hypoxia, tissue injury, and infection. Hypotension is sensed as a decreased stretch of baroreceptors located in the carotid sinus and aortic arch. Peripheral chemoreceptors in the carotid and aortic bodies sense oxygen levels. Tissue injury and infection are detected by the innate immune system that recognizes both pathogen-associated molecular patterns and host damage-associated molecular patterns that may occur as a result of direct tissue injury. ^, Innate immune cells elaborate cytokines that signal stress to the rest of the body. These cytokines and various other soluble mediators provide afferent signaling to the brain. Additionally, the vagus nerve facilitates bidirectional communication between the brain and immune system as well as the various organs that it innervates. Multiple afferent stress signals are integrated at the level of the hypothalamus, where the stress response is initiated. ^, ^,

Peripheral responses

Efferent signaling from the brain involves descending neuroendocrine and autonomic pathways that ultimately control hemodynamic, endocrine, immune, and metabolic aspects of the stress response. Activation of the stress system triggers release of the corticotropin-releasing hormone from the hypothalamus, which induces release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH, in turn, stimulates the adrenal cortex to produce cortisol, which is essential to the stress response to critical illness and injury. Cortisol affects the transcription of approximately 25% of the entire genome, mediating a wide range of hemodynamic, immunologic, and metabolic actions. Detailed discussion of cortisol metabolism in critical illness is provided in Chapter 84 .

The parvicellular neurons of the hypothalamus secrete thyrotropin releasing hormone, which acts on the anterior pituitary gland to release thyroid-stimulating hormone (TSH). Early in critical illness, TSH and T ₄ levels increase transiently, but this is associated peripherally with a rapid decline in T ₃ levels and an increase in rT ₃ levels due to alterations in peripheral conversion of T ₄ . Elevated TSH levels quickly return to normal but T ₃ levels remain low, resulting in the sick-euthyroid syndrome, which is discussed in more detail in Chapter 84 .

Activation of the stress response also causes anterior pituitary growth hormone release in response to hypothalamic growth hormone–releasing hormone secretion. Prolactin production, which facilitates the immune response by augmenting lymphocyte activation, is under tonic inhibition from dopaminergic neurons in the hypothalamus. Its secretion is enhanced by decreased dopaminergic signaling from the hypothalamus under stress.

Vasopressin is another early response to stress that is crucial to survival in critical illness. ^, The magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei project their axons through the pituitary stalk and onto the capillary bed of the posterior pituitary gland where they release vasopressin directly into the circulation. Vasopressin induces peripheral vasoconstriction to counteract hypotension and increases renal water reabsorption to maintain or restore circulating blood volume, which is particularly important in shock states.

Receiving inputs from the hypothalamus and limbic system, the autonomic nervous system, is also activated in the stress response. The locus ceruleus, located in the posterior area of the rostral pons, is an important center of sympathetic outflow, which results in increased arousal, concentration, and alertness. Additionally, noradrenergic signals originating in the locus ceruleus descend through autonomic efferent pathways to stimulate a peripheral sympathetic response. Simultaneously, a parasympathetic response is initiated in order to balance the magnitude of initial proinflammatory aspects of the stress response. This balancing of the stress response has been called the inflammatory reflex . Increased vagal efferent signaling suppresses peripheral cytokine release through macrophage nicotinic receptors and the cholinergic antiinflammatory pathway.

The peripheral effects of the stress response are seen most quickly with activation of the sympathetic arm of the autonomic nervous system. The heart, blood vessels, bronchioles, and most endocrine cells are richly innervated with adrenergic nerve fibers. Norepinephrine release from sympathetic axon terminals in the adrenal medulla stimulates secretion of epinephrine into the blood. The combination of circulating epinephrine and release of norepinephrine from adrenergic neurons increases heart rate and blood pressure, augmenting cardiac output and maintaining perfusion to vital organs.

