The Physiologic Response to Injury

I. Introduction

Trauma results in significant physiologic changes in nearly all organ systems. The sympathetic nervous system and the neurohormonal response systems, acting locally and systemically, mediate the physiologic compensation that normally occurs with traumatic injury. Fear, pain, hemorrhage, hypovolemia, hypox-emia, hypercarbia, acidosis, and tissue injury can contribute to the stress response in proportion to the extent of injury. An appropriate response maintains homeostasis and allows for healing, whereas deficiencies or excesses of these responses cause morbidity. Critical illness and death can result when the stress response is excessive and sustained after severe trauma.

• Stress response syndrome Psychological and physical perceptions of pain, injury, and shock can contribute to the stress response. Afferent impulses from the injury site are transmitted to the central nervous system where they are processed. Efferent signals mediate the physiologic response designed to correct the inciting event.

II. Afferent Stimuli (Sympathoadrenal Axis and Hypothalamic-Pituitary-Adrenal Axis)

Neural afferent signals via periphery sensory nerves converge on the brain and activate the reflex arcs, which initiate the sympathetic nervous system output and hypothalamic stimulation. Epinephrine and norepinephrine are released from the sympathetic nervous system, resulting in an immediate increase in blood pressure, heart rate, myocardial contractility, and minute ventilation. Hypothalamic release of corticotropin-releasing hormone results in the production of corticotropin from the anterior pituitary gland, which stimulates the adrenal cortex to synthesize the release of cortisol. The effects of these physiologic increases in cor-tisol, designed to restore lost circulatory volume and provide energy substrates to sustain vital organ function, include gluconeogenesis, lipolysis, insulin resistance, sodium retention, and protein catabolism. The sympathoadrenal axis and hypothalamic-pituitary-adrenal axis are designed to initiate corrective responses to maintain essential organ perfusion and function.

• Sensory neural input (pain) The perception of pain and pain itself are important activators of the sympathetic nervous system and the hypothalamic-pituitary axis. Afferent signals from the injured tissue project to the thalamus via the sympathetic tracts and result in activation of the hypothalamic-pituitary-adrenal axis and subsequent release of cortisol. In addition, catecholamine release from the adrenal medulla is increased by direct neural stimulation.
• Baroreceptors (hypovolemia) Hemorrhage and intravascular hypovolemia stimulate baroreceptors in the aorta and carotid bodies and volume receptors in the atria, which signal to the central nervous system. Atrial baroreceptors are activated, first with low-volume hemorrhage, whereas arterial baroreceptors respond to more severe hemorrhage. Baroreceptors normally exert tonic inhibition of the autonomic nervous system. With hypovolemia, there is a reduction in barorecep-tor impulses, which results in increased neural activity and centrally mediated vasoconstriction.
• Chemoreceptors (hypoxemia, acidosis, hypercarbia, hypothermia) Chemo-receptors, located in the carotid bodies and aorta, are activated by hypoxemia, acidosis, and hypercarbia. These receptors activate the centrally mediated stress

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  response systems. In addition, hypothermia is sensed by the preoptic area of the hypothalamus and triggers the hypothalamic-pituitary-adrenal axis.
• Wound mediators (cytokines/chemokines) Wounded and ischemic tissues and vascular endothelium produce a number of both locally and systemically acting mediators. The extent of these responses, which is dependent on the size and the degree of injury at the tissue level, serves to initiate mechanisms important in coagulation, metabolism, and inflammation. These mediators are a less rapid response to injury than are the aforementioned neural inputs, and they frequently play a role in cell-to-cell communication (i.e., cytokines such as interleukin-6).

III. Efferent Response

The purpose of the efferent response is to reestablish home-ostasis by restitution of the effective circulating plasma volume, to provide fuel, and to maintain vital organ function.

