Principles of Surgery, Companion Handbook - page 2

 
ACKNOWLEDGMENTS


The abstracts of the chapters of the seventh edition of Principles of Surgery, which comprise this companion handbook, were produced by members of the Department of Surgery at the University of Rochester School of Medicine and Dentistry. I am indebted to them for their efforts.

I also express my deep appreciation to Andrea Weinstein of the University of Rochester, who worked with the contributors, the publisher, and with me in every step of the production of the book.

Seymour I. Schwartz,
Editor-in-Chief

Chapter 1 The Systemic Response to Injury

Principles of Surgery Companion Handbook

CHAPTER
1
THE SYSTEMIC RESPONSE TO INJURY

Endocrine Response to Injury
 Overview of Hormone-Mediated Response
 Hormones Under Anterior Pituitary Regulation
 Hormones Under Posterior Pituitary Regulation
 Hormones of the Autonomic System
Immune Response to Injury
 Cytokine-Mediated Response
 Programmed Cell Death
 Hormones and Cytokine Interactions
Other Mediators of Injury Response
 Endothelial Cell Mediators
 Intracellular Mediators
 Other Inflammatory Mediators
Metabolic Response to Injury
 Metabolic Response to Fasting
 Metabolism after Injury
Nutrition in the Surgical Patient
 Surgery, Trauma, Sepsis
 Assessment and Requirements
 Indications and Methods for Nutritional Support

The host response to injury—surgical, traumatic, or infectious—is characterized by various endocrine, metabolic, and immunologic alterations. If the inciting injury is minor and of limited duration, wound healing and restoration of metabolic and immune homeostasis occur readily. More significant insults lead to further deterioration of the host regulatory processes, which, without appropriate intervention, often precludes full restoration of cellular and organ function or results in death. The spectrum of cellular metabolic and immunologic dysfunction resulting from injury suggests a complex mechanism for identifying and initially quantifying the injurious event. This initial response is inherently inflammatory, inciting the activation of cellular processes designed to restore or maintain function in tissues while also promoting the eradication or repair of dysfunctional cells. These dynamic processes imply the existence of anti-inflammatory or counterregulatory processes that promote the restoration of homeostasis. A discussion of the response to injury must account for the collective dynamics of neuroendocrine, immunologic, and metabolic alterations characteristic of the injured patient.

ENDOCRINE RESPONSE TO INJURY

Overview of Hormone-Mediated Response

The classic response to injury comprises multiple axes. These hormone response pathways are activated by (1) mediators released by the injured tissue, (2) neural and nociceptive input originating from the site of injury, or (3) baroreceptor stimulation from intravascular volume depletion. The hormones released in response to these activating stimuli may be divided into those primarily under hypothalamopituitary control and those primarily under autonomic nervous system control (Table 1-1). The interaction between these origins forms the basis of the hypothalamic-pituitary axis, which represents a series of signaling and feedback loops that regulate the endocrine response to injury.



TABLE 1-1 HORMONES REGULATED BY THE HYPOTHALAMUS, PITUITARY, AND AUTONOMIC SYSTEM



Hormone-Mediated Receptor Activity Hormones may be classified according to chemical structure and to the mechanisms by which they elicit biologic effects (Table 1-2 and Table 1-3). Central to the hormone-mediated response at the cellular level is the hormone (ligand)—receptor interaction and subsequent postreceptor activity. Most macroendocrine hormone receptors can be categorized on the basis of their mechanisms of signal transduction into three major types: (1) receptor kinases with ligands such as insulin and insulinlike growth factors, (2) guanine nucleotide–binding or G protein–coupled receptors that are activated by peptide hormones, neurotransmitters, and prostaglandins, and (3) ligand-gated ion channels that permit ion transport on ligand-receptor binding (Fig. 1-1).



TABLE 1-2 CHEMICAL CLASSES OF HORMONES





TABLE 1-3 HORMONE CLASSIFICATIONS BASED ON MECHANISM OF ACTION





FIGURE 1-1 Three major classes of membrane receptors for hormones and neurotransmitters. Receptor Kinases: Mediators such as insulin bind receptors that activate the tyrosine kinase pathway that leads to phosphorylation of proteins. G Protein-Coupled Receptors: Some hormones, such as the peptides, neurotransmitters, and prostaglandins, bind to receptors (R) coupled to guanine nucleotide-binding or G proteins (G). The G proteins in turn activate effectors (E), which may be enzymes such as adenylate cyclase. G proteins coupled to adenylate cyclase increase cAMP. If G protein is coupled to phospholipase C, the active second messenger products are inositol triphospate (IP3) and diacylglycerol (DAG). IP3 stimulates the release of free calcium from the endoplasmic reticulum. The free calcium then binds to calmodulin to activate a specific phosphorylase kinase. DAG (not shown) remains in the membrane, where it activates protein kinase C, which opens a membrane channel for calcium entry. This activity, resulting from the initial activation of G proteins, may be coupled with the activity of Ligand-Gated Ion Channels. (From: Habener JF: Genetic control of hormone formation, in Wilson JD, Foster DW: Williams Textbook of Endocrinology, 8th ed. Philadelphia, WB Saunders, 1992, chap 4, with permission.)



Hormone-Mediated Intracellular Pathways One of the most common intracellular second messengers by which hormones exert their effects is the modulation of cyclic adenosine monophosphate (cAMP). Receptor occupation by stimulatory hormones induces a cell membrane alteration that activates the enzyme adenylate cyclase. Adenylate cyclase catalyzes the conversion of adenosine triphosphate (ATP) to cAMP, which activates various intracellular protein kinases. Substances that decrease cAMP generally exert an influence opposite to those observed for substances that increase cAMP. Increases in intracellular cAMP are associated with functional lymphocyte responses that generally are immunosuppressive. In T lymphocytes, agents that increase cAMP levels diminish proliferation, lymphokine production, and cytotoxic functions. Plasma cell production of immunoglobulins is markedly attenuated. Neutrophils manifest decreased chemotaxis and reduced production of superoxides, H2O2, and lysosomal enzymes. Basophils or mast cells demonstrate a decreased release of histamine. Many prolonged hormone-mediated responses to injury increase intracellular cAMP levels through a direct action on membrane receptors or by increasing the sensitivity of leukocytes to substances that directly increase cAMP.

Hormonal actions are further mediated by intracellular receptors. These intracellular receptors have binding affinities for the hormone and for the targeted gene sequence on the DNA. These intracellular receptors may be located within the cytosol or may already be localized in the nucleus, bound to the DNA. The classic example of a cytosolic hormonal receptor is glucocorticoid receptor. Intracellular glucocorticoid receptors are maintained in an active state by linking to the stress-induced protein heat-shock protein (HSP). When the hormone ligand binds to the receptor, the dissociation of HSP from the receptor activates the receptor-ligand complex, which is transported to the nucleus.

Hormones Under Anterior Pituitary Regulation

Corticotropin-Releasing Hormone Pain, fear, anxiety, or emotional arousal generate neural signals to the paraventricular nucleus of the hypothalamus, stimulating the synthesis of corticotropin-releasing hormone (CRH), which is then delivered by way of the hypothalamic-hypophyseal portal circulation to the anterior pituitary. Proinflammatory cytokines and arginine vasopressin (AVP) also can induce CRH synthesis and release. In the anterior pituitary, CRH serves as the major stimulant of adrenocorticotropic hormone (ACTH, adrenocorticotropin) production and release (Fig. 1-2). This is accomplished by CRH-mediated activation of adenylate cyclase in the ACTH-producing corticotrophs, which increases intracellular cAMP levels and activates the pathway leading to increased ACTH production. CRH secretion can be activated by angiotensin II, neuropeptide Y (NPY), serotonin, acetylcholine, interleukin-1 (IL-1), and IL-6. The release of CRH can be inhibited by g-aminobutyric acid (GABA), substance P, atrial natriuretic peptide (ANP), endogenous opioids, and L-arginine. Circulating glucocorticoids serve as potent negative feedback signals to the hypothalamus and have demonstrated in animal models an ability to reduce CRH mRNA transcription. CRH-binding proteins (CRH-BPs) synthesized by the liver also serve as regulators of CRH activity. These collectively demonstrate endogenous pathways that may potentially regulate or preclude excessive CRH-mediated responses to injury. Injured tissues also produce CRH that may contribute locally to the inflammatory response.



FIGURE 1-2 Hormones produced by the anterior pituitary and the hypothalamic hormones that regulate their secretion. Somatostatin and dopamine are endogenous inhibitors. (From: Reichlin S: Neuroendocrine control of pituitary function, in Besser GM, Cudworth AG (eds): Clinical Endocrinology: An Illustrated Text. Philadelphia, JB Lippincott, 1987, with permission.)



Adrenocorticotropic Hormone ACTH is synthesized, stored, and released by the anterior pituitary on CRH stimulation. ACTH is a 39–amino acid peptide that is synthesized as a larger precursor complex known as proopiomelanocortin (POMC). POMC is cleaved within the cytosol to the components a-melanocyte-stimulating hormone (a-MSH), b-lipotropin, the endogenous opioid b-endorphin, and ACTH. In the nonstressed healthy human, ACTH release is regulated by circadian signals; the greatest elevation of ACTH occurs late at night and lasts until just before sunrise. This pattern is dramatically altered or obliterated in injured subjects. Most injury is characterized by elevations in CRH and ACTH that are proportional to the severity of injury. While pain and anxiety are prominent mediators of ACTH release, other ACTH-promoting mediators may become relatively more active in the injured patient. These include vasopressin, angiotensin II, cholecystokinin, vasoactive intestinal polypeptide (VIP), catecholamines, oxytocin, and proinflammatory cytokines. Within the zona fasciculata of the adrenal gland, ACTH signaling activates intracellular adenylate cyclase, the cAMP-dependent protein kinase pathway, and the mitochondrial cytochrome P-450 system. This chain of activities leads to increased glucocorticoid production via desmolase-catalyzed side-chain cleavage of cholesterol. Conditions of excess ACTH stimulation result in adrenal cortical hypertrophy.

Cortisol/Glucocorticoids Cortisol is the major glucocorticoid in humans and is essential for survival after significant physiologic stress. Cortisol levels in response to injury are not under the influence of normal diurnal variations and can remain persistently elevated, depending on the type of systemic stress. Burn patients have demonstrated elevated circulating cortisol levels for up to 4 weeks, and patients with soft tissue injury and hemorrhage may sustain elevated cortisol levels for up to a week. Circulating cortisol rapidly returns to normal levels on restoration of blood volume after hemorrhage. Conversely, adequate cortisol levels after mild hemorrhage are a prerequisite for timely restitution of blood volume in experimental animals. Coexisting systemic stress, such as infections, also can prolong the elevated cortisol levels after injury.

Cortisol is a major effector of host metabolism. It potentiates the actions of glucagon and epinephrine, leading to hyperglycemia in the host. In the liver, cortisol stimulates the enzymatic activities favoring gluconeogenesis, including induction of phosphoenol pyruvate carboxykinase and transaminases. Peripherally, it decreases insulin binding to insulin receptors in muscles and adipose tissue. In skeletal muscle, cortisol induces proteolysis and augments the release of lactate. The release of available lactate and amino acids has the net effect of shifting substrates for hepatic gluconeogenesis. Cortisol also stimulates lipolysis and inhibits glucose uptake by adipose tissues. It increases the lipolytic activities of ACTH, growth hormones, glucagon, and epinephrine. The resulting rises in plasma free fatty acids, triglycerides, and glycerol from adipose tissue mobilization serve as available energy sources and additional substrates for hepatic gluconeogenesis.