An important arm of the peripheral stress response system that works in concert with the adrenergic and vasopressin arms is the renin-angiotensin-aldosterone system. The primary purpose of this system is to help regulate sodium and water balance in the body. Renin is released from the juxtaglomerular granular cells of the afferent renal arterioles in the setting of (1) decreased afferent renal arteriole blood pressure, (2) sympathetic stimulation from noradrenergic autonomic input, and (3) decreased sodium flow through the nephron. Renin release results in the generation of angiotensin II, which is a potent vasoconstrictor that stimulates secretion of aldosterone from the adrenal cortex. Aldosterone increases sodium and water reabsorption in the kidneys, augmenting intravascular volume.

Counterregulatory hormones mediate important aspects of the stress response. Adrenergic stimulation triggers the release of glucagon from α-cells in the pancreatic islets while inhibiting the release of insulin from the β-cells. This effect of the sympathetic response has important metabolic ramifications. Glucagon—in concert with cortisol, growth hormone, and circulating epinephrine—initiates widespread catabolic mechanisms that affect tissues throughout the body. The initiation of this catabolic state mobilizes energetic substrate and molecular building blocks for the highly resource-intensive functions of the stress response.

These counterregulatory hormones stimulate hepatic gluconeogenesis and glycogenolysis, thereby increasing blood glucose levels. Peripheral tissues become resistant to the effects of insulin under the influence of glucagon and growth hormone, which leads to critical illness–associated hyperglycemia. This phenomenon, associated with a decrease in the thyroid hormone T ₃ , reduces the metabolism and energy consumption of nonessential tissues, allowing circulating glucose to be used primarily by processes directly involved in immune response and tissue repair.

In adipose tissue, epinephrine and glucagon activate hormone-sensitive lipase, which catalyzes the first step in triglyceride hydrolysis and liberates free fatty acids and glycerol into the circulation. Glycerol is used as a gluconeogenic substrate in the liver, and the fatty acids are taken up by metabolically active cells to provide energy for essential functions or to provide structural components necessary for cellular growth and division. Leukocytes, for example, undergo rapid clonal expansion in inflammatory states and require abundant lipid substrate for both activation and production of cell membranes. ^,

Skeletal muscle is also significantly affected by the stress-imposed catabolic state. Epinephrine, cortisol, and glucagon initiate glycogenolysis in the muscle. However, because myocytes lack the glucose-6-phosphatase enzyme expressed by the liver, they cannot release glucose into the bloodstream. Any glucose liberated from glycogen that is not used for the energy demands of the myocyte is converted to lactate and released into the bloodstream. Indeed, significant β-adrenergic stimulation (e.g., exogenous epinephrine) can induce the production of lactate even in the presence of adequate oxygen by inhibiting pyruvate decarboxylase, the final step of glycolysis that converts pyruvate into acetyl-CoA for incorporation in the mitochondrial citric acid cycle. Some tissues, such as the myocardium, can use lactate as a primary energy source, but most of the lactate is taken up by the liver and used as gluconeogenic substrate. Protein catabolism in the muscle releases amino acids into the circulation, which are also used by the liver for gluconeogenesis and for the elaboration of acute-phase proteins necessary for the stress response. The protein catabolism in muscle tissues is significantly enhanced by cytokine stimulation from the inflammatory response.

Cellular responses

The stress response extends down through organismal and tissue hierarchies to individual cells, which also employ conserved, stereotypical allostatic mechanisms to promote survival in the face of maladaptive environmental changes. These include the cellular integrated stress response, which deactivates protein translation for the majority of cellular messenger ribonucleic acids (mRNAs) but allows translation of transcripts involved with cell survival. The deoxyribonucleic acid (DNA) damage response activates systems to stop cell growth and division and to repair altered or disrupted nucleotide sequences. The unfolded protein response seeks to resolve the accumulation of unfolded or misfolded polypeptides at the endoplasmic reticulum. Cells can also enter a catabolic state by activating autophagy, a process that breaks down damaged or dysfunctional organelles for recycling or to provide energy for other essential survival mechanisms.