• Autonomic nervous system Increased sympathetic output directly stimulates arteries and veins to produce vasoconstriction leading to decreased venous capacitance and increased arterial resistance. These responses are rapidly initiated to correct hypovolemia and to maintain end-organ perfusion. In addition, sympathetic stimulation results in catecholamine release from the adrenal medulla, which produces a more sustained effect.
  • Catecholamines. Tyrosine from the diet or by the endogenous conversion of phenylalanine serves as the substrate for catecholamine synthesis. Tyrosine is hydroxylated to form dihydroxyphenylalanine (Dopa), which undergoes decarboxylation to form dopamine. Norepinephrine is then formed by the hydroxylation of dopamine. Epinephrine is subsequently produced by the methylation of norepinephrine in the adrenal medulla.
    • Norepinephrine is released from neurons and diffuses into the circulation from the synapses.
    • Epinephrine is released from the adrenal medulla.
    • 伪1-mediated peripheral vasoconstriction is increased.
    • 尾1-mediated heart rate and contractility is increased.
    • Glucose availability is increased by stimulating hepatic glycogenolysis, gluconeogenesis, and ketogenesis.
    • Skeletal muscle glycogenolysis is increased and skeletal muscle glucose uptake is decreased.
    • Glucagon secretion is increased.
    • Insulin release is suppressed.
    • Fatty acids are immobilized.
  • Cholinergic anti-inflammatory pathway. Recent studies have demonstrated the efferent activity in the vagus nerve leads to acetylcholine release in organs of the reticuloendothelial system, including the liver, heart, spleen, and gastrointestinal tract. Acetylcholine interacts with nicotinic receptors on tissue macrophages, which inhibits release of TNF, IL-1, and other cytokines.
• Hormonal response Traumatic injury initiates multiple endocrine responses. The net effect of these endocrine responses to injury is an increased secretion of catabolic hormones. This promotes the catabolism of carbohydrate, fat, and protein. In evolutionary terms, this may have served as a survival mechanism that allowed injured animals to sustain until their injuries were healed. In current surgical practice, it is questionable whether some of these endocrine stress responses are necessary.
  • Corticotropin is released form the pituitary gland after stimulation by hypothalamic corticotropin-releasing hormone.
    • Corticotropin stimulates the adrenal release of cortisol, which stimulates hepatic gluconeogenesis and increases skeletal muscle amino acid release.
  • Vasopressin (antidiuretic hormone). The posterior pituitary gland releases vasopressin in response to increases in plasma osmolality that occur with hemorrhage (major stimulus) and decreases in the effective circulating plasma volume.
    • Increases peripheral vasoconstriction
    • Increases water reabsorption
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    • Increases hepatic gluconeogenesis and glycogenolysis
    • Decreases hepatic ketogenesis
  • Growth hormone. Growth hormone is released from the anterior pituitary gland in response to hypothalamic release of growth hormone releasing hormone.
    • Increases amino acid uptake and hepatic protein synthesis
    • Mediates the biological activity of growth hormone by somatomedins
    • Decreases hepatic glucose transport
  • Thyroxine (T₄). Release of T₄ from the thyroid in response to thyroid-stimulating hormone from the anterior pituitary gland increases after injury. The conversion of T₄ to T₃ (a more potent form) decreases following trauma.
    • Increases oxygen consumption and sympathetic output
    • Increases glycolysis and gluconeogenesis
    • Increases metabolic rate and heat production
  • Renin, angiotensin, aldosterone. The major regulator of aldosterone production is the renin-angiotensin system. Decreases in renal arterial blood flow and renal tubular sodium concentration, and increased 尾-adrenergic stimulation serve to stimulate renin secretion from the juxtaglomerular cells of the renal afferent arteriole. Renin results in the enzymatic conversion of angiotensinogen in the liver to the inactive angiotensin I. Angiotensin-converting enzyme produced by the lung converts angiotensin I to angiotensin II. Besides acting as a potent vasoconstrictor, angiotensin II also stimulates the release of aldosterone.
    • Angiotensin II
      • Increases peripheral vasoconstriction
      • Increases splanchnic vasoconstriction
      • Decreases renal excretion of salt and water
    • Aldosterone
      • Produced in the adrenal zona glomerulosa
      • Increases distal tubular sodium and chloride resorption
      • Increases potassium secretion
  • Glucagon is released from pancreatic 伪-cells in response to 伪-adrenergic stimulation, hypoglycemia, and elevated circulating levels of amino acids.
    • Increases hepatic glycogenolysis and gluconeogenesis
    • Increases lipolysis
  • Insulin is released from pancreatic 尾 cells in response to 尾-adrenergic stimulation, glucagon, elevated plasma glucose, and amino acid levels.
    • Increases glycolysis and glycogenesis.
    • Increases protein synthesis.
    • Decreases gluconeogenesis.
    • The initial hyperglycemia seen following injury is secondary to an increase in the glucagon:insulin ratio and peripheral insulin resistance.
• Systemic mediators A variety of mediators are released after injuries that have both local and systemic effects. In addition, many of these mediators are released as a result of reperfusion and can lead to amplification of the inflammatory response. Many of these mediators are also released in infection, sepsis, and inflammation.
  • Complement. Ischemia and endothelial injuries result in the activation of this cascade of plasma proteins, which initiates the inflammatory response and results in the destruction and lysis of invading organisms. Complement activation, which results in leukocyte adherence, activation, and degranulation, can contribute to tissue destruction and damage as seen in acute respiratory distress syndrome.
  • Oxygen radicals. Highly reactive and short-lived oxygen species are produced by leukocytes and parenchymal cells in many tissues in response to ischemia and hypoxia. The activation of endogenous xanthine oxidase and other cellular oxidases by injury produces hydrogen peroxide (H₂O₂), superoxide (O₂^-) and hydroxyl radical (OH^-). Endogenous antioxidant defenses (superoxide

