CHAPTER 1 - The Systemic Response to Injury Edward Lin Stephen F Lowry Ste!e E Ca"!

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INTRODUCTION The host response to injurysurgical, traumatic, or infectiousis characterized y !arious endocrine, meta olic, and immunologic alterations" If the inciting injury is minor and of limited duration, #ound healing and restoration of meta olic and immune homeostasis readily occurs" $ore significant insults lead to further deterioration of the host regulatory processes, #hich, #ithout appropriate inter!ention, often precludes full restoration of cellular and organ function or results in death" The spectrum of cellular meta olic and immunologic dysfunction resulting from injury suggests a comple% mechanism for identifying and initially &uantifying the injurious e!ent" This initial response is inherently inflammatory, inciting the acti!ation of cellular processes designed to restore or maintain function in tissues #hile also promoting the eradication or repair of dysfunctional cells" These dynamic processes imply the e%istence of antiinflammatory or counterregulatory processes that promote the restoration of homeostasis '(ig" )*)+" , discussion of the response to injury must account for the collecti!e dynamics of neuroendocrine, immunologic, and meta olic alterations characteristic of the injured patient" This chapter discusses concepts related to macroendocrine and microendocrine contri utions to the asic meta olic and immunological conse&uences of injury and also the current concepts of meta olism and nutritional support for the surgical patient as a practical and readily applica le adjunct for the pro!ision of essential su strates" The dynamics of hormonal and immunologic influences on the meta olic and su strate re&uirements of the injured patient are emphasized" -NDOCRIN- R-./ON.- TO IN0UR1 O!er!ie# of 2ormone*$ediated Response The classic response to injury comprises multiple a%es" These hormone response path#ays are acti!ated y ')+ mediators released y the injured tissue, '3+ neural and nocicepti!e input originating from the site of injury, or '4+ aroreceptor stimulation from intra!ascular !olume depletion" The hormones released in response to these acti!ating stimuli may e di!ided into those primarily under hypothalamopituitary control and those primarily under autonomic ner!ous system control 'Ta le )*)+" The interaction et#een these origins form the asis of the hypothalamic*pituitary a%is, #hich represents a series of signaling and feed ac5 loops regulating the endocrine response to injury '(ig" )*3+" 2ormone*$ediated Receptor ,cti!ity 2ormones may e classified according to chemical structure and to the mechanisms y #hich they elicit iologic effects 'Ta les )*3 and )*4+" Central to the hormone* mediated response at the cellular le!el is the hormone 'ligand+6receptor interaction and su se&uent postreceptor acti!ity" $ost macroendocrine hormone receptors can e categorized on the asis of their mechanisms of signal transduction into three major types7 ')+ receptor 5inases #ith ligands such as insulin and insulinli5e gro#th factors8 '3+ guanine nucleotide6 inding or 9 protein6coupled receptors that are acti!ated y

peptide hormones, neurotransmitters, and prostaglandins8 and '4+ ligand*gated ion channels that permit ion transport upon ligand*receptor inding '(ig" )*4+" 2ormone*$ediated Intracellular /ath#ays One of the most common intracellular second messengers y #hich hormones e%ert their effects is the modulation of cyclic adenosine monophosphate 'c,$/+" Receptor occupation y stimulatory hormones induces a cell mem rane alteration that acti!ates the enzyme adenylate cyclase" ,denylate cyclase catalyzes the con!ersion of adenosine triphosphate ',T/+ to c,$/, #hich acti!ates !arious intracellular protein 5inases" .u stances that decrease c,$/ generally e%ert an influence opposite to those o ser!ed for su stances that increase c,$/" Increases in intracellular c,$/ are associated #ith functional lymphocyte responses that generally are immunosuppressi!e" In T lymphocytes, agents that increase c,$/ le!els diminish proliferation, lympho5ine production, and cytoto%ic functions" /lasma cell production of immunoglo ulins is mar5edly attenuated" Neutrophils manifest decreased chemota%is and reduced production of supero%ides, 23O3, and lysosomal enzymes" :asophils or mast cells demonstrate a decreased release of histamine" $any prolonged hormone*mediated responses to injury increase intracellular c,$/ le!els through a direct action on mem rane receptors or y increasing the sensiti!ity of leu5ocytes to su stances that directly increase c,$/" 2ormonal actions are further mediated y intracellular receptors" These intracellular receptors ha!e inding affinities for the hormone and for the targeted gene se&uence on the DN," These intracellular receptors may e located #ithin the cytosol or may already e localized in the nucleus, ound to the DN," The classic e%ample of a cytosolic