About 10 percent of plasma cortisol is present in the free, biologically active form. The remaining 90 percent is bound to corticosteroid-binding globulin (CBG) and albumin. With injury, total plasma cortisol concentrations increase, but CBG and albumin levels decrease by as much as 50 percent. This can lead to an increase in the free cortisol level of as much as 10 times the normal.

Acute adrenal insufficiency is a life-threatening complication most commonly associated with adrenal suppression from the use of exogenous glucocorticoids with consequent atrophy of the adrenal glands. These patients present with weakness, nausea, vomiting, fever, and hypotension. Objective findings include hypoglycemia from decreased gluconeogenesis, hyponatremia from impaired renal tubular sodium resorption, and hyperkalemia from diminished kaliuresis. Although hyponatremia and hyperkalemia generally are a result of insufficient mineralocorticoid (aldosterone) activity, the loss of cortisol activity also contributes to electrolyte abnormalities.

Glucocorticoids have long been used as effective immunosuppressive agents. Administration of glucocorticoids can induce rapid lymphopenia, monocytopenia, eosinopenia, and neutrophilia. Immunologic changes include thymic involution and depressed cell-mediated immune responses reflected by decreases in T-killer and natural-killer functions. Neutrophil function is affected by glucocorticoid treatment in terms of intracellular superoxide reactivity and depressed chemotaxis. Phagocytosis of polymorphonuclear leukocytes (PMNs) remains unchanged. Glucocorticoids are omnibus inhibitors of immunocyte proinflammatory cytokine synthesis and secretion. This glucocorticoid-induced downregulation of cytokine stimulation serves an important negative regulatory function in the inflammatory response to injury.

Thyrotropin-Releasing Hormone and Thyroid-Stimulating Hormone Thyrotropin-releasing hormone (TRH) serves as the primary stimulant for the synthesis, storage, and release of thyroid-stimulating hormone (TSH) in the anterior pituitary. TSH in turn stimulates thyroxine (T4) production from the thyroid gland. T4 is converted to triiodothyronine (T3) by peripheral tissues. T3 is more potent than T4, but both are transported intracellularly by cytosolic receptors, which then bind DNA to mediate the transcription of multiple protein products. Free forms of T4 and T3 in the circulation can inhibit the hypothalamic release of TRH and pituitary release of TSH via negative feedback loops. TRH and estrogen stimulate TSH release by the pituitary, and T3, T4, corticosteroids, growth hormones, somatostatin, and fasting inhibit TSH release.

Thyroid hormones (thyronines), when elevated above normal levels, exert various influences on cellular metabolism and function. Thyronines enhance membrane transport of glucose and increase glucose oxidation. These hormones increase the formation and storage of fat when carbohydrate intake is excessive, but this process decreases during starvation. The increase in cellular metabolism from excess thyroid hormone production leads to proportional elevations in overall oxygen consumption as well as heat production. Although T3 levels are frequently decreased after injury, there is no compensatory rise in TSH release. After major injury, reduced available T3 and circulating TSH levels are observed, and peripheral conversion of T4 to T3 is impaired. This impaired conversion may be explained in part by the inhibitory effects of cortisol and an increased conversion of T4 to the biologically inactive molecule known as reverse T3 (rT3). Proinflammatory cytokines also may contribute to this effect. Elevated rT3 but reduced T4 and T3 is an observation characteristic of acute injury or trauma, referred to as euthyroid sick syndrome or nonthyroidal illness.

While total T4 (protein bound and free) levels may be reduced after injury, free T4 concentrations remain relatively constant. In severely injured or critically ill patients, a reduced free T4 concentration has been predictive of high mortality. One consequence of exposure to thyronines is an increase in the uptake of amino acids and glucose into the cell. Whether this is a direct effect of thyroid hormones or a secondary effect of increased cellular metabolism is unknown. Leukocyte metabolism measured by oxygen consumption is increased in hyperthyroid individuals and subjects to whom thyroid hormones have been administered. Animal studies have demonstrated that surgically or chemically induced thyroid hormone depletion significantly decreases cellular and humoral immunity. Conversely, thyroid hormone repletion is associated with enhancement of both types of immunity. Human monocytes, natural killer cells, and activated B lymphocytes express receptors for TSH. Exposure of B cells to TSH in vitro induces a moderate increase in immunoglobulin secretion.

Growth Hormones Hypothalamic growth hormone–releasing hormone (GHRH) travels through the hypothalamic-hypophyseal portal circulation to the anterior pituitary and stimulates the release of growth hormone (GH) in a pulsatile fashion mostly during the sleeping hours. In addition to GHRH, GH release is influenced by autonomic stimulation, thyroxine, AVP, ACTH, a-melanocyte-stimulating hormone, glucagon, and sex hormones. Other stimuli for GH release include physical exercise, sleep, stress, hypovolemia, fasting hypoglycemia, decreased circulating fatty acids, and increased amino acid levels. Conditions that inhibit GH release include hyperglycemia, hypertriglyceridemia, somatostatin, beta-adrenergic stimulation, and cortisol.

The role of GH during stress is to promote protein synthesis while enhancing the mobilization of fat stores. Fat mobilization occurs by direct stimulation in conjunction with potentiation of adrenergic lipolytic effects on adipose stores. In the liver, hepatic ketogenesis also is promoted by GH. GH inhibits insulin release and decreases glucose oxidation, leading to elevated glucose levels. The protein synthesis properties of GH after injury are partially mediated by the secondary release of insulinlike growth factor-1 (IGF-1). This hormone, which circulates predominantly in bound form with several binding proteins, promotes amino acid incorporation and cellular proliferation and attenuates proteolysis in skeletal muscle and in the liver. IGFs, formerly referred to as somatomedins, are mediators of hepatic protein synthesis and glycogenesis. In adipose tissue, IGF increases glucose uptake and lipid synthesis. In skeletal muscle it increases glucose uptake and protein synthesis. IGF also has a role in skeletal growth by promoting the incorporation of sulfate and proteoglycans into cartilage. Interleukin-1a, tumor necrosis factor-alpha (TNF-a), and IL-6 can inhibit the effects of IGF-1.

There is a rise in circulating GH levels after injury, major surgery, and anesthesia. The associated decrease in protein synthesis and observed negative nitrogen balance is attributed to a reduction in IGF-1 levels. GH administration has improved the clinical course of pediatric burn patients. Its use in injured adult patients is unproved. The liver is the predominant source of IGF-1, and preexisting hepatic dysfunction may contribute to the negative nitrogen balance after injury. IGF-binding proteins also are produced within the liver and are necessary for effective binding of IGF to the cell. IGF has the potential for attenuating the catabolic effects after surgical insults.

Leukocytes express high-affinity surface receptors for GH. GH and IGF-1 are immunostimulatory and promote tissue proliferation. Macrophages also respond to GH with a modest respiratory burst. GH-deficient human beings do not demonstrate any significant immunologic abnormalities. Normal subjects given intravenous GH demonstrate no significant immunologic changes except for neutrophilia.

Gonadotrophins and Sex Hormones Luteinizing hormone–releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) is released from the hypothalamus and stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release from the anterior pituitary. The most relevant clinical correlation is seen after injury, stress, or severe illness, when LH and FSH release is suppressed. The reduction in LH and FSH consequently reduces estrogen and androgen secretion. This is attributed to the inhibitory activities of CRH on LH and FSH release and accounts for the menstrual irregularity and decreased libido reported after surgical stress and other injuries.

Estrogens inhibit cell-mediated immunity, natural killer cell activity, and neutrophil function but are stimulatory for antibody-mediated immunity. Conditions associated with high estrogen levels appear to predispose the patient to increased infectious complications. Androgens appear to be predominantly immunosuppressive. Castration is associated with enhanced immune function that can be reversed by exogenous androgens.

Prolactin The hypothalamus suppresses prolactin secretion from the anterior pituitary by the activities of LHRH/GnRH and dopamine. Stimulants for prolactin release are CRH, TRH, GHRH, serotonin, and vasoactive intestinal polypeptide (VIP). Elevated prolactin levels after injury have been reported in adults, whereas reduced levels are noted in children. The hyperprolactinemia also may account for the amenorrhea frequently seen in women after injury or major operations. Like growth hormone, prolactin has immunostimulatory properties. There is increasing evidence that prolactin also is synthesized and secreted by T lymphocytes and may function in an autocrine or paracrine fashion.

Endogenous Opioids Elevated endogenous opioids are measurable after major operations or insults to the patient. The b-endorphins have a role in attenuating pain perception, and they are capable of inducing hypotension through a serotonin-mediated pathway. Conversely, the enkephalins produce hypertension. In the gastrointestinal (GI) tract, the activation of opioid receptors reduces peristaltic activity and suppresses fluid secretion. The role of endogenous opioids in glucose metabolism is complex. While b-endorphins and morphine induce hyperglycemia, they also increase insulin and glucagon release by the pancreas. Studies demonstrating the presence of opioid receptors in the adrenal medulla also suggest a role in regulating catecholamine release.

Certain immune cells also release endorphins that share an antinociceptive role in modulating the response of local sensory neurons to noxious stimuli. Endorphins also influence the immune system by increasing natural killer cell cytotoxicity and T-cell blastogenesis. IL-1 activates the release of POMC from the pituitary gland.

Hormones Under Posterior Pituitary Regulation

Arginine Vasopressin Vasopressin or arginine vasopressin (AVP) (or antidiuretic hormone, ADH) is synthesized in the anterior hypothalamus and transported by axoplasmic flow to the posterior pituitary for storage. The major stimulus for AVP release is elevated plasma osmolality, which is detected by sodium-sensitive hypothalamic osmoreceptors. There is evidence of extracerebral osmoreceptors for AVP release in the liver or the portal circulation. AVP release is enhanced by beta-adrenergic agonists, angiotensin II stimulation, opioids, anesthetic agents, pain, and elevated glucose concentrations. Changes in effective circulating volume of as little as 10 percent can be sensed by baroreceptors, left atrial stretch receptors, and chemoreceptors, leading to AVP release. Release is inhibited by alpha-adrenergic agonists and atrial natriuretic peptide (ANP).

In the kidney, AVP promotes reabsorption of water from the distal tubules and collecting ducts. Peripherally, AVP mediates vasoconstriction. This effect in the splanchnic circulation may cause the trauma-induced ischemia-reperfusion phenomenon that precedes gut barrier impairment. AVP, on a molar basis, is more potent than glucagon in stimulating hepatic glycogenolysis and gluconeogenesis. The resulting hyperglycemia increases the osmotic effect that contributes to the restoration of effective circulating volume. Elevated AVP secretion is another characteristic of trauma, hemorrhage, open-heart surgery, and other major operations. This elevated level typically persists for 1 week after the insult.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) refers the excessive vasopressin release that is manifested by low urine output, highly concentrated urine, and dilutional hyponatremia. This diagnosis can be made only if the patient is euvolemic. Once normal volume is established, a plasma osmolality below 275 mOsm/kg H2O and a urine osmolality above 100 mOsm/kg H2O are indicative of SIADH. SIADH is commonly seen in patients with head trauma and burns.