Mitochondria are central to cellular stress responses because they generate the energy necessary to fuel survival mechanisms and because they form a central node within the intracellular danger signaling system. ^, Beyond maintaining cellular respiration, mitochondrial function determines cell fate in the face of significant stressors. If strain on the cell exceeds its capacity of resilience, the mitochondria direct the cell toward senescence (a state of functional arrest and metabolic hibernation) or programmed cell death (apoptosis). These end points may contribute to mechanisms of the multiple-organ dysfunction syndrome (see Chapter 111 ).

Stress response in critical illness

Critical illness reflects the ultimate manifestation of severe stress. Three phases of the stress response may be observed in the ICU:

1.

Acute phase: During this early time period after exposure to the critical stressor, analogous to the “golden hour” of resuscitation, the stress response comprises primarily those rapidly acting mechanisms designed to preserve tissue perfusion and oxygenation. Blood pressure, cardiac output, and intravascular volume are all maintained through adrenergic signaling, vasopressin secretion, and activation of the renin-angiotensin-aldosterone system. The response time in these systems is rapid because they rely on preformed mediators to bring about their physiologic effects.
2.

Established phase: As time passes, the full breadth of the stress response is brought to bear as endocrine and metabolic mechanisms come into play. These are slower to activate because they rely predominantly on neuroendocrine regulation of gene transcription and protein translation. The focus of this phase of the response is to adapt host physiology to preserve vital functions while directing resources toward resolving the inciting stressor. Nonessential systems are deactivated. To achieve their desired ends, these allostatic changes may permit, or even seek, physiologic parameters incongruent with baseline homeostasis. For example, cytokines stimulate the hypothalamic thermostat to increase body temperature. Though abnormal relative to baseline conditions, fever is an important physiologic adaptation that facilitates leukocyte eradication of infectious agents. This ability to adapt to the needs of the circumstances is the physiologic resilience referred to at the outset of this chapter.
3.

Recovery or repair phase: When the inciting stressor is removed, the stress response is attenuated, the strain on host systems is relieved, and the body returns incrementally to normal homeostatic parameters.

From a teleologic point of view, the acute stress response is intended to be self-terminating within hours to a few days at most rather than a prolonged condition persisting weeks or more. Clearly, failure to mount an adequate stress response is associated with worse outcomes. However, excessive and/or chronic stress compromises the body’s allostatic responses and may itself promote pathology. ^, Due to the magnitude and nature of life-threatening conditions, the stress response in critical illness can become dysregulated and prolonged. When this occurs, the stress response devolves into a “distress response” as pathologic results emerge from misdirected or excessive allostatic adaptations. This is observed very frequently in the ICU.

Decreased neurologic function secondary to the inciting disease process itself or iatrogenic sedation precludes appropriate threat appraisal and stress system regulation by the central nervous system. Excessive adrenergic output can directly impair cardiac function. ^, The antiinflammatory neurogenic reflex may play a role in the immunoparalysis seen so often after trauma and sepsis. ^,

Both very high and low cortisol levels are observed in critically ill children and are associated with increased mortality. ^, Elevated levels of cortisol likely contribute to immune dysfunction and metabolic dysregulation whereas insufficient cortisol secretion is associated with cardiovascular collapse. The debate over steroid administration in critical illness has raged for decades and will likely continue for several more. These topics are reviewed in much greater depth in Chapter 84 .