hormonal receptor is glucocorticoid receptor" Intracellular glucocorticoid receptors are maintained in an acti!e state y lin5ing to the stress*induced protein, heat*shoc5 protein '2./+" ;hen the hormone ligand inds to the receptor, the dissociation of 2./ from the receptor acti!ates the receptor*ligand comple% and is transported to the nucleus '(ig" )*<+" 2ormones Under ,nterior /ituitary Regulation Corticotropin*Releasing 2ormone /ain, fear, an%iety, or emotional arousal generate neural signals to the para!entricular nucleus of the hypothalamus, stimulating the synthesis of corticotropin*releasing hormone 'CR2+, #hich is then deli!ered y #ay of the hypothalamic*hypophyseal portal circulation to the anterior pituitary '(ig" )*=+" /roinflammatory cyto5ines and arginine !asopressin ',>/+ also can induce CR2 synthesis and release" In the anterior pituitary, CR2 ser!es as the major stimulant of adrenocorticotropic hormone ',CT2, adrenocorticotropin+ production and release '(ig" )*?+" This is accomplished y CR2*mediated acti!ation of adenylate cyclase in the ,CT2* producing corticotrophs, #hich increases intracellular c,$/ le!els and acti!ates the path#ay leading to increased ,CT2 production" CR2, formerly referred to as corticotropin*releasing factor, has induced, in la oratory animals, hyperdynamic cardio!ascular and catecholamine release characteristic of the sympathetic stress response" CR2 secretion can e acti!ated y angiotensin II, neuropeptide 1 'N/1+, serotonin, acetylcholine, interleu5in*), and interleu5in*?" The release of CR2 can e inhi ited y g* amino utyric acid '9,:,+, su stance /, atrial natriuretic peptide ',N/+, endogenous opioids, and l*arginine" Receptors for CR2 in primates ha!e een descri ed not only in the pituitary gland and the central ner!ous

system ut also in the renal medulla, in the marginal zone and red pulp of the spleen, and in the sympathetic ganglia" Circulating glucocorticoids ser!e as potent negati!e feed ac5 signals to the hypothalamus and ha!e demonstrated in animal models an a ility to reduce CR2 mRN, transcription" Con!ersely, adrenalectomized animals demonstrate ele!ated CR2 mRN, transcriptional acti!ities that are re!ersed #ith e%ogenous administration of de%amethasone or prednisolone" CR2* inding proteins 'CR2*:/+ synthesized y the li!er also ser!e as regulators of CR2 acti!ity" These collecti!ely demonstrate endogenous path#ays that may potentially regulate or preclude e%cessi!e CR2* mediated responses to injury" Injured tissues also produce CR2 that may contri ute locally to the inflammatory response" -%perimental studies suggest a role for CR2 in pre!enting !ascular lea5age in injured or inflamed tissues, although the implications ha!e not een identified" ,drenocorticotropic 2ormone ,CT2 is synthesized, stored, and released y the anterior pituitary upon CR2 stimulation" ,CT2 is a 4@6amino acid peptide that is synthesized as a larger precursor comple% 5no#n as proopiomelanocortin '/O$C+" /O$C is clea!ed #ithin the cytosol to the components a*melanocyte stimulating hormone 'a*$.2+, * lipotropin, the endogenous opioid *endorphin, and ,CT2" In the nonstressed healthy human eing, ,CT2 release is regulated y circadian signals8 the greatest ele!ation of ,CT2 occurs late at night and lasts until just efore sunrise" This pattern is dramatically altered or o literated in injured su jects" $ost injury is characterized y ele!ations in CR2 and ,CT2 that are proportional to the se!erity of injury" ;hile pain and an%iety are prominent mediators of ,CT2 release in the conscious injured patient, other ,CT2*promoting mediators may ecome relati!ely more acti!e in the injured patient" These include !asopressin, angiotensin II, cholecysto5inin, !asoacti!e intestinal polypeptide '>I/+, catecholamines, o%ytocin, and proinflammatory cyto5ines" ;ithin the zona fasciculata of the adrenal gland, ,CT2 signaling acti!ates intracellular adenylate cyclase, the c,$/*dependent protein 5inase path#ay, and mitochondrial cytochrome /*<=A system" This chain of acti!ities leads to increased glucocorticoid production !ia desmolase*catalyzed side*chain clea!age of cholesterol '(ig" )*B+" Conditions of e%cess ,CT2 stimulation result in adrenal cortical hypertrophy" CortisolC9lucocorticoids Cortisol is the major glucocorticoid in human eings and is essential for sur!i!al after significant physiological stress" Cortisol le!els in response to injury are not under the influence of normal diurnal !ariations and can remain persistently ele!ated, depending on the type of systemic stress" :urn patients ha!e demonstrated ele!ated circulating cortisol le!els for up to < #ee5s, and soft*tissue injury and hemorrhage may sustain ele!ated cortisol le!els for up to a #ee5" Circulating cortisol rapidly returns to normal le!els on restoration of lood !olume after hemorrhage" Con!ersely, ade&uate cortisol le!els after mild hemorrhage is a prere&uisite for timely restitution of lood !olume in e%perimental animals" Coe%isting systemic stress, such as infections, also can prolong the ele!ated cortisol le!els after injury" Cortisol is a major effector of host meta olism" It potentiates the actions of glucagon and epinephrine, leading to hyperglycemia in the host" In the li!er, cortisol stimulates the enzymatic acti!ities fa!oring gluconeogenesis, including induction of