In the absence of AVP, central diabetes insipidus occurs, and there is voluminous output of dilute urine. Frequently seen in comatose patients, the polyuria in untreated diabetes insipidus can precipitate a state of hypernatremia and hypovolemic shock. Attempts at reversal should include free water and exogenous vasopressin (desmopressin).

Oxytocin Oxytocin and AVP are the only known hormones secreted by the posterior pituitary. They share structural similarities, but the role of oxytocin in the injury response is unknown.

Hormones of the Autonomic System

Catecholamines Catecholamines exert significant influence on the physiologic response to stress and injury. The hypermetabolic state observed after severe injury has been attributed to activation of the adrenergic system. Both the major catecholamines, norepinephrine and epinephrine, are increased in plasma after injury, with average elevations of three to four times above baseline immediately after injury, reaching their peak in 24–48 h before returning to baseline levels. The patterns of norepinephrine and epinephrine appearance parallel each other after injury. Most of the norepinephrine in plasma results from synaptic leakage during sympathetic nervous system activity, whereas virtually all plasma epinephrine derives from the secretions of chromaffin cells of the adrenal medulla.

Catecholamines exert metabolic, hormonal, and hemodynamic influences on diverse cell populations. In the liver, epinephrine promotes glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. It causes decreased insulin secretion but increased glucagon secretion. Peripherally, epinephrine increases lipolysis in adipose tissues and inhibits insulin-facilitated glucose uptake by skeletal muscle. These collectively promote the often evident stress-induced hyperglycemia, not unlike the effects of cortisol on blood glucose. Catecholamines also increase the secretion of thyroid and parathyroid hormones, T4 and T3, and renin but inhibit the release of aldosterone.

Catecholamines exert discernible influences on immune function; e.g., epinephrine occupation of beta receptors on leukocytes increases intracellular cAMP. This ultimately decreases immune responsiveness in lymphocytes. Like cortisol, epinephrine enhances leukocyte demargination with resulting neutrophilia and lymphocytosis. Immunologic tissue such as the spleen, thymus, and lymph nodes possess extensive adrenergic innervation. Chemical sympathectomy of peripheral nerves has been demonstrated to augment antibody response after immunization with a specific antigen. Normal volunteers infused with epinephrine exhibited depressed mitogen-induced T lymphocyte proliferation.

Aldosterone The mineralocorticoid aldosterone is synthesized, stored, and released in the adrenal zona glomerulosa. Its release may be induced by angiotensin II, hyperkalemia, and the pituitary hormone known as aldosterone-stimulating factor (ASF), but ACTH is the most potent stimulus for aldosterone release in the injured patient.

The major function of aldosterone is to maintain intravascular volume by conserving sodium and eliminating potassium and hydrogen ions. While the major effect is exerted in the kidneys, this hormone also is active in the intestines, salivary glands, sweat glands, vascular endothelium, and brain. In the early distal convoluted tubule, aldosterone increases sodium and chloride reabsorption and excretion of hydrogen ions. In the late distal convoluted tubule, further sodium reabsorption takes place while potassium ions are excreted. Vasopressin also acts in concert with aldosterone to increase osmotic water flux into the tubules.

Patients with aldosterone deficiency develop hypotension and hyperkalemia, whereas patients with aldosterone excess develop edema, hypertension, hypokalemia, and metabolic alkalosis. After injury, ACTH stimulates a brief burst of aldosterone release. Angiotensin II induces a protracted aldosterone release that persists well after ACTH returns to baseline. As with cortisol, normal aldosterone release also is influenced by the circadian cycle, although this effect is lost in the injured patient.

Renin-Angiotensin Renin is synthesized and stored primarily within the renal juxtaglomerular apparatus near the afferent arteriole. The juxtaglomerular apparatus comprises the juxtaglomerular neurogenic receptor, the juxtaglomerular cell, and the macula densa. Renin initially exists in an inactive form as prorenin. The activation of renin and its release are mediated by ACTH, AVP, glucagon, prostaglandins, potassium, magnesium, and calcium. The juxtaglomerular cells are baroreceptors that respond to a decrease in blood pressure by increasing renin secretion. The macula densa detects changes in chloride concentration in the renal tubules.

Angiotensinogen is a protein primarily synthesized by the liver but also identified in the kidney. Renin catalyzes the conversion of angiotensinogen to angiotensin I within the kidney. Angiotensin I remains physiologically inactive until it is converted in the pulmonary circulation to angiotensin II by angiotensin-converting enzyme present on endothelial surfaces.

Angiotensin II is a potent vasoconstrictor that also stimulates aldosterone and vasopressin synthesis. It also is capable of regulating thirst. Angiotensin II stimulates heart rate and myocardial contractility. It also potentiates the release of epinephrine by the adrenal medulla, increases CRH release, and activates the sympathetic nervous system. It can induce glycogenolysis and gluconeogenesis. The renin-angiotensin system participates in the response to injury by maintaining volume homeostasis.

Insulin Insulin is derived from pancreatic beta islet cells and released on stimulation by certain substrates, autonomic neural input, and other hormones. In normal metabolism, glucose is the major stimulant of insulin secretion. Other substrate stimulants include amino acids, free fatty acids, and ketone bodies. Hormonal and neural influences during stress alter this response. Epinephrine and sympathetic stimulation inhibit insulin release. Peripherally, cortisol, estrogen, and progesterone interfere with glucose uptake. The net result of impaired insulin production and function after injury is stress-induced hyperglycemia, which is in keeping with the general catabolic state.

Insulin exerts a global anabolic effect; it promotes hepatic glycogenesis and glycolysis, glucose transport into cells, adipose tissue lipogenesis, and protein synthesis. In the injured patient, a biphasic pattern of insulin release is observed. The first phase occurs within a few hours after injury and is manifested as a relative suppression of insulin release, reflecting the influence of catecholamines and sympathetic stimulation. The later phase is characterized by a return to normal or excessive insulin production but with persistent hyperglycemia, demonstrating a peripheral resistance to insulin.

Activated lymphocytes express receptors for insulin. Insulin enhances T lymphocyte proliferation and cytotoxicity. Institution of insulin therapy to newly diagnosed diabetics is associated with increased B and T lymphocyte populations.

Glucagon Glucagon is a product of pancreatic alpha islet cells. As with insulin, the release of glucagon also is mediated by its substrates, autonomic neural input, and other hormones. Whereas insulin is an anabolic hormone, glucagon serves more of a catabolic role. The primary stimulants of glucagon secretion are plasma glucose concentrations and exercise. Glucagon stimulates hepatic glycogenolysis and gluconeogenesis, which under basal conditions account for approximately 75 percent of the glucose produced by the liver. The release of glucagon after injury is initially decreased but returns to normal 12 h later. By 24 h, glucagon levels are supranormal and can persist for up to 3 days.

IMMUNE RESPONSE TO INJURY

While the classic neuroendocrine response to injury has been extensively investigated, many characteristics of the inflammatory response associated with injury remain unexplained. Even after the normalization of macroendocrine hormone function after the primary injury, the persistence of systemic inflammation, the progression of organ dysfunction, and even late mortality indicate the presence of other potent mediators influencing the injury response. These mediators usually are small proteins or lipids that are synthesized and secreted by immunocytes. These molecules, collectively referred to as cytokines, are indispensable in tissue healing and in the immune response generated against microbial invasions. As mounting evidence suggests, the activities of these cytokine mediators are integrally related to classic hormone function and metabolic responses to injury.

Cytokine-Mediated Response

Patients with injuries or infections exhibit hemodynamic, metabolic, and immune responses partially orchestrated by endogenous cytokines. Unlike classic hormonal mediators such as catecholamines and glucocorticoids, which are produced by specialized tissues and exert their influence predominantly by endocrine routes, cytokines are produced by diverse cell types at the site of injury and by systemic immune cells (Table 1-4). Cytokine activity is exerted primarily locally via cell-to-cell interaction (paracrine).



TABLE 1-4 CATALOGUE OF RECOGNIZED CYTOKINES RELEASED IN RESPONSE TO INJURY



Cytokines are small polypeptides or glycoproteins that exert their influence at very low concentrations. Most are less than 30 kD in weight, but in their biologically active form, some of these cytokines function as oligomers (e.g., trimeric tumor necrosis factor-alpha) with higher molecular weights. Most cytokines also differ from classic hormones in that they are not stored as preformed molecules. Their relatively rapid appearance after injury reflects active gene transcription and translation by the injured or stimulated cell.

Cytokines exert their influence by binding to specific cell receptors and activating intracellular signaling pathways leading to modulation of gene transcription. By this mechanism, cytokines influence immune cell production, differentiation, proliferation, and survival. These mediators also regulate the production and actions of other cytokines, which may either potentiate (proinflammatory) or attenuate (anti-inflammatory) the inflammatory response. The capacity of cytokines to activate diverse cell types and to incite equally diverse responses underscores the pleiotropism of these inflammatory mediators. There is also a marked degree of overlapping activity among different cytokines.

Cytokines are effector molecules that direct the inflammatory response to infections (bacterial, viral, and fungal) and injury, and they actively promote wound healing. These responses are manifested by fever, leukocytosis, and alterations in respiratory and heart rates. Exaggerated, acute production of proinflammatory cytokines is responsible for the hemodynamic instability characteristic of septic shock. Chronic and excessive production of these cytokines is partly responsible for the metabolic derangements of the injured patients, such as debilitating muscle wasting and cachexia. The presence of anti-inflammatory cytokines may serve to attenuate some of these exaggerated responses. The excessive release of anti-inflammatory cytokines, however, may render the patient immunocompromised and increase susceptibility to infections.

Understanding of the pathophysiology of inflammatory cytokine mediators has been derived largely from patients with endotoxemia or sepsis. Inflammatory mediator responses to infections and traumatic injury are not dissimilar, particularly in the temporal sequence of cytokine expression. The cytokine response evidenced by fever, leukocytosis, hyperventilation, and tachycardia commonly seen in injury is referred to as systemic inflammatory response syndrome (SIRS), but it is not necessarily the result of an identifiable infectious process. Central to the insult suffered by the host and the subsequent inflammatory response is the activity of the host's immunocyte population, circulating and tissue-fixed.

The cytokine cascade activated in response to injury consists of a complex network with diverse effects on all aspects of physiologic regulatory mechanisms. Cytokines are pivotal determinants of the host response after injury, and a proper perspective on their immunobiologic sequelae can have important applications in the comprehensive care of the surgical patient. The number of cytokines identified has expanded to nearly 30, but their functions and elicited responses, particularly in injury, are incompletely understood largely because of the pleiotropic, redundant, and mutual interactions among these mediators. The cytokines described here represent a limited list of mediators related to injury and the inflammatory response.

Tumor Necrosis Factor-alpha The inflammatory response to severe cross-sectional tissue injury or infectious agents evokes a complex cascade of proinflammatory cytokines. Among these, tumor necrosis factor-alpha (TNF-a) is the earliest and one of the most potent mediators of the subsequent host response. The sources of TNF-a synthesis include monocytes/macrophages and T cells, which are abundant in the peritoneum and splanchnic tissues. Kupffer cells represent the single largest concentrated population of macrophages in the human body. Surgical or traumatic injuries to the viscera may have profound influences on the generation of inflammatory mediators and homeostatic responses such as acute phase protein production (Fig. 1-3).