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    dismutase, catalase, glutathione, the bilirubin-biliverdin redox cycle) serve to protect against cellular injury.
  • Cytokines. Both local tissues and migratory inflammatory cells release a variety of polypeptide mediators that have paracrine effects and serve to amplify the inflammatory response and signal wound repair. The cytokines act on surface receptors on many different target cells and their effects are produced ultimately by influencing protein synthesis within these cells. Many of these substances reach the systemic circulation and initiate a systemic inflammatory response. These factors include the interleukins (IL-1, IL-2, IL-6), tumor necrosis factor, and the interferons.
  • Eicosanoids are a group of lipid mediators (prostaglandins, leukotrienes, and thromboxanes) derived from plasma membrane phospholipids by phospholipase A₂ (PLA₂). PLA₂ produces arachidonic acid, which is further metabolized to the specific isoforms (prostaglandin [PGE]₂, PGE₁, prostacyclin [PGI]₂, thrombox-ane A₂ [TXA₂], Leukotriene C₄ [LTC₄]). Different compounds have vasoactive properties and induce vasodilation (PGI₂) or vasoconstriction (TXA₂). They can also influence leukocyte function (LTC₄). Some prostaglandins are thought to modulate the immune response but their role in injury and hemorrhage is not fully known.
  • Nitric oxide (NO). Normally, constitutively produced NO from endothelial cells is a homeostatic regulator of blood pressure that provides second-to-second vasodilation. Inflammation produces increased NO from a variety of cells and may contribute to the profound hypotension typical of patients with decom-pensated hemorrhagic shock.
  • Other mediators. A variety of growth factors and other mediators are expressed after traumatic injury, which serve to regulate wound healing. These include platelet-derived growth factor, epidermal growth factor, transforming growth factors, bradykinins, endothelin, and platelet-activating factor.

IV. Metabolic Response

The metabolic response to traumatic injury and hemorrhagic shock is directly related to the aforementioned neuroendocrine response. Oxygen consumption and carbon dioxide production increase secondary to increased catecholamine production from increased sympathetic activity and from increased expression of inflammatory mediators produced at the tissue level. The metabolic responses seen after trauma have traditionally been defined according to the definitions outlined by Cuthbertson.

• Cuthbertson's two phases
  • Ebb phase, which occurs initially after traumatic injury, is characterized by physiologic responses designed to restore tissue perfusion and circulating volume.
  • Flow phase begins once the patient is successfully resuscitated.
    • The flow phase can be further subdivided into catabolic and anabolic phases.
      • The catabolic phase, which is characterized by the hyperdynamic response to trauma, includes hypermetabolism, hyperglycemia, and sodium and water retention. This response can last from days to weeks.
      • The anabolic phase, beginning after wounds have closed, is characterized by the return of normal homeostasis.
• The metabolic response to trauma can also be divided into the following four phases.
  • Shock phase. Characterized by hypoperfusion secondary to hemorrhage and tissue injury.
  • The resuscitation phase is seen with active volume resuscitation and operation to control hemorrhage. It is characterized by elaboration of many of the inflammatory mediators.
  • The hypermetabolic phase (postinjury), similar to the catabolic phase described by Cuthbertson, is characterized by an increased sympathetic and adrenal response. The increased secretion of catecholamines, cortisol, and

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    insulin causes increased protein catabolism, negative nitrogen balance, and lipolysis. Acutely, this response serves to protect the individual. However, with prolonged and sustained hypermetabolism, the patient can develop Systemic Inflammatory Response Syndrome (SIRS). Persistence of SIRS can lead to Multiple Organ Dysfunction Syndrome (MODS).
  • MODS can be caused by the sustained overexpression of injury-induced inflammatory mediators or the development of infectious complications. MODS is the most important cause of late death in the trauma intensive care unit. Mortality increases by approximately 20% to 25% per organ that fails.