phosphoenol pyru!ate car o%y5inase and transaminases" /eripherally, it decreases insulin* inding to insulin receptors in muscles and adipose tissue" In s5eletal muscle, cortisol induces proteolysis and augments the release of lactate" The release of a!aila le lactate and amino acids has the net effect of shifting su strates for hepatic gluconeogenesis" Cortisol also stimulates lipolysis and inhi its glucose upta5e y adipose tissues" It increases the lipolytic acti!ities of ,CT2, gro#th hormones, glucagon, and epinephrine" The resulting rises in plasma free fatty acids, triglycerides, and glycerol from adipose tissue mo ilization ser!e as a!aila le energy sources and additional su strates for hepatic gluconeogenesis" , out )A percent of plasma cortisol is present in the free, iologically acti!e form" The remaining @A percent is ound to corticosteroid* inding glo ulin 'C:9+ and al umin" ;ith injury, total plasma cortisol concentrations increase, ut C:9 and al umin le!els decrease y as much as =A percent" This can lead to an increase in free cortisol le!el of as much as ten times the normal le!el" ,cute adrenal insufficiency is a life*threatening complication most commonly associated #ith adrenal suppression from the use of e%ogenous glucocorticoids #ith conse&uent atrophy of the adrenal glands" These patients present #ith #ea5ness, nausea, !omiting, fe!er, and hypotension" O jecti!e findings include hypoglycemia from decreased gluconeogenesis, hyponatremia from impaired renal tu ular sodium resorption, and hyper5alemia from diminished 5aliuresis" ,lthough hyponatremia and hyper5alemia generally are a result of insufficient mineralocorticoid 'aldosterone+ acti!ity, the loss of cortisol acti!ity also contri utes to electrolyte a normalities" 9lucocorticoids ha!e long een used as effecti!e immunosuppressi!e agents" ,dministration of glucocorticoids can induce rapid lymphopenia, monocytopenia, eosinopenia, and neutrophilia" Immunologic changes include thymic in!olution, depressed cell*mediated immune responses reflected y decreases in T 5iller and natural 5iller functions, T lymphocyte lastogenesis, mi%ed lymphocyte responsi!eness, graft*!ersus*host reactions, and delayed hypersensiti!ity responses" ;ith glucocorticoid administration, monocytes lose the capacity for intracellular 5illing, ut they appear to maintain normal chemotactic and phagocytic properties" Neutrophil function is affected y glucocorticoid treatment in terms of intracellular supero%ide reacti!ity and depressed chemota%is" /hagocytosis of polymorphonuclear leu5ocytes '/$Ns+ remains unchanged" 9lucocorticoids are omni us inhi itors of immunocyte proinflammatory cyto5ine synthesis and secretion" This glucocorticoid* induced do#n* regulation of cyto5ine stimulation ser!es an important negati!e regulatory function in the inflammatory response to injury" $acrophage Inhi itory (actor Initially identified as a T lymphocyte6deri!ed inhi itor of macrophage migration, macrophage inhi itory factor '$I(+ is a glucocorticoid antagonist produced y the anterior pituitary" This hormone can potentially re!erse the immunosuppressi!e effects of glucocorticoids systemically !ia anterior pituitary secretion and at local sites of inflammation #here $I( is produced y T lymphocytes" In e%periments in #hich anti*$I( anti odies #ere administered to endoto%emic mice, sur!i!al increased presuma ly ecause glucocorticoid antiinflammatory effects #ere not counterregulated y $I(" Thyrotropin*Releasing 2ormone and Thyroid .timulating 2ormone Thyrotropin*releasing hormone 'TR2+ ser!es as the primary stimulant for the synthesis, storage, and release of thyroid*stimulating hormone 'T.2+ in the anterior

pituitary" T.2 in turn stimulates thyro%ine 'T<+ production from the thyroid gland" T< is con!erted to triiodothyronine 'T4+ y peripheral tissues" T4 is more potent than T<, ut oth are transported intracellularly y cytosolic receptors, #hich then ind DN, to mediate the transcription of multiple protein products" (ree forms of T< and T4 in the circulation can inhi it the hypothalamic release of TR2 and pituitary release of T.2 !ia negati!e feed ac5 loops" TR2 and estrogen stimulate T.2 release y the pituitary, and T4, T<, corticosteroids, gro#th hormones, somatostatin, and fasting inhi it T.2 release" Thyroid hormones 'thyronines+, #hen ele!ated a o!e normal le!els, e%ert !arious influences on cellular meta olism and function" Thyronines enhance mem rane transport of glucose and increase glucose o%idation" These hormones increase the formation and storage of fat #hen car ohydrate inta5e is e%cessi!e, ut this process decreases during