FIGURE 1-3 Inflammatory mediators that modulate hepatic acute phase reactants synthesis in humans. E = enhancement of activity; OSM = oncostatin M; CNTF = ciliary neurotrophic factor; ApoAl = apolipoprotein Al. (From: Steel DM, Whitehead AS: The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol Today 15:81, 1994, with permission.)



The release of TNF-a in response to acute injury is rapid and short-lived. Experiments simulating an acute inflammatory response by means of endotoxin challenge in human subjects have demonstrated a monophasic tumor necrosis factor (TNF) appearance curve, peaking at approximately 90 min and followed by a return to undetectable levels within 4 h. Even with a half-life of 15–18 min, the brief appearance of TNF can induce marked metabolic and hemodynamic changes and activate cytokines distally in the cascade. The abbreviated appearance of TNF reflects the presence of effective endogenous modulators that serve to prevent unregulated TNF-a activity. Several natural mechanisms antagonize TNF production or activity. Endogenous inhibitors in the form of cleaved extracellular domains of the transmembrane TNF receptors (soluble TNF receptors, sTNFRs) are readily detectable in the circulation. These receptors may serve a protective role by competitively sequestering excess circulating TNF but are probably only capable of doing so against low levels of TNF activity and for brief periods.

TNF-a also is a major cytokine related to muscle catabolism and cachexia during stress. Amino acids are mobilized from skeletal muscles and shunted toward the hepatic circulation as fuel substrates. Studies have demonstrated that TNF-a–induced muscle catabolism occurs through a ubiquitin-proteasome proteolytic pathway with increased expression of the ubiquitin gene. Other associated functions of TNF-a include activation of coagulation and promotion of the release of prostaglandin E2 (PGE2), platelet-activating factor (PAF), glucocorticoids, and eicosanoids.

Interleukin-1 TNF-a also induces the biosynthesis and release of IL-1 from macrophages and endothelial cells. There are two known proinflammatory species of IL-1, IL-1a and IL-1b. IL-1a is predominantly cell membrane–associated and exerts its influence via cellular contacts. The more detectable form released in the circulation is IL-1b, which is produced in greater quantities than IL-1a and is capable of inducing the characteristic systemic derangements after injury.

The potency and effects of IL-1 reflect those of TNF-a, eliciting similar physiologic and metabolic alterations. At high doses of IL-1 and TNF-a, these cytokines independently initiate a state of hemodynamic decompensation. At low doses, they can produce the same response only if administered simultaneously. These observations emphasize the synergism of TNF-a and IL-1 in eliciting proinflammatory responses. The half-life of IL-1 is approximately 6 min, which, along with its primary role as a local inflammatory mediator, makes its detectability in acute injury or illness even less likely than that of TNF-a.

Among its effects, IL-1 induces the classic febrile response to injury by stimulating local prostaglandin activity in the anterior hypothalamus. Associated with the hypothalamic activity is the induction of anorexia by an IL-1 effect on the satiety center. This cytokine also augments T-cell proliferation by enhancing the production of IL-2 and also may influence skeletal muscle proteolysis. Attenuated pain perception after surgery can be mediated by IL-1 by promoting the release of b-endorphins from the pituitary gland and increasing the number of central opioid-like receptors. Like TNF, IL-1 is a potent stimulant for ACTH and glucocorticoid release via its actions on the hypothalamus and pituitary gland. A nonagonist IL-1 species, known as IL-1 receptor antagonist (IL-1ra), also is released during injury. This molecule effectively competes for binding to IL-1 receptors yet exacts no overt signal transduction. IL-1ra, which is often detectable during inflammation or injury, serves as a potent regulator of IL-1 activity. Distal cytokine mediators, released as part of the inflammatory cascade initiated by TNF-a and IL-1, include IL-2, IL-4, IL-6, IL-8, granulocyte/macrophage colony-stimulating factor (GM-CSF), and interferon-g (IFN-g).

Interleukin-2 Although necessary as an inflammatory mediator in promoting T lymphocyte proliferation, immunoglobulin production, and gut barrier integrity, IL-2 has not been readily detectable in the circulation during acute injury. Similar to IL-1, its short half-life of less than 10 min adds to the difficulty in detecting it after injury. IL-2 secretion by lymphocytes is impaired after acute injury and several disease states, notably cancer and acquired immune-deficiency syndrome (AIDS). Perioperative blood transfusions also are associated with reduced IL-2 production. Attenuated IL-2 expression contributes to the transient immunocompromised state of the surgical patient. A low point in gut barrier IL-2 activity resulting from injuries can predispose the patient to enteric organism activation of the inflammatory cytokine cascade. The combined diminution of lymphocyte survival and IL-2 activity may contribute to the immunocompromised phenotype of the injured patient.

Interleukin-4 IL-4 is a glycoprotein molecule, produced by activated T cells, with diverse biologic effects on hemopoietic cells, including induction of B lymphocyte proliferation. As a potent anti-inflammatory cytokine, IL-4 downregulates several functions associated with activated human macrophages, namely, the effects of IL-1b, TNF-a, IL-6, IL-8, and superoxide production. These anti-inflammatory effects of IL-4 are not seen in resting monocytes. The importance of this cytokine is its capacity to downregulate the response of inflammatory macrophages exposed to stimuli such as bacterial endotoxin or proinflammatory cytokines. IL-4 can induce programmed cell death in inflammatory macrophages. IL-4 also appears to increase macrophage susceptibility to the anti-inflammatory effects of glucocorticoids. IL-13 may share several properties with IL-4.

Interleukin-6 Because of the elevated blood levels of IL-6 often observed during acute injury or stress, it is used frequently as an indicator of the systemic inflammatory response and a predictor of preoperative morbidity. TNF-a and IL-1 are major inducers of IL-6. IL-6 can be produced by virtually all cell types, including the intestines. After injury, IL-6 levels in the circulation are detectable by 60 min, peak at between 4 and 6 h, and can persist for as long as 10 days. The relatively long half-life partially explains its ease of detectability. IL-6 levels appear to be proportional to the extent of tissue injury during an operation rather than the duration of the surgical procedure itself.

IL-6 appears to play a complex role in mediating proinflammatory and anti-inflammatory activities. IL-1 and IL-6 are important mediators of the hepatic acute-phase protein response during injury and appear to enhance C-reactive protein, fibrinogen, haptoglobin, amyloid A, a1-antitrypsin, and complement production (see Fig. 1-3). IL-6 not only induces PMN activation during injury and inflammation but also may delay the phagocytic disposal of senescent or dysfunctional PMNs during injury. The persistence of inflammatory PMNs after injury might explain the injurious effects on distant tissues, such as the pulmonary or renal system.

IL-6 mediates the anti-inflammatory pathway during injury through different mechanisms. It is capable of attenuating TNF and IL-1 activity while promoting the release of sTNFRs and IL-1ra. Prolonged and persistent expression of IL-6 is associated with immunosuppression and postoperative infectious morbidity.

Interleukin-8 The appearance of IL-8 activity is temporally associated with IL-6 after injury and has been proposed as an additional biomarker for the risk of multiple organ failure. IL-8 does not produce the hemodynamic instability characteristic of TNF-a and IL-1 but rather serves as a PMN activator and potent chemoattractant. IL-8 may be a major contributor to organ injury, such as acute lung injury.

Interleukin-10 IL-10 acts primarily by modulating TNF-a activity. Its appearance in the circulation during endotoxemia closely follows the appearance TNF-a. Neutralization of IL-10 during endotoxemia increases monocyte TNF-a production and mortality, but restitution of IL-10 reduces TNF-a levels and its associated deleterious effects. In addition, IL-10 may be protective during injury-induced inflammation by promoting IL-1ra and sTNFR production. In animal experiments, the sustained systemic production of IL-10 during septic peritonitis modulates the systemic inflammatory response; mortality increases when IL-10 is blocked with an anti-IL-10 antibody. This immunomodulatory effect also may abrogate the proinflammatory response necessary for local clearance of invading organisms.

Interleukin-12 IL-12 can promote the differentiation of T-helper cells and the production of IFN-g. Thus it is a pivotal molecule in cell-mediated immunity after injury or infection. In mice with fecal peritonitis, survival increases with IL-12 administration. IL-12 also is implicated in preventing programmed cell death (apoptosis) in certain T lymphocyte populations after their activation.

Interleukin-13 IL-13 is a pleiotropic cytokine that shares many of the properties of IL-4. IL-13 is produced during T-helper cell responses. IL-4 and IL-13 modulate macrophage function, but IL-13 has no identifiable effect on T lymphocytes and only has influence on subpopulations of B lymphocytes. IL-13 can inhibit nitric oxide production and the expression of proinflammatory cytokines, and it can enhance the production of IL-1ra. The net effect of IL-13, along with IL-4 and IL-10, is anti-inflammatory.

Interferon-g Much of IL-12 biology is mediated through the production and activities of IFN-g. Human T-helper (TH) cells activated by the bacterial antigens IL-2 or IL-12 readily produce IFN-g. Conversely, IFN-g can induce the production of IL-2 and IL-12 by T-helper cells. With its release from activated T cells, IFN-g is detectable in vivo by 6 h and has a half-life of approximately 30 min. IFN-g levels peak at 48–72 h and may persist for 7–8 days. Injured tissues, such as operative wounds, also demonstrate the presence of IFN-g production 5–7 days after injury. IFN-g has important roles in activating circulating and tissue macrophages. Alveolar macrophage activation mediated by IFN-g may induce acute lung inflammation after major surgery or trauma.

Granulocyte/Macrophage Colony-Stimulating Factor Granulocyte/macrophage colony-stimulating factor (GM-CSF) production is induced by IL-2 and endotoxin. In vitro studies have demonstrated a prominent role for GM-CSF in delaying apoptosis of macrophages and PMNs. This growth factor is effective in promoting the maturation and recruitment of functional leukocytes necessary for normal inflammatory cytokine response and potentially in wound healing. The mechanisms may be the result of the suppression of IL-10 production. Results of perioperative GM-CSF administration in patients undergoing major oncologic procedures have demonstrated augmentation of neutrophil numbers and function.

Programmed Cell Death

During systemic inflammation, the response mounted by the host to injury and infection manifests the collective activities of circulating and tissue-fixed immunocytes and endothelial cell populations. In the normal host, programmed cell death (apoptosis) is the principal mechanism by which senescent or dysfunctional cells, including macrophages and PMNs, are systematically disposed of without activating other immunocytes or the release of proinflammatory contents. The signals inducing normal apoptosis differ from cell to cell but most likely converge at a common final pathway. These signals arise from the extracellular environment and may include hormonal and paracrine activities.

The inflammatory milieu disrupts the normal apoptotic machinery in dysfunctional or aging cells, consequently delaying the disposal of activated macrophages and PMNs. Several proinflammatory cytokines delay the normal temporal sequence of macrophage and PMN apoptosis in vitro. These include TNF, IL-1, IL-3, IL-6, GM-CSF, granulocyte colony-stimulating factor (G-CSF), and IFN-g. By contrast, IL-4 and IL-10 accelerate apoptosis in activated monocytes. The prolonged survival of inflammatory immunocytes may perpetuate and augment the inflammatory response to injury and infection, precipitating multiple organ failure and eventual death in severely injured and critically ill patients.