V. Summary of Organ System Response to Stress

The physiologic responses seen following trauma are designed to preserve organ blood flow and, if necessary, shunt cardiac output to the heart and brain.

• Cardiovascular system
  • Increases cardiac output by increasing heart rate and contractility (CO = HR 脳 SV).
  • Maintains perfusion to the heart and brain by shunting blood from the skeletal and splanchnic vascular beds.
  • Increases peripheral vasoconstriction secondary to increased angiotensin II and vasopressin activity.
  • Preserves effective circulating plasma volume by increasing transcapillary movement of fluid from the interstitium to the intravascular space.
• Renal system
  • Maintains glomerular filtration rate secondary to increased efferent arteriolar vasoconstriction.
  • Increases aldosterone and vasopressin expression resulting in increased sodium and water absorption.
  • Shunts blood flow from renal cortex to medulla.
• Adrenal system
  • Regulates stress response through increased catecholamine, cortisol, and aldosterone production.
• Pulmonary system
  • Increases minute ventilation from hyperventilation and increased tidal volume.
  • Produces angiotensin-converting enzyme.
• Central nervous system
  • First interprets physiologic responses to trauma, and then initiates the physiologic responses.
  • Coordinates afferent stimuli into a multisystem response.
  • Increases sympathetic nervous system activity.
  • Governs neuroendocrine response.
• Splanchnic system
  • Decreases blood flow secondary to shunting of blood to preserve blood flow to the heart and brain.
  • Provides glucose from hepatic glycogen and gluconeogenesis as well as from the conversion of amino acids and free fatty acids.
  • Produces mediators secondary to the low blood flow state that can contribute to the inflammatory response.

VI. Physiologic Responses

• Altered mental status Belligerence, anxiety, immobilization, withdrawal, and antagonism are commonly seen after major trauma. It is important to be aware that this can signify severe hypovolemia, hypoxemia, or both.
• Altered vital signs Fever may be seen after fluid resuscitation, which can be caused by the sustained inflammatory response. It is critical to be vigilant for infectious causes.
• Blood pressure may not become significantly decreased until the patient has lost 30% to 40% of circulating blood volume. Therefore, blood pressure correlates poorly with either blood volume or flow.
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• Tachycardia can persist even after fluid resuscitation and pain is adequately controlled.
• Increased minute ventilation secondary to both tachypnea and increased tidal volume is common.
• Generalized edema is common secondary to increased total body salt and water within the interstitium. This is a result of increased sympathetic vasocon-striction, altered capillary permeability, and hypoproteinemia. Also, local inflammation at the wound site leads to edema formation secondary to the release of locally acting chemokines.
• Increased cardiac output Heart rate and contractility increase with injury. However, with hypovolemia, preload may be decreased to a degree that significantly lowers cardiac output.
• Hypermetabolism Energy demands, oxygen consumption, and carbon dioxide production are all elevated following trauma.
• Altered protein, glucose, and fat metabolism Energy requirements are increased following injury, with the magnitude of the additional energy need dependent on the severity of injury, magnitude of tissue destruction, and lean body mass of the patient.
  • Protein loss is approximately 300 to 500 grams per day (g/day) of lean body mass, with visceral proteins spared at the expense of skeletal muscle proteins.
  • Proteins are broken down to constituent amino acids that are catabolized to ammonia (forms urea) and precursors of the tricarboxylic cycle (TCA).
  • Carbohydrates provide 4 kilocalories per gram (kcal/g) when oxidized. Muscle glycogen (storage form of glucose) is used only by skeletal muscle (i.e., not released systemically), whereas hepatic glycogen provides glucose for glucose-dependent tissues (brain, leukocytes).
    • Gluconeogenesis can occur from amino acids, glycerol, lactate, or pyruvate via TCA or Krebs' cycle.
  • Lipids, which are used by tissues that are not glucose dependent, are the largest source of energy (9.4 kcal/g) in the body. Lipids are catabolized to form ketone bodies in the liver along with CO₂ and energy from glycerol and fatty acids.
• Leukocytosis Elevation in the white blood cell count can be seen after injury.

VII. Summary

The physiologic effect of stress response is to maintain perfusion and function of the heart and brain. Acutely, this results in a survival advantage. However, with prolonged activation of the inflammatory response, deleterious effects can be seen including SIRS, MODS, and even death.