star!ation" The increase in cellular meta olism from e%cess thyroid hormone production leads to proportional ele!ations in o!erall o%ygen consumption as #ell as heat production" ,lthough T4 le!els are fre&uently decreased after injury, there is no compensatory rise in T.2 release" ,fter major injury, reduced a!aila le T4 and circulating T.2 le!els are o ser!ed and peripheral con!ersion of T< to T4 is impaired" This impaired con!ersion may e e%plained in part y the inhi itory effects of cortisol and an increased con!ersion of T< to the iologically inacti!e molecule 5no#n as re!erse T4 'rT4+" /roinflammatory cyto5ines also may also contri ute to this effect" -le!ated rT4, ut reduced T< and T4, is an o ser!ation characteristic of acute injury or trauma, referred to as euthyroid sic5 syndrome or nonthyroidal illness" -%perimental mild endoto%emia in other#ise healthy human su jects has sho#n that thyroid hormone alterations in systemic inflammation is not mediated y endogenous ID*)" ;hile total T< 'protein ound and free+ le!els may e reduced after injury, free T< concentrations remain relati!ely constant" In se!erely injured or critically ill patients, a reduced free T<concentration has een predicti!e of high mortality '(ig" )*E+" Dymphoid cells ha!e high*affinity nuclear and cytoplasmic inding sites for thyronines" One conse&uence of e%posure to thyronines is an increase in the upta5e of amino acids and glucose into the cell" ;hether this is a direct effect of thyroid hormones or a secondary effect of increased cellular meta olism is un5no#n" Deu5ocyte meta olism measured y o%ygen consumption is increased in hyperthyroid indi!iduals and su jects to #hom thyroid hormones ha!e een administered" ,nimal studies ha!e demonstrated that surgically or chemically induced thyroid hormone depletion significantly decreases cellular and humoral immunity" Con!ersely, thyroid hormone repletion is associated #ith enhancement of oth types of immunity" 2uman monocytes, natural 5iller cells, and acti!ated : lymphocytes e%press receptors for T.2" -%posure of : cells to T.2 in !itro induces a moderate increase in immunoglo ulin secretion" 9ro#th 2ormones 2ypothalamic gro#th hormone releasing hormone '92R2+ tra!els through the hypothalamic*hypophyseal portal circulation to the anterior pituitary and stimulates the release of gro#th hormone '92+ in a pulsatile fashion mostly during the sleeping hours" In addition to 92R2, 92 release is influenced y autonomic stimulation, thyro%ine, ,>/, ,CT2, a*melanocyte stimulating hormone, glucagon, and se% hormones" Other stimuli for 92 release include physical e%ercise, sleep, stress, hypo!olemia, fasting hypoglycemia, decreased circulating fatty acids, and increased

amino acid le!els" Conditions that inhi it 92 release include hyperglycemia, hypertriglyceridemia, somatostatin, eta*adrenergic stimulation, and cortisol" The role of 92 during stress is to promote protein synthesis #hile enhancing the mo ilization of fat stores" (at mo ilization occurs y direct stimulation in conjunction #ith potentiation of adrenergic lipolytic effects on adipose stores" In the li!er, hepatic 5etogenesis also is promoted y 92" 92 inhi its insulin release and decreases glucose o%idation, leading to ele!ated glucose le!els" The protein synthesis properties of 92 after injury are partially mediated y the secondary release of insulinli5e gro#th factor*) 'I9(*)+" This hormone, #hich circulates predominantly in ound form #ith se!eral inding proteins, promotes amino acid incorporation and cellular proliferation and attenuates proteolysis in s5eletal muscle and in the li!er" I9(s, formerly referred to as somatomedins, are mediators of hepatic protein synthesis and glycogenesis" In the adipose tissue, I9( increases glucose upta5e and lipid synthesis" In s5eletal muscles, it increases glucose upta5e and protein synthesis" I9( also has a role in s5eletal gro#th y promoting the incorporation of sulfate and proteoglycans into cartilage" In !itro studies using proteoglycan synthesis as a mar5er for I9(*) acti!ity ha!e demonstrated that interleu5in*)a, tumor necrosis factor*alpha 'TN(* a+, and interleu5in*? can inhi it the effects of I9(*)" There is a rise in circulating 92 le!els after injury, major surgery, and anesthesia" The associated decrease in protein synthesis and o ser!ed negati!e nitrogen alance is attri uted to a reduction in I9(*) le!els" 92 administration has impro!ed the clinical course of pediatric urn patients" Its use in injured adult patients is unpro!en" The li!er is the predominant source of I9(*) and pree%isting hepatic dysfunction may contri ute to the negati!e nitrogen alance after injury" I9(* inding proteins also are produced #ithin the li!er and are necessary for effecti!e inding of I9( to the cell" I9( has the potential for attenuating the cata olic effects after surgical insults" Deu5ocytes e%press high*affinity surface receptors for 92" 92 and I9(*) are immunostimulatory and promote tissue proliferation" In !itro, 92 augments the proliferation of T lymphocytes to mitogens and the cytoto%icity of T 5iller cells to allogenic stimuli" $acrophages also respond to 92 #ith a modest respiratory urst" 92*deficient mice manifest immune deficiencies that can e partially re!ersed y the administration of 92" 92* deficient human eings do not demonstrate any significant immunologic a normalities" Normal su jects gi!en intra!enous 92 demonstrate no significant immunological changes e%cept for neutrophilia" 92 has immunomodulating effects, ut the rele!ance of this influence remains to e determined" .omatostatin .omatostatin is a )<6amino acid polypeptide produced y !arious cell types, including gastric antrum cells and pancreatic islet D cells" It is a potent inhi itor of 92, T.2, renin, insulin, and glucagon release" The role of somatostatin in the response to injury is unclear, ut it may regulate e%cessi!e nutrient a sorption and the acti!ities of 92 and I9( during con!alescence from injury" 9onadotrophins and .e% 2ormones Duteinizing*hormone releasing hormone 'D2R2+ or gonadotropin*releasing hormone '9nR2+ is released from the hypothalamus and stimulates follicle* stimulating hormone '(.2+ and luteinizing hormone 'D2+ release from the anterior pituitary" The release of these hormones can e effecti!ely loc5ed y CR2, prolactin, estrogen,

progestins, and androgens" The most rele!ant clinical correlation is seen after injury, stress, or se!ere illness, #hen D2 and (.2 release is suppressed" The reduction in D2 and (.2 conse&uently reduces estrogen and androgen secretion" This is attri uted to the inhi itory acti!ities of CR2 on D2 and (.2 release and accounts for the menstrual irregularity and decreased li ido reported after surgical stress and other injuries" -strogens inhi it cell*mediated immunity, natural 5iller cell acti!ity, and neutrophil function, ut are stimulatory for anti ody*mediated immunity" Conditions associated #ith high*estrogen le!els appear to predispose the patient to increased infectious complications" ,ndrogens appear to e predominantly immunosuppressi!e" Castration is associated #ith enhanced immune function that can e re!ersed y e%ogenous androgens" /rolactin The hypothalamus suppresses prolactin secretion from the anterior pituitary y the acti!ities of D2R2C9nR2 and dopamine" .timulants for prolactin release are CR2, TR2, 92R2, serotonin, and !asoacti!e intestinal polypeptide '>I/+" -le!ated prolactin le!els after injury ha!e een reported in adults, #hereas reduced le!els are noted in children" The hyperprolactinemia also may account for the amenorrhea fre&uently seen in #omen after injury or major operations" Di5e gro#th hormone, prolactin has immunostimulatory properties" Chemically induced inhi ition of prolactin in animals has demonstrated increased suscepti ility to infection, decreased lymphocyte proliferation, decreased interleu5in*3 production and receptor e%pression, decreased interferon*g production, and macrophage dysfunction" -%ogenous administration of prolactin re!ersed these effects" There is increasing e!idence that prolactin also is synthesized and secreted y T lymphocytes and may function in an autocrine or paracrine fashion" -ndogenous Opioids -le!ated endogenous opioids are measura le after major operations or insults to the patient 'Ta le )*<+" The *endorphins ha!e a role in attenuating pain perception, and they are capa le of inducing hypotension through a serotonin*mediated path#ay" Con!ersely, the en5ephalins produce hypertension" In the gastrointestinal tract, the acti!ation of opioid receptors reduces peristaltic acti!ity and suppresses fluid secretion" The role of endogenous opioids in glucose meta olism is comple%" ;hile * endorphins and morphine induce hyperglycemia, they also increase insulin and glucagon release y the pancreas" In animal models, endogenous opioids, such as dynorphins, ha!e demonstrated a paracrine role in modulation of !asopressin and o%ytocin secretion" .tudies 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 antinocicepti!e role in modulating the response of local sensory neurons to no%ious stimuli" -ndorphins also influence the immune system y increasing natural 5iller cell cytoto%icity and T cell lastogenesis" Interleu5in*) acti!ates the release of /O$C from the pituitary gland" -ndogenous opioids 'endorphin and en5ephalin+ and e%ogenous opiates oth mediate their effects through mammalian delta, 5appa, and mu receptors" Opioids compromise the natural 'innate+ and specific 'adapti!e+ immune system" They inhi it the proliferation and differentiation of lymphocytes and monocytesCmacrophages" The