Hormones and Cytokine Interactions

Cortisol/Glucocorticoids Hypercortisolemia differentially influences leukocyte counts and cytokine expression in a temporal fashion. Glucocorticoid administration immediately before or concomitantly with endotoxin infusion in healthy human beings is able to attenuate the symptoms (e.g., fever, tachycardia), catecholamine response, and acute-phase response. It increases IL-10 release, however, which release may contribute to the acute anti-inflammatory effect of glucocorticoids.

Glucocorticoids also can influence the regulation of T-lymphocyte proliferation or programmed cell death. Glucocorticoid-induced apoptosis of T lymphocytes requires elevations of intracellular cAMP. IL-2, IL-4, and IL-10 protects these T lymphocytes from glucocorticoid-induced apoptosis. IL-1, TNF, and IL-6 can activate the hypothalamus-pituitary-adrenal axis and induce the release of CRH and ACTH, leading to increased circulatory glucocorticoid levels. Glucocorticoids, in turn, inhibit endotoxin-induced production of TNF at the level of mRNA translation. Dexamethasone also inhibits neutrophil apoptosis and prolongs their functional responsiveness. This can be detrimental to the patient because the delay in clearance from tissues may perpetuate the injurious effects of activated neutrophils.

Catecholamines Catecholamines inhibit endotoxin-induced macrophage production of TNF-a in vitro. In normal human subjects, short-term preexposure to epinephrine effectively inhibits endotoxin-induced TNF production. Concurrently, short-term preexposure to epinephrine increases the production of the anti-inflammatory cytokine IL-10. Endogenous or exogenous epinephrine may serve to limit excessive proinflammatory effects of the cytokine network during the early phase of systemic infection. Thus the use of catecholamines in treatment may have the potential for influencing immune cell function.

OTHER MEDIATORS OF INJURY RESPONSE

Endothelial Cell Mediators

Endothelial Cell Function In addition to modulating coagulation and vascular tone, mediators elaborated by the vascular endothelium participate in the inflammatory process. In a paracrine fashion, TNF-a, IL-1, endotoxin, thrombin, histamine, and IFN-g are capable of stimulating or activating the endothelial cell during local tissue injury. In response, the endothelial cell releases several mediators, including IL-1, platelet-activating factor (PAF), prostaglandins (PGI2 and PGE2), GM-CSF, growth factors, endothelin, nitric oxide, and small amounts of thromboxane A2 (TxA2). Activated endothelial cells also release collagenases capable of digesting their own basement membranes. This permits neovascularization and vascular remodeling at sites of injury in order to facilitate adequate oxygen supply and immunocyte transport. Angiotensin-converting enzymes (ACE) convert angiotensin I to angiotensin II on the surface of endothelial cells, making it a potent regulator of vascular tone. Endothelial cell mediators can modulate cardiovascular and renal function and influence the hypothalamus-pituitary-adrenal axis.

The activated endothelial cell upregulates its expression of leukocyte adhesion receptor molecules such as E-selectin (formerly referred to as endothelial-leukocyte adhesion molecule-1, ELAM-1), P-selectin, and intercellular adhesion molecules (ICAM-1, ICAM-2). The adhesion of leukocytes and platelets to the endothelial surface occurs early in the endothelial-derived inflammatory process. The expression of E-selectin on endothelial cell surfaces is maximal at 4–6 h. Recovery from the inflammatory process is characterized by internalization of these adhesion molecules within the endothelial cell.

Neutrophil adhesion to the endothelium during injury has important clinical implications for increasing vascular permeability and passage of leukocytes into injured tissues. In the nonstressed state, the endothelium possesses little capacity to recognize and bind circulating leukocytes. Local injuries and inflammatory mediator stimulation promote the margination of circulating PMNs to the endothelial surfaces. These marginated PMNs are deformable and travel along the endothelial surfaces at markedly reduced velocities, which is referred to as rolling. Rolling represents a process of transient attachment and detachment between receptors of PMNs and the endothelium. The subsequent development of stronger receptor adhesions, PMN activation by the endothelial mediators, and release of PMN proteinases at endothelial junctions precedes the migration of PMNs out of the vascular compartment, a process referred to as diapedesis. Although necessary for local tissue inflammation and eradication of microbes, activated PMNs and the subsequent release of inflammatory mediators and reactive oxygen metabolites are implicated in capillary leakage, acute lung injury, and postischemic injury. The ability to attract leukocytes and produce inflammatory mediators makes endothelial cells important participants in the immune response to injury.

Endothelium-Derived Nitric Oxide Endothelium-derived nitric oxide or relaxing factor (EDNO or EDRF) can be released in response to acetylcholine stimulation, hypoxia, endotoxin, cellular injury, or mechanical shear stress from circulating blood. Its vasodilatory activity has been demonstrated in large (conduit) arteries and in resistance vessels of most mammalian species, including human beings. Induction of vascular smooth muscle relaxation by EDNO increases cytosolic cyclic guanosine monophosphate (cGMP) within the myocytes. cGMP is present in platelets and can be activated by EDNO. Increased cGMP in platelets is associated with reduced adhesion and aggregation. EDNO induces vasodilation and platelet deactivation. EDNO is a readily diffusible substance with a half-life of a few seconds, and it decomposes spontaneously into nitrate and nitrite. EDNO is formed from oxidation of L-arginine, a process catalyzed by nitric oxide synthase (NO synthase). In addition to the endothelium, this enzymatic activity also is present in PMNs, macrophages, renal cells, Kupffer cells, and cerebellar neurons. In normal vasculature, experiments blocking EDNO activity induce a state of vasoconstriction that is readily reversed with L-arginine administration. This demonstrates that the vasculature is in a constant state of vasodilation because of the continuous basal release of EDNO. Endogenous inhibitors of EDNO have been identified that are autoregulators of endothelial tone. Elevations of EDNO in septic shock and trauma are associated with low systemic vascular resistance.

Prostacyclin Prostacyclin (PGI2) is an important endothelium-derived vasodilator synthesized in response to vascular shear stress and hypoxia. It has functions similar to those of EDNO. Prostacyclin is derived from arachidonic acid and causes relaxation and platelet deactivation by increasing cAMP. It has been used to reduce pulmonary hypertension, particularly in pediatric patients.

Endothelins Endothelins (ETs) are elaborated by vascular endothelial cells in response to injury, thrombin, IL-1, angiotensin II, arginine vasopressin, catecholamines, and anoxia. ET is a small peptide with potent vasoconstrictor properties. Among the peptides in this family, ET-1 is the most biologically active and potent vasoconstrictor known. It is estimated to be 10 times more potent than angiotensin II. ET receptors are linked to the formation of EDNO and PGI2, which are negative feedback mechanisms, and the vasoconstrictor activity of ET can be reversed by the administration of acetylcholine, which stimulates EDNO production. Thus both EDNO and ET interact to maintain physiologic tone in vascular smooth muscles. Increased serum levels of ET are correlated with the severity of injury after major trauma, major surgical procedures, and in cardiogenic or septic shock.

Platelet-Activating Factor Another endothelium-derived product is PAF, a phospholipid constituent of cell membranes that can be induced by TNF, IL-1, AVP, and angiotensin II. This inflammatory mediator stimulates production of TxA2, which is a potent vasoconstrictor. Experimentally, PAF can induce hypotension and increase vascular permeability, hemoconcentration, pulmonary hypertension, bronchoconstriction, primed PMN activity, eosinophil chemotaxis/degranulation, and thrombocytopenia. It induces a general leukocytopenia by way of margination. Administration of antagonists to PAF in experimental human endotoxemia partially attenuates myalgias and rigors, but they do not reverse hemodynamic derangements. PAF alters the shape of endothelial cells, causing them to contract and increase permeability sufficiently to permit the passage of macromolecules, such as albumin, across cell junctions. PAF is a chemotactant for leukocyte adherence to the vascular wall and facilitates migration out of the vascular compartment. The disparity between PAF-induced vascular permeability and PAF-induced vasoconstriction is most likely the result of differences in receptor types and affinity in different vascular segments. Other cells that secrete PAF include macrophages, PMNs, basophils, mast cells, and eosinophils.

Atrial Natriuretic Peptides Atrial natriuretic peptides (ANPs) are released by the central nervous system and by specialized endothelium found in atrial tissues in response to wall tension. ANPs are potent inhibitors of aldosterone secretion and prevent reabsorption of sodium. In rats, myocardial EDNO inhibits the release of ANP, while ET-1 stimulates it. The role of ANP in human response to injury is unknown.

Intracellular Mediators

Heat-Shock Proteins In addition to heat, hypoxia, trauma, heavy metals, and hemorrhage induce the production of intracellular heat-shock proteins (HSPs). These proteins are presumed to protect cells during stress states. HSPs function intracellularly in the assembly, disassembly, stability, and transport of proteins. The classic example of HSP activity is the intracellular transport of steroid molecules. Gene expression occurs in parallel with hormonal activities of the hypothalamus-pituitary-adrenal axis. This response may be ACTH-sensitive, and the production may decline with age. Although HSPs are important intracellular effectors, their relevance in the human response to injury can only be inferred from animal data.

Reactive Oxygen Metabolites Reactive oxygen metabolites (ROMs) are short-lived, highly reactive molecular oxygen species with an unpaired outer orbit. They cause tissue injury by peroxidation of cell membrane fatty acids. ROMs are produced by complex processes that involve anaerobic glucose oxidation coupled with the reduction of oxygen to superoxide anion. Superoxide anion is a potent ROM. It is metabolized to form other reactive species, such as hydrogen peroxide and hydroxyl radical. Cells are not immune to damage by their own ROMs but are generally protected by oxygen scavengers that include glutathione and catalases. In ischemic tissues, the intracellular mechanisms for production of ROMs become fully activated but are nonfunctional because of a lack of oxygen supply. With restoration of blood flow and oxygen, large quantities of ROMs are produced that can induce reperfusion injury. In response to a stimulus, activated leukocytes are potent generators of reactive oxygen metabolites. ROMs also can induce apoptosis.

Other Inflammatory Mediators

Eicosanoids The eicosanoid class of mediators, which encompasses prostaglandins (PG), thromboxanes (Tx), and leukotrienes (LT), consists of oxidation derivatives of the membrane phospholipid arachidonic acid (eicosatetraenoic acid). The eicosanoids are secreted by virtually all nucleated cells except lymphocytes. The synthesis of arachidonic acid from phospholipids requires enzymatic activation of phospholipase A2 (Fig. 1-4). There are two subsequent synthetic pathways. Products of the cyclooxygenase pathway include all the prostaglandins and thromboxanes. The lipoxygenase pathway generates the leukotrienes. Initial phospholipase A2 activation can be achieved by compounds such as epinephrine, angiotensin II, bradykinin, histamine, and thrombin. The synthesis of prostaglandins and thromboxanes is inhibited by nonsteroidal anti-inflammatory drugs and salicylates, which are cyclooxygenase inhibitors. Eicosanoids are not stored in cells but are synthesized rapidly on stimulation by hypoxic and ischemic injury, direct tissue injury, endotoxin, norepinephrine, AVP, angiotensin II, bradykinin, serotonin, acetylcholine, and histamine.



FIGURE 1-4 Arachidonic acid metabolism. Corticosteroids can block the conversion of phospholipids to arachidonic acid. Salicylates can inhibit prostaglandin synthesis. (From: Robertson RP: Prostaglandins and other arachidonic acid metabolites, in Becker KL, et al (eds): Principles and Practice of Endocrinology and Metabolism, 2d ed. Philadelphia, JB Lippincott 1996, chap 170, with permission.)