The overall tone of the stress system in severe or prolonged critical illness is one of generalized depression. As noted earlier, thyroid hormone levels are suppressed, which may be an adaptive response, to a degree, decreasing global cellular metabolism to allow energy resources to be consumed by more vital processes. When taken to an extreme, however, very depressed thyroid levels are associated with mortality. ^, Growth hormone and prolactin release surges early in the stress response but drops to very low levels with persistent critical illness, resulting in dysregulated metabolism and immunity. ^,

Vasopressin is elevated early in the acute phase of shock states, but very rapidly declines and remains quite low through prolonged critical illness. ^, In septic shock, regulation of vasopressin is characterized by decreased plasma concentrations, unaltered clearance, depleted neurohypophyseal vesicles, and altered osmolar signaling. Likewise, the renin-angiotensin-aldosterone system can be dysregulated in critical illness. Elevated renin and angiotensin are observed in sepsis and correlate with measures of microvascular dysfunction and organ system failure. In a subset of critically ill patients, however, aldosterone levels are inappropriately low despite elevated plasma renin activity. Therefore, mineralocorticoid deficiency may contribute to the hyponatremia sometimes observed in pediatric ICU (PICU) patients.

Significant metabolic dysregulation can be seen with severe and persistent stress responses. The combined effect of increased glucose production and peripheral insulin resistance can result in extremely elevated blood sugar levels, which correlate with organ system dysfunction and survival. Intense hypercytokinemia and adrenergic stimulation both mobilize lipid and amino acid substrate from adipose tissue and skeletal muscle, which can result in hypertriglyceridemia and severe muscle wasting. ^, ^, The clinical significance of elevated serum triglyceride levels is uncertain, but muscle wasting leads to critical illness–related weakness and prolonged mechanical ventilation, with all of their comorbidities.

Analogous to inflammation, stress is beneficial acutely but when prolonged may generate collateral damage. Complicated or prolonged critical illness may represent a stress-related decompensation syndrome. A complicated ICU course may reflect elements of an ongoing stress response manifested as protein catabolism with poor wound healing and diffuse weakness and immunosuppression associated with hospital-acquired infections, all of this reflecting a persistent inflammation immunosuppression catabolism syndrome (PICS). ^, When stress evolves into distress, allostatic overload occurs, resulting in mitochondrial hibernation as an antecedent of metabolic shutdown and widespread energy failure associated with multiple organ dysfunction syndrome. Maladaptive response to stress can outlast the actual stress phase by months or even years, and chronic stress can lead to development of the metabolic syndrome long after discharge from the PICU.

Recommendations and conclusions

An understanding of the stress response should influence the care that children receive in the PICU. Because pathophysiology can change rapidly in critical illness and varies along the continuum from injury to resolution, the clinical posture of PICU providers must adapt to fluctuating physiologic parameters in different phases of the stress response.

1.

Acute phase: In the golden hour, emphasis is directed at avoiding hypoxemia and ischemia. Attention must also be paid to removing the inciting stressor that has precipitated the stress response as quickly as possible. For example, in infectious causes of critical illness, achieving early source control is paramount. The longer the stimulus persists, the more intense and prolonged the stress response it elicits.
2.

Established phase: During this interval, clinicians should focus on permissive treatment that respects the stress response and avoids iatrogenic injury, recognizing that many ICU interventions can exacerbate stress system dysregulation (vasoactive infusions, systemic steroids, and so on). Healthy physiologic values routinely targeted in the critically ill may not be appropriate considering the adaptations necessary for the stress response. The therapeutic implication here is that most of the acute endocrine and metabolic responses are likely to be adaptive and thus should probably not be aggressively treated. In many situations, providing less intervention may yield greater long-term benefit.
3.

Recovery or repair phase: In this phase, clinicians refocus on targeting normal physiologic values. Here, the environment of the ICU plays a key role in terms of avoiding prolongation or reinitiation of an acute stress response.

In addition to providing critical care interventions targeted at removing the primary pathophysiologic stressors, the multidisciplinary care team can optimize long-term outcomes by implementing interventions to destress their critically ill patients: avoiding supraphysiologic resuscitation, facilitating sleep, reestablishing circadian rhythms, decreasing noise levels, avoiding pain and discomfort, providing anxiolysis, promoting early mobilization, providing natural light, and restoring entitlement.