immunoinhi itory effects of e%ogenous opiates can e dose dependent and sensiti!e to the state of acti!ation of the immune system" 2ormones Under /osterior /ituitary Regulation ,rginine >asopressin >asopressin or arginine !asopressin ',>/+ 'or antidiuretic hormone, ,D2+ is synthesized in the anterior hypothalamus and transported y a%oplasmic flo# to the posterior pituitary for storage" The major stimulus for ,>/ release is ele!ated plasma osmolality, #hich is detected y sodium*sensiti!e hypothalamic osmoreceptors" There is e!idence of e%tracere ral osmoreceptors for ,>/ release in the li!er or the portal circulation" ,>/ release is enhanced y eta*adrenergic agonists, angiotensin II stimulation, opioids, anesthetic agents, pain, and ele!ated glucose concentrations" Changes in effecti!e circulating !olume y as little as )A percent can e sensed y aroreceptors, left atrial stretch receptors, and chemoreceptors, leading to ,>/ release" Release is inhi ited y alpha*adrenergic agonists, and atrial natriuretic peptide ',N/+" In the 5idney, ,>/ promotes rea sorption of #ater from the distal tu ules and collecting ducts" /eripherally, ,>/ mediates !asoconstriction" This effect in the splanchnic circulation may cause the trauma*induced ischemiaCreperfusion phenomenon that precedes gut arrier impairment" ,>/, on a molar asis, is more potent than glucagon in stimulating hepatic glycogenolysis and gluconeogenesis" The resulting hyperglycemia increases the osmotic effect that contri utes to the restoration of effecti!e circulating !olume" -le!ated ,>/ secretion is another characteristic of trauma, hemorrhage, open*heart surgery, and other major operations" This ele!ated le!el typically persists for ) #ee5 after the insult" The syndrome of inappropriate antidiuretic hormone secretion '.I,D2+ refers the e%cessi!e !asopressin release that is manifested y lo# urine output, highly concentrated urine, and dilutional hyponatremia" This diagnosis can e made only if the patient is eu!olemic" Once normal !olume is esta lished, a plasma osmolality elo# 3B= mOsmC5g 23O and a urine osmolality a o!e )AA mOsmC5g 23O is indicati!e of .I,D2" .I,D2 is commonly seen in patients #ith head trauma and urns" In the a sence of ,>/, central dia etes insipidus occurs and there is !oluminous output of dilute urine" (re&uently seen in comatose patients, the polyuria in untreated dia etes insipidus can precipitate a state of hypernatremia and hypo!olemic shoc5" ,ttempts at re!ersal should include free #ater and e%ogenous !asopressin 'desmopressin+" O%ytocin O%ytocin and ,>/ are the only 5no#n hormones secreted y the posterior pituitary" They share structural similarities, ut the role of o%ytocin in the injury response is un5no#n" In human eings, the only consistent stimulus for secretion of o%ytocin is suc5ling or other nipple stimulation in lactating #omen" This stimulates contraction of lactating mammary glands and induces uterine contractions in parturition" There is no recognized stimulus for o%ytocin release, nor are there any 5no#n functions in men" 2ormones of the ,utonomic .ystem Catecholamines Catecholamines e%ert significant influence in the physiologic response to stress and injury" The hypermeta olic state o ser!ed after se!ere injury has een attri uted to

acti!ation of the adrenergic system" :oth of the major catecholamines, norepinephrine and epinephrine, are increased in plasma after injury, #ith a!erage ele!ations of three to four times a o!e aseline immediately after injury, reaching their pea5 in 3< to <E h efore returning to aseline le!els" The patterns of norepinephrine and epinephrine appearance parallel each other after injury" $ost of the norepinephrine in plasma results from synaptic lea5age during sympathetic ner!ous system acti!ity, #hile !irtually all plasma epinephrine deri!es from the secretions of chromaffin cells of the adrenal medulla" Catecholamines e%ert meta olic, hormonal, and hemodynamic influences on di!erse cell populations" In the li!er, epinephrine promotes glycogenolysis, gluconeogenesis, lipolysis, and 5etogenesis" It causes decreased insulin secretion ut increased glucagon secretion" /eripherally, epinephrine increases lipolysis in adipose tissues and inhi its insulin*facilitated glucose upta5e y s5eletal muscle" These collecti!ely promote the often e!ident stress*induced hyperglycemia, not unli5e the effects of cortisol on lood glucose" Catecholamines also increase the secretion of thyroid and parathyroid hormones, T< and T4, and renin, ut inhi it the release of aldosterone" Catecholamines e%ert discerni le influences on immune function, e"g", epinephrine occupation of eta receptors on leu5ocytes increases intracellular c,$/" This ultimately decreases immune responsi!eness in lymphocytes" Di5e cortisol, epinephrine enhances leu5ocyte demargination #ith resultant neutrophilia and lymphocytosis" -pinephrine also lo#ers the ratio of CD< to CDE T lymphocytes" Immunologic tissue such as the spleen, thymus, and lymph nodes possess e%tensi!e adrenergic inner!ation" Chemical sympathectomy of peripheral ner!es has een demonstrated to augment anti ody response after immunization #ith a specific antigen" It also re!erses the depressed mitogenic response of splenocytes preincu ated #ith endoto%in" Normal !olunteers infused #ith epinephrine e%hi it depressed mitogen*induced T lymphocyte proliferation" ,ldosterone The mineralocorticoid aldosterone is synthesized, stored, and released in the adrenal zona glomerulosa" Its release may e induced y angiotensin II, hyper5alemia, and the pituitary hormone 5no#n as aldosterone stimulating factor ',.