The products of arachidonic acid metabolism are functionally cell/tissue specific. Vascular endothelium primarily synthesizes PGI2, which causes vasodilation and platelet deactivation. Thromboxane synthetase converts platelet prostaglandins to TxA2, a potent vasoconstrictor and platelet aggregator. Macrophages are capable of synthesizing cyclooxygenase and lipoxygenase products. Second messengers mediate much of eicosanoid activity.

Eicosanoids have diverse effects systemically on endocrine and immune function, neurotransmission, and vasomotor regulation (Table 1-5). Eicosanoids promote changes in vascular permeability, leukocyte migration, and vasodilation after injury. They can potentially contribute to acute lung injury, pancreatitis, and renal failure. Leukotrienes are produced by cells of the lung, connective tissue, smooth muscle, macrophages, and mast cells that mediate the reactions characteristic of anaphylaxis. Leukotrienes promote capillary leakage, leukocyte adherence, neutrophil activation, bronchoconstriction, and vasoconstriction.



TABLE 1-5 SYSTEMIC STIMULATORY AND INHIBITORY ACTIONS OF EICOSANOIDS



Products of the cyclooxygenase pathway inhibit pancreatic beta cell release of insulin, whereas products of the lipoxygenase pathway promote beta cell activity. Hepatocytes also express specific receptors for PGE2 that, when activated, inhibit gluconeogenesis. PGE2 inhibits hormone-stimulated lipolysis. Small amounts of PGE2 suppress proliferation of human T lymphocytes by mitogens, an effect mediated by downregulation of IL-2 production. Enhanced lymphocyte activation can be achieved with the administration of indomethacin, a PGE2 inhibitor.

Kallikrein-Kinin System Bradykinins are potent vasodilators produced through kininogen degradation by the serine protease kallikrein. Kallikrein exists in blood and tissues in an inactive form and is activated by various chemical and physical factors, such as Hageman factor, trypsin, plasmin, factor XI, glass surfaces, kaolin, and collagen. Kinins are rapidly metabolized. One of these enzymes, kinase II, is identical to angiotensin-converting enzyme. The use of angiotensin-converting enzyme inhibitors (ACE inhibitors) in controlling hypertension may serve partially to block kinin degradation in some patients and enhance the kinin-induced injurious effects on the bronchial tree. Kinins increase capillary permeability and tissue edema, evoke pain, and increase bronchoconstriction. They also increase renin formation, which promotes sodium and water retention via the renin-angiotensin system.

Bradykinin release is stimulated by hypoxic and ischemic injury. Increased kallikrein activity and bradykinin levels have been detected after hemorrhage, sepsis, endotoxemia, and tissue injury. These observations are correlated with the magnitude of injury and mortality. Clinical trials using bradykinin antagonists in attempts to reduce the deleterious sequelae of septic shock have demonstrated only modest effects and no overall improvement in survival. Kinins increase glucose clearance by inhibiting gluconeogenesis.

Serotonin The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is a tryptophan derivative that is found in the intestine and in platelets. Patients with midgut carcinoid tumors often secrete excessive 5-HT. This neurotransmitter stimulates vasoconstriction, bronchoconstriction, and platelet aggregation. It also has chronotropic and inotropic effects. Although it is released at sites of injury, its role in the injury response is unclear.

Histamine Histamine is derived from histidine and stored in neurons, skin, gastric mucosa, mast cells, basophils, and platelets. There are two receptors for histamine binding. H1 binding mediates increased uuptake of the histamine precursor, L-histidine, and stimulates bronchoconstriction, intestinal motility, and myocardial contractility. H2 binding inhibits histamine release. H1 and H2 receptor activation induces vasodilation and increases vascular permeability. Histamine administration causes hypotension, peripheral pooling of blood, increased capillary permeability, decreased venous return, and myocardial failure. Histamine is released in hemorrhagic shock, trauma, thermal injury, endotoxemia, and sepsis. Histamine levels are correlated with mortality from septic shock.

METABOLIC RESPONSE TO INJURY

The description of human biochemical responses to injury and the classification of such responses into an ebb and flow phase provide a useful model by which the metabolic response to injury may be characterized. The ebb phase corresponds to the earliest moments to hours after injury, often in association with hemodynamic instability or reductions in effective circulating blood volume. The metabolic consequences of this phase are less well studied but generally are associated with reductions in total body energy expenditure and urinary nitrogen loss. The ebb phase is associated with neuroendocrine hormone appearance, including catecholamines and cortisol. Less is known about the microendocrine mediator response. It is difficult to separate the immune cell mediator response from responses to fluid or volume resuscitation and tissue reperfusion and reoxygenation.

The flow phase is ushered in by compensatory mechanisms resulting from volume repletion and cessation of initial injury conditions. The metabolic response associated with the flow phase serves to direct energy and protein substrates both to preserve organ function and repair damaged tissues. This includes an increase in whole-body oxygen consumption and metabolic rate, enhancement of enzyme pathways for oxidation of energy substrates such as glucose, and stimulation of the immune system to repair tissue and prevent additional breaks in epithelial barriers. A reprioritization of substrate processing occurs to support the production of acute-phase reactants, immunoreactive proteins, and coagulation factors. Wound healing begins during the early flow phase.

Metabolic Response to Fasting

A comparison between the metabolic physiology of injury and that of unstressed fasting is useful for assessing the physiologic alterations under these widely varying conditions. Factors such as antecedent health status, age, and lean body mass also influence the absolute rates of substrate utilization after fasting and injury.

Substrate Metabolism A healthy adult of 70 kg body weight expends 1700–1800 kcal/day of energy obtained from the oxidation of lipid, carbohydrate, and protein. Obligate glycolytic cells, such as neurons, leukocytes, and erythrocytes, require 180 g of glucose per 24 h for basal energy needs. During acute starvation, glucose is derived from existing storage pools, including approximately 75 g glucose stored as hepatic glycogen. Skeletal muscle cannot directly release free glucose because it lacks the glucose-6-phosphatase necessary for this. The reduction of circulating glucose during prolonged fasting stimulates hormonal release that modulates gluconeogenesis and substrate substitution for those tissues which require glucose for energy. Glucose concentration falls within hours after the onset of fasting in association with decreases in insulin and increases of circulating glucagon GH, catecholamines, AVP, and angiotensin II. Glucagon and epinephrine enhance cAMP to promote glycogenolysis, and cortisol and glucagon promote gluconeogenesis. Norepinephrine, AVP, and angiotensin II also promote glycogenolysis. Cortisol and epinephrine limit pyruvate use. The effect of these actions is an increase in glucose production. Sustained glucose production depends on the presentation of amino acids, glycerol, and fatty acids to the liver.

The primary gluconeogenic precursors used by the liver and to a lesser extent by the kidney for gluconeogenesis are lactate, glycerol, and amino acids such as alanine and glutamine. Skeletal muscle releases lactate by the breakdown of endogenous glycogen stores and by glycolysis of transported glucose. Lactate is also released by erythrocytes and white blood cells after aerobic glycolysis and release of newly formed lactate into the circulation. This lactate is reconverted to glucose in the liver by the Cori cycle.

The quantity of glucose made from lactate produced by skeletal muscle is not sufficient to maintain glucose homeostasis. Consequently, approximately 75 g of protein must be degraded daily during fasting and starvation to provide gluconeogenic amino acids to the liver. Proteolysis, which results primarily from decreased insulin and increased cortisol, is associated with an increase in urinary nitrogen excretion from the normal 6–8 g/day to approximately 8–11 g within the initial 5 days of fasting. Protein mobilized in starvation is derived primarily from skeletal muscle, but the loss of protein from other organs also occurs. The amino nitrogen load resulting from deamination of amino acids for gluconeogenesis increases urinary ammonia excretion. The renal excretion of ammonium ion becomes the primary route of elimination of alpha-amino nitrogen during starvation because the normally active hepatic enzymes are diminished. Renal gluconeogenesis increases through metabolism of glutamine and glutamate. The kidney may account for up to 45 percent of glucose production during late starvation.

After approximately 5 days, the rate of whole-body proteolysis diminishes to a level of 15–20 g/day, and urinary nitrogen excretion stabilizes at 2–5 g/day for several weeks. This reduction in proteolysis occurs because the nervous system and other previous glucose-utilizing tissues adapt to ketone oxidation as the predominant energy source. Consequently, the amount of protein required for gluconeogenesis is significantly reduced. A reduction in anabolic growth factors such as IGF-1 (formerly somatomedin C) also is observed during the first several days of fasting. This leads to a reduction in transcellular amino acid transport and tissue protein synthesis contemporaneously with reductions in proteolysis.

Energy requirements for gluconeogenesis and basal enzymatic and muscular function, such as neural transmission and cardiac contraction, can be met by the mobilization of approximately 160 g of triglycerides from adipose tissue in the form of free fatty acids and glycerol in a resting, fasting 70-kg subject. Free fatty acid release is stimulated by a reduction in the serum insulin concentration. Increased glucagon may participate in this alteration, as do catecholamines. The free fatty acids and ketone bodies generated by the liver are used as a source of energy by tissues such as the heart, kidney, muscle, and liver. Lipid stores provide up to 40 percent of the caloric expenditure during starvation. Lipid oxidation during starvation diminishes the absolute glucose requirement to sustain tissue and body energy expenditure. Fatty acid use occurs at a rate that is proportional to serum fatty acid concentration. Ketone bodies inhibit pyruvate dehydrogenase and spare glucose. The use of fat as a main fuel source decreases the amount of mandatory glycolysis, which diminishes the requirements for gluconeogenesis and protein degradation.

Whole-body energy expenditure decreases during prolonged fasting. This reduction in resting energy expenditure is a consequence of decreased sympathetic nervous system activity and reduced skeletal muscle activity, as well as reduced secretory enzyme production and intestinal energy needs.

Metabolism after Injury

The metabolic consequences of injury differ in many fundamental ways from those of simple starvation. Well-defined changes in hormone levels and associated substrates accompany injury. These changes can reflect the degree of underlying injury. It is the sustained activities of macroendocrine hormones in conjunction with immune cell activation that provide the signals that differentiate injury metabolism from unstressed starvation.

Energy Balance Injury of any magnitude is associated with increases in energy expenditure and oxygen consumption that vary directly with the severity of injury or burn surface area. The increase in energy expenditure results initially from the increased activity of the sympathetic nervous system and increased circulating concentrations of catecholamines.

Lipid Metabolism Lipolysis is enhanced by the immediate elevations in ACTH, cortisol, catecholamines, glucagon, and growth hormone, reduction in insulin, and increased sympathetic nervous system activity. Lipolysis observed during the ebb phase results in elevated levels of plasma free fatty acids and glycerol. Acidosis, hyperglycemia, and anesthetic agents can alter lipid mobilization early after injury. During the flow phase, net lipolysis continues, as reflected by increased concentrations and clearance of plasma free fatty acids. In the presence of oxygen, the released fatty acids can be oxidized by cardiac and skeletal muscle to produce energy. The roles of cytokines, such as TNF, IL-1, and PGE, in fat metabolism are not fully understood. The high concentrations of intracellular fatty acids and the elevated concentration of glucagon during the ebb and flow phases inhibit fatty acid synthesis. Ketogenesis is variable and is inversely correlated with the severity of injury. Ketogenesis is decreased after major injury, severe shock, and sepsis. It is suppressed by increases in levels of insulin and other energy substrates, by increased uptake and oxidation of free fatty acids, and by an associated counterregulatory hormone response. After minor injury or mild infection, ketogenesis increases but to a lesser extent than that seen during nonstressed starvation. Injuries that are associated with minor ketone body formation also appear to be associated with a small or absent increase in plasma free fatty acid concentrations.

Carbohydrate Metabolism Glucose intolerance is well documented in injured patients. By contrast, basal insulin levels are elevated by several times during the early flow phase, indicating a state of relative insulin resistance. A 50–60 percent increase in net splanchnic glucose output is observed in septic patients, and a 50–100 percent increase is noted in thermally injured patients. The associated macroendocrine hormone milieu contributes to this net gluconeogenic response and is believed to be largely under the active control of glucagon with permissive requirement for cortisol. The precise contributions of other macroendocrine hormones are unclear. Proinflammatory mediators such as IL-6 also may exert an influence on hepatic glucose production. Definable acute changes in substrate turnover are associated with the proinflammatory mediator activity induced by endotoxin administration or TNF infusion.

Increases in plasma glucose levels are proportional to the severity of injury and to some extent are correlated with survival. With the presence of hyperglycemia, resulting largely from increased hepatic production, a ready source of substrate is provided to tissues such as those of the nervous system, wound, and red blood cells, which do not require insulin for glucose transport. Elevated concentrations of glucose and of some amino acids may be necessary for leukocyte energy requirements in inflamed tissues and in defense of epithelial barriers or other sites of microbial invasion. Insulin resistance is of teleologic benefit to the host in that the accompanying neuroendocrine hormone response precludes the adaptation to ketone body production. To a large extent, the deprivation of glucose to nonessential organs such as skeletal muscle and adipose tissues is mediated by catecholamines and cortisol. Mechanisms for reduced glucose oxidation are not fully understood. Reduction of skeletal muscle pyruvate dehydrogenase activity diminishes the conversion of glucose to acetyl CoA and subsequent entry into the tricarboxylic acid cycle. The consequent accumulation and shunting of three carbon skeletons to the liver provides substrate for gluconeogenesis.

Glucose must be provided to inflammatory and healing cells in the wound. Glucose uptake and lactate production in wounded tissue are significantly increased. Wound inflammatory cells require glucose as an energy substrate, and glucose uptake in wounded tissue is correlated with the inflammatory cellular infiltrate.

Protein and Amino Acid Metabolism The intake of protein for a healthy young adult is approximately 80–120 g, or 13–20 g of nitrogen per day. Daily fecal and urinary excretion of nitrogen is 2–3 g and 13–20 g, respectively. After injury, daily nitrogen excretion in the urine increases to 30–50 g as urea nitrogen and represents net proteolysis. The increased excretion of urea after injury also is associated with the urinary loss of sulfur, phosphorus, potassium, magnesium, and creatinine, which indicates breakdown of intracellular compounds and a loss of lean tissue. Skeletal muscle is depleted, while visceral tissues, such as liver and kidney, are relatively preserved. The mechanisms for this visceral protein preservation are unclear. The net changes in catabolism and synthesis depend on the severity of the injury. Elective operations and minor injuries result in decreased protein synthesis and normal rates of protein breakdown. Severe trauma, burns, and sepsis are associated with increased whole-body protein turnover and increased net protein catabolism (Table 1-6). Accelerated proteolysis and gluconeogenesis persist after major injury and during sepsis. The rise in urinary nitrogen and negative nitrogen balance begin shortly after injury, reach a peak about the first week, and may continue for 3–7 weeks. The magnitude of nitrogen loss also is related to the age, sex, and physical condition of the patient. Young, healthy males lose more protein in response to an injury than do women or the elderly, presumably because they have a higher lean body mass than the latter two patient subsets.



TABLE 1-6 SUBSTRATE TURNOVER IN RESPONSE TO LPS AND TNF ADMINISTRATION



The amino acid composition of normal human beings varies according to tissue origin. After trauma, substrate cycling occurs between skeletal muscle, liver, and the wound. Increases by several times in the splanchnic uptake of alanine and glutamine in conjunction with similar trends for peripheral tissue efflux are observed after injury. Although the precise mechanisms for the net increase in skeletal muscle protein breakdown remain unclear, the combined extracellular hormonal milieu of relative insulin resistance, cortisol excess, and proinflammatory cytokine activity exert a synergistic influence. The intracellular muscle concentrations of several essential amino acids decrease at the same time that net efflux is occurring from skeletal muscle. The release of glutamine and alanine is greater than can be predicted from their relative abundance in muscle tissue protein, indicating their net synthesis in muscle before release. Glutamine is a major energy source for lymphocytes, fibroblasts, and the GI tract, especially during conditions of increased stress. Glutamine may act as a conditionally essential amino acid during periods of catabolism, since depletion of this substrate has pronounced negative effects on enterocytes and mucosal integrity and since administration of glutamine reverses these effects.

NUTRITION IN THE SURGICAL PATIENT

Most patients undergoing elective surgical operations withstand the brief period of catabolism and starvation without noticeable difficulty. Maintaining adequate nutrition may be of critical importance, however, in managing seriously ill patients, especially those with preexisting weight loss. Between these two extremes are patients for whom nutritional support is not essential for life but may serve to shorten the postoperative recovery phase and minimize complications. It is essential that the surgeon have a sound grasp of the fundamental metabolic changes associated with surgery, trauma, and sepsis and an awareness of the methods available to reverse or ameliorate these events.

Surgery, Trauma, Sepsis

In contrast to energy and protein conservation during unstressed starvation, the injured patient manifests increases in energy expenditure and nitrogen loss (Fig. 1-5). While the extent and duration of this response to injury are modified by a variety of factors, including the adequacy of resuscitation, infection, and medication, the inability to downregulate body energy expenditure and nitrogen losses may rapidly deplete labile and functional energy stores. The postinjury metabolic environment precludes the efficient oxidation of fat and production of ketones, thereby promoting continued erosion of protein. If unchecked, this enhanced net protein catabolism may lead to organ failure.



FIGURE 1-5 The minimum anticipated daily urinary nitrogen excretion of adult patients in relation to the injury stimulus. These losses may be modulated by a number of variables, including the age and nutritional status of the patient. (Adapted from: Grant JP: Handbook of Total Parenteral Nutrition. Phialdelphia, WB Saunders, 1980, with permission.)



The sequence of flow phase metabolic and endocrine events occasioned by injury may be divided into several phases. The magnitude of the changes and the duration of each phase vary considerably and are directly related to the severity of the injury. The benefits of exogenous nutritional support in each of these recovery phases are controversial. Based on the current understanding of endocrine and immune system interactions, tissue restoration and substrate-dependent immune competence should be facilitated during periods of attenuated mediator activity. This does not preclude a rationale for earlier efforts at nutritional intervention, but it provides a biologic basis for reasonable expectations of therapy.

Catabolic Phase Once patients have received initial resuscitation and stabilization of wounds, the earliest definable metabolic response is one of catabolism. This phase has been termed the adrenergic-corticoid phase because it corresponds to the period during which changes induced by adrenergic and adrenal corticoid hormones are most striking. It is also likely that components of the micromediator systems exert significant influences during this phase. To variable degrees, rates of gluconeogenesis, acute-phase protein production, and immune cell activity are all altered during the catabolic phase. The administration of moderate amounts of glucose to these individuals produces little or no change in the rate of protein catabolism. Provision of sufficient nonprotein calories and amino acids may reduce the rate of protein breakdown. In the catabolic phase, glucose turnover is increased, whereas Cori cycle activity is stimulated and three-carbon intermediates are converted back to glucose in the liver. Lipolysis also is stimulated by this hormonal milieu, and an obligatory oxidation of fatty acids is evident.

Efforts directed at interruption of afferent neurogenic stimuli by extradural anesthesia have met with partial success in attenuating some of these abnormalities of energy substrate turnover. The impact of such therapy on nitrogen loss has been far less dramatic, suggesting that circulating or tissue paracrine factors other than classic neuroendocrine hormones are of major importance in early postinjury metabolic responses. Blockade of TNF and IL-1 activities during conditions of human endotoxinemia does not prevent the characteristic increase in metabolic rate and glucose or protein turnover.

Early Anabolic Phase The transition from a catabolic to an anabolic phase may occur within 3–8 days after uncomplicated elective surgery. It may be delayed for weeks, however, in patients with extensive cross-sectional tissue injury, sepsis, or ungrafted thermal injury. This turning point, also known as the corticoid-withdrawal phase, is characterized by a sharp decline in nitrogen excretion and restoration of appropriate potassium-nitrogen balance. This phase is also biochemically characterized by a reprioritization of acute-phase reactants, as early inflammatory response proteins are supplanted by tissue repair and anabolic factors such as IGF-1. Clinical manifestations of this transition period are brief and coincide with initial diuresis of retained water and renewed interest in oral nutrition. The early anabolic phase may last from a few weeks to a few months depending on the capacity to ingest adequate nutrition and the extent to which erosion of protein stores has occurred. Nitrogen balance is positive, indicating synthesis of proteins, and there is a rapid and progressive gain in weight and muscular strength. Positive nitrogen balance reaches a maximum of approximately 4 g/day, which represents the synthesis of approximately 25 g of protein and the gain of over 100 g of lean body mass per day. The total amount of nitrogen gain ultimately equals the amount lost during the catabolic phase, although the rate of gain will be much slower than the rate of initial loss.

Late Anabolic Phase The final period of convalescence, or the late anabolic phase, may last from several weeks to several months after a severe injury. This phase is associated with the gradual restoration of adipose stores as the previously positive nitrogen balance declines toward normal. Weight gain is much slower during this phase because of the higher caloric content of fat and can be realized only if intake is in excess of caloric expenditure. In most individuals, the phase ends with a gradual return to the previously normal body weight. The patient who is partially immobilized during this period of time, however, may exhibit a marked gain in weight as a result of decreased energy expenditure.

Assessment and Requirements

Nutritional homeostasis assumes that proper timing and administration of nutrients have a favorable impact on the outcome of therapy. Nutritional assessment is undertaken to determine the severity of nutrient deficiencies or excesses and to aid in predicting nutritional requirements. Important information is obtained by determining the presence of weight loss and of chronic illnesses or dietary habits influencing the quantity and quality of food intake prior to injury. Physical examination seeks to assess loss of muscle and adipose tissues, organ dysfunction, and subtle change in skin, hair, or neuromuscular function reflecting an impending nutritional deficiency. Anthropometric data (weight change, skin-fold thickness, and arm circumference muscle area) and biochemical determinations (levels of creatinine excretion, albumin, and transferrin) can be used to substantiate the patient's history and physical findings. It is imprecise to rely on any single or fixed combination of these findings to assess nutritional status or morbidity. Appreciation for the stresses and natural history of the disease process, in combination with nutritional assessment, is the basis for identifying patients in acute or anticipated need of nutritional support.