(+, ut ,CT2 is the most potent stimulus for aldosterone release in the injured patient" The major function of aldosterone is to maintain intra!ascular !olume y conser!ing sodium and eliminating potassium and hydrogen ions" ;hile the major effect is e%erted in the 5idneys, this hormone also is acti!e in the intestines, sali!ary glands, s#eat glands, !ascular endothelium, and the rain" In the early distal con!oluted tu ule, aldosterone increases sodium and chloride rea sorption and e%cretion of hydrogen ions" In the late distal con!oluted tu ule, further sodium rea sorption ta5es place #hile potassium ions are e%creted" >asopressin also acts in concert #ith aldosterone to increase osmotic #ater flu% into the tu ules" /atients #ith aldosterone deficiency de!elop hypotension and hyper5alemia, #hereas patients #ith aldosterone e%cess de!elop edema, hypertension, hypo5alemia, and meta olic al5alosis" ,fter injury, ,CT2 stimulates a rief urst of aldosterone release" ,ngiotensin II induces a protracted aldosterone release that persists #ell after ,CT2 returns to aseline" ,s #ith cortisol, normal aldosterone release also is influenced y the circadian cycle, though this effect is lost in the injured patient" Renin*,ngiotensin

Renin is synthesized and stored primarily #ithin the renal ju%taglomerular apparatus near the afferent arteriole" The ju%taglomerular apparatus comprises the ju%taglomerular neurogenic receptor, the ju%taglomerular cell, and the macula densa" Renin initially e%ists in an inacti!e form as prorenin" The acti!ation of renin and its release is mediated y ,CT2, ,>/, glucagon, prostaglandins, potassium, magnesium, and calcium" The ju%taglomerular cells are aroreceptors that respond to a decrease in lood pressure y increasing renin secretion" The macula densa detects changes in chloride concentration in the renal tu ules" ,ngiotensinogen is a protein primarily synthesized y the li!er ut also identified in the 5idney" Renin catalyzes the con!ersion of angiotensinogen to angiotensin I #ithin the 5idney" ,ngiotensin I remains physiologically inacti!e until it is con!erted in the pulmonary circulation to angiotensin II y angiotensin*con!erting enzyme present on endothelial surfaces" ,ngiotensin II is a potent !asoconstrictor that also stimulates aldosterone and !asopressin synthesis" It also is capa le of regulating thirst" ,ngiotensin II stimulates heart rate and myocardial contractility" It also potentiates the release of epinephrine y the adrenal medulla, increases CR2 release, and acti!ates the sympathetic ner!ous system" It can induce glycogenolysis and gluconeogenesis" The renin*angiotensin system participates in the response to injury y maintaining !olume homeostasis" Insulin Insulin is deri!ed from pancreatic eta islet cells and released upon stimulation y certain su strates, autonomic neural input, and other hormones" In normal meta olism, glucose is the major stimulant of insulin secretion" Other su strate stimulants include amino acids, free fatty acids, and 5etone odies" 2ormonal and neural influences during stress alter this response" -pinephrine and sympathetic stimulation inhi it insulin release" Other factors that diminish insulin release include glucagon, somatostatin, gastrointestinal hormones, *endorphins, and interleu5in*)" /eripherally, cortisol, estrogen, and progesterone interfere #ith glucose upta5e" The net result of impaired insulin production and function after injury is stress* induced hyperglycemia, #hich is in 5eeping #ith the general cata olic state" Insulin e%erts a glo al ana olic effect8 it promotes hepatic glycogenesis and glycolysis, glucose transport into cells, adipose tissue lipogenesis, and protein synthesis" In the injured patient, a iphasic pattern of insulin release is o ser!ed" The first phase occurs #ithin a fe# hours after injury and is manifested as a relati!e suppression of insulin release, reflecting the influence of catecholamines and sympathetic stimulation" The later phase is characterized y a return to normal or e%cessi!e insulin production ut #ith persistent hyperglycemia, demonstrating a peripheral resistance to insulin" The ratio of insulin to glucose 'not their indi!idual !alues+ is used as a predictor of mortality and sur!i!al" ,cti!ated lymphocytes e%press receptors for insulin" Insulin enhances T lymphocyte proliferation and cytoto%icity" $ouse spleen cells transiently e%posed to a mitogen can continue to proliferate and maintain cytoto%icity if insulin is added to the medium" Institution of insulin therapy to ne#ly diagnosed dia etics is associated #ith increased : and T lymphocyte populations" 9lucagon 9lucagon is a product of pancreatic alpha islet cells" ,s #ith insulin, the release of glucagon also is mediated y its su strates, autonomic neural input, and other hormones" ;hereas insulin is an ana olic hormone, glucagon ser!es more of a