The caloric and nitrogen requirements necessary to maintain an individual in balance after severe injury depend on the extent of injury, the source and route of administered nutrients, and to some extent, the degree of antecedent malnutrition. A fundamental goal of nutritional support is to meet the energy requirements for metabolic processes, core temperature maintenance, and tissue repair. Failure to provide adequate nonprotein energy sources leads to dissolution of lean tissue stores. The requirements for energy may be measured by indirect calorimetry or estimated from urinary nitrogen excretion, which is proportional to resting energy expenditure. Basal energy expenditure (BEE) also can be estimated by the equations of Harris and Benedict:

where W is weight (kg), H is height (cm), and A is age (years). These equations are suitable for estimating energy requirements in at least 80 percent of hospitalized patients. Nonprotein calories are supplied in excess of energy expenditure because the use of exogenous nutrients is decreased and energy substrate demands are increased after traumatic or septic insult. Appropriate nonprotein caloric needs are 1.2–1.5 times resting energy expenditure (REE) during enteral nutrition and 1.5–2.0 times REE during intravenous nutrition. It is seldom, if ever, appropriate to exceed this level of nonprotein energy intake during the height of the catabolic phase.

The second objective of nutritional support is to meet the substrate requirements for protein synthesis. Maintenance of protein synthesis depends on many factors, including the nature and degree of the insult, the source and amount of exogenous protein, and previous nutritional status. Consequently, no single nutritional formulation is appropriate for all patients. An appropriate calorie-nitrogen ratio (150–200:1) should be maintained, but evidence suggests that increased protein intake (and a lower calorie-nitrogen ratio) may be efficient in selected hypermetabolic patients. In the absence of severe renal or hepatic dysfunction precluding the use of standard nutritional regimens, approximately 0.25–0.35 g of nitrogen per kilogram of body weight should be provided daily. Specialized nutritional formulations designed to improve nitrogen use in organ dysfunction such as acute renal and hepatic failure are targeted either to supplement deficiencies associated with the disease process or to correct characteristic amino acid abnormalities.

Vitamins usually are not given in the absence of preoperative deficiencies. Patients maintained on elemental diets or parenteral hyperalimentation require complete vitamin and mineral supplementation. The commercial defined-formula enteral diets contain varying amounts of essential minerals and vitamins. It is necessary to ensure that adequate replacement is available in the diet or by supplementation. Commercial vitamin preparations often do not contain vitamin K, and some do not provide vitamin B12 or folic acid. Supplemental trace minerals may be given intravenously. Essential fatty acid supplementation also may be necessary. Patients receiving intravenous feeding require all the preceding micronutrients to prevent the development of deficiencies.

Indications and Methods for Nutritional Support

The ability to provide nutritional support to stressed patients and to attenuate nitrogen losses in catabolic states is an important adjunct to surgical care. The need for nutritional support should be assessed during the preoperative and postoperative courses of all but the most routine cases. Most surgical patients, however, tolerate a brief period of starvation (up to 1 week) well and do not require special nutritional regimens. If the patient has a relatively uncomplicated postoperative course and resumes normal oral intake at the end of this period, defined-formula diets or parenteral alimentation is unnecessary and inadvisable because of the associated risks. During the early anabolic phase, the patient needs an adequate caloric intake, a high calorie-to-nitrogen ratio (approximately 150 kcal/g nitrogen), and an adequate supply of vitamins and minerals for maximum anabolism.

For other surgical patients, an adequate nutritional regimen can be of critical importance for a successful outcome. These include patients who are chronically debilitated preoperatively from their diseases or from malnutrition and patients who have suffered trauma, sepsis, or surgical complications. In many cases the need for nutritional therapy during the early catabolic phase is apparent. This most certainly includes patients for whom there is a high expectation of prolonged hospitalization and diminished capacity for voluntary nutrient intake, such as patients with extensive burns or those with other severe injuries and incipient or overt organ failure. Despite the intuitively obvious decision to initiate nutritional support in such populations, documentation of nutrition-specific benefits or improvements in outcome are generally lacking. Nevertheless, such highly stressed and at-risk patients should receive consideration of nutritional support early.

The dilemma more commonly presented to the clinician is the identification of other patients in whom a reasonable expectation of benefit from nutritional intervention can be met. Prospective, randomized trials have significantly narrowed the populations in whom this expectation might be met. In general, the indications for preoperative nutritional support, at least in hospitalized patients, appear largely confined to patients with clinical evidence of erosion of lean body mass and adipose tissue stores. It is also possible that nutritional support in the ambulatory setting might benefit those with evidence of organ failure or immunosuppression before elective surgery.

Specialized nutritional support can be given enterally or enterally with supplements via peripheral vein or by central venous routes. The enteral route always should be used when possible because it is considered to be more economical and well tolerated, even in patients who have had recent abdominal surgery. Nasopharyngeal, gastrostomy, and jejunostomy tube feedings may be considered for alimentation in patients who have a relatively normal GI tract but cannot or will not eat. Elemental diets may be administered by similar routes when bulk and fat-free nutrients requiring minimal digestion are indicated. Parenteral alimentation may be used for supplementation in the patient with limited oral intake or, more commonly, for complete nutritional management in the absence of oral intake. Clinical studies demonstrate that parenteral feeding potentially enhances the magnitude of endocrine and cytokine responses. While the mechanisms for this observation in parenterally fed subjects remain to be fully elucidated, a loss of intestinal barrier function permitting acute or chronic host exposure to luminal toxins has been proposed. In human beings, it has not been clearly determined whether parenteral nutrition significantly alters intestinal barrier function instead of intracellular and intercellular anatomy. While several studies suggest a higher incidence of infectious complications in parenterally fed subjects compared with an enterally fed cohort, this observation is largely confined to traumatically injured populations.

Despite the failure to document clinical differences between the enteral and parenteral feeding routes for exogenous nutrients, the GI tract serves a number of synthetic and immunologic functions that bear consideration in the design of nutritional support regimens. A number of approaches for preserving GI mucosal integrity and gut mass, including luminal stimulation by digestible or nondigestible substrates and infusion of critical intestinal fuel sources such as glutamine or short-chain fatty acids, are undergoing clinical trials. To date, these products have not been clearly documented to improve outcome in the majority of populations studied.

The patient's ability to tolerate and absorb enteral feedings is determined by the rate of infusion, the osmolality, and the chemical nature of the product. Enteral feedings often are begun at a rate of 30–50 mL/h and are increased by 10–25 mL/h per day until the optimal volume is delivered. After full volume is attained, the concentration of the solution is increased slowly to the desired strength. If esophageal or gastric feedings are given, residual gastric volume should be monitored to reduce the risk of a major aspiration episode. If abdominal cramping or diarrhea occurs, the rate of administration or the concentration of the solution should be decreased. All feeding tubes should be thoroughly irrigated clear of solutions if feedings are interrupted or medications are given by this route.

Parenteral alimentation involves the continuous infusion of a hyperosmolar solution containing carbohydrates, proteins, fat, and other necessary nutrients through an indwelling catheter inserted into the superior vena cava. In order to obtain the maximum benefit, the ratio of calories to nitrogen must be adequate (at least 100–150 kcal/g nitrogen), and the two materials must be infused simultaneously. These nutrients can be given in quantities considerably greater than basal caloric and nitrogen requirements, and this method has proved highly successful in achieving growth and development, positive nitrogen balance, and weight gain in a variety of clinical situations.

Indications for the Use of Intravenous Feedings It is difficult to demonstrate that parenteral feeding significantly alters the clinical course or outcome in most nonsurgical patient populations. Preoperative nutritional support may benefit some surgical patients, particularly those with preexisting malnutrition. Evidence of benefit from the use of nutritional support in the elective postoperative setting is lacking. The routine use of parenteral alimentation in the critical care environment has yet to be adequately assessed, and so it is currently used intuitively.

The principal indications for parenteral alimentation are found in seriously ill patients suffering from malnutrition, sepsis, or trauma when use of the GI tract for feedings is not possible. In some instances, intravenous nutrition may be used to supplement inadequate oral intake. The safe and successful use of this regimen requires proper selection of patients with specific nutritional needs, experience with the technique, and an awareness of the associated complications. The fundamental goals are to provide sufficient calories and nitrogen substrate to promote tissue repair and to maintain the integrity or growth of lean tissue mass. Listed below are situations in which parenteral nutrition has been used in an effort to achieve these goals. Indications 1 and 2 below usually are used exclusively for intravenous nutrition. Indications 3 to 13 might be appropriate for enteral or parenteral nutrition.

  1. Newborn infants with catastrophic GI anomalies such as tracheoesophageal fistula, gastroschisis, omphalocele, or massive intestinal atresia
  2. Infants who fail to thrive nonspecifically or secondarily to GI insufficiency associated with the short-bowel syndrome, malabsorption, enzyme deficiency, meconium ileus, or idiopathic diarrhea
  3. Adult patients with short-bowel syndrome secondary to massive small-bowel resection or enteroenteric, enterocolic, enterovesical, or enterocutaneous fistulas
  4. Patients with high alimentary tract obstructions without vascular compromise secondary to achalasia, stricture, or neoplasia of the esophagus, gastric carcinoma, or pyloric obstruction
  5. Surgical patients with prolonged paralytic ileus after major operations, multiple injuries, or blunt or open abdominal trauma or patients with reflex ileus complicating various medical diseases
  6. Patients with normal bowel length but with malabsorption secondary to sprue, hypoproteinemia, enzyme or pancreatic insufficiency, regional enteritis, or ulcerative colitis
  7. Adult patients with functional GI disorders such as esophageal dyskinesia after cerebrovascular accident, idiopathic diarrhea, psychogenic vomiting, or anorexia nervosa
  8. Patients who cannot ingest food or who regurgitate and aspirate oral or tube feedings because of depressed or obtunded sensorium after severe metabolic derangements, neurologic disorders, intracranial surgery, or central nervous system trauma
  9. Patients with excessive metabolic requirements secondary to severe trauma such as extensive full-thickness burns, major fractures, or soft tissue injuries
  10. Patients with granulomatous colitis, ulcerative colitis, and tuberculous enteritis in whom major portions of the absorptive mucosa are diseased
  11. Paraplegics, quadriplegics, or debilitated patients with indolent decubitus ulcers in the pelvic areas, particularly when soilage and fecal contamination are a problem
  12. Patients with malignancy, with or without cachexia, in whom malnutrition might jeopardize successful delivery of a therapeutic option
  13. Patients with potentially reversible acute renal failure, in whom marked catabolism results in the liberation of intracellular anions and cations, inducing hyperkalemia, hypermagnesemia, and hyperphosphatemia

Contraindications to hyperalimentation include the following:

  1. Lack of a specific goal for patient management or when, instead of extending a meaningful life, inevitable dying is prolonged
  2. Periods of cardiovascular instability or severe metabolic derangement requiring control or correction before attempting hypertonic intravenous feeding
  3. Feasible GI feeding (In the vast majority of instances, this is the best route by which to provide nutrition.)
  4. Patients in good nutritional status, in whom only short-term parenteral nutrition support is required or anticipated
  5. Infants with less than 8 cm of small bowel, since virtually all have been unable to adapt sufficiently despite prolonged periods of parenteral nutrition
  6. Patients who are irreversibly decerebrate or otherwise dehumanized

For a more detailed discussion, see Lin E, Lowry SF, and Calvano SE: The Systemic Response to Injury, chap. 1 in Principles of Surgery, 7th ed.

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Copyright © 1998 McGraw-Hill
Seymour I. Schwartz
Principles of Surgery Companion Handbook