cata olic role" The primary stimulants of glucagon secretion are plasma glucose concentrations and e%ercise" 9lucagon stimulates hepatic glycogenolysis and gluconeogenesis, #hich under asal conditions account for appro%imately B= percent of the glucose produced y the li!er" In contrast to insulin, glucagon promotes hepatic 5etogenesis and lipolysis in adipose tissue" The release of glucagon after injury is initially decreased, ut returns to normal )3 h later" :y 3< h, glucagon le!els are supranormal and can persist for up to 4 days" I$$UN- R-./ON.- TO IN0UR1 ;hile the classic neuroendocrine response to injury has een e%tensi!ely in!estigated, many characteristics of the inflammatory response associated #ith injury remain une%plained" -!en after the normalization of macroendocrine hormone function after the primary injury, the persistence of systemic inflammation, the progression of organ dysfunction, and e!en 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 y immunocytes" These micromolecules, collecti!ely referred to as cyto5ines, are indispensa le in tissue healing and in the immune response generated against micro ial in!asions" ,s mounting e!idence suggests, the acti!ities of these cyto5ine mediators are integrally related to classic hormone function and meta olic responses to injury" Cyto5ine*$ediated Response /atients #ith injuries or infections e%hi it hemodynamic, meta olic, and immune responses partially orchestrated y endogenous cyto5ines" Unli5e classical hormonal mediators such as catecholamines and glucocorticoids, #hich are produced y specialized tissues and e%ert their influence predominantly y endocrine routes, cyto5ines are produced y di!erse cell types at the site of injury and y systemic immune cells 'Ta le )*=+" Cyto5ine acti!ity is primarily e%erted locally !ia cell*to* cell interaction 'paracrine+" Cyto5ines are small polypeptides or glycoproteins that e%ert their influence at !ery lo# concentrations" In their monomeric form, most are less than 4A 5ilodaltons '5D+" In their iologically acti!e form, some of these cyto5ines function as oligomers 'e"g", trimeric tumor necrosis factor*alpha+ #ith higher molecular #eights" $ost cyto5ines also differ from classical hormones in that they are not stored as preformed molecules" Their relati!ely rapid appearance after injury reflects acti!e gene transcription and translation y the injured or stimulated cell" Cyto5ines e%ert their influence y inding to specific cell receptors and acti!ating intracellular signaling path#ays leading to modulation of gene transcription" :y this mechanism, cyto5ines influence immune cell production, differentiation, proliferation, and sur!i!al" These mediators also regulate the production and actions of other cyto5ines, #hich may either potentiate 'proinflammatory+ or attenuate 'antiinflammatory+ the inflammatory response" The capacity of cyto5ines to acti!ate di!erse cell types and to incite e&ually di!erse responses underscores the pleiotropism of these inflammatory mediators 'Ta le )*?+" There is also a mar5ed degree of o!erlapping acti!ity among different cyto5ines" Cyto5ines are effector molecules that direct the inflammatory response to infections ' acterial, !iral, and fungal+ and injury and acti!ely promote #ound healing" These responses are manifested y fe!er, leu5ocytosis, and alterations in respiratory and heart rates" It is the e%aggerated, acute production of proinflammatory cyto5ines that is responsi le for the hemodynamic insta ility characteristic of septic shoc5" The

chronic and e%cessi!e production of these cyto5ines is partly responsi le for the meta olic derangements of the injured patients, such as de ilitating muscle #asting and cache%ia" /ree%isting cyto5ine production can contri ute to end* organ injury leading to multiple organ failure and late mortality in se!erely injured or infected patients" The presence of antiinflammatory cyto5ines may ser!e to attenuate some of these e%aggerated responses" The e%cessi!e release of antiinflammatory cyto5ines may render the patient immunocompromised and increase suscepti ility to infections" Understanding of the pathophysiology of inflammatory cyto5ine mediators has een deri!ed largely from patients #ith endoto%emia or sepsis" Inflammatory mediator responses to infections and traumatic injury are not dissimilar, particularly in the temporal se&uence of cyto5ine e%pression" The cyto5ine response e!idenced y fe!er, leu5ocytosis, hyper!entilation, and tachycardia commonly seen in injury is referred to as systemic inflammatory response syndrome '.IR.+ and is not necessarily the result of an identifia le infectious process" Central to the insult suffered y the host and the su se&uent inflammatory response is the acti!ity of the hostFs immunocyte population, circulating and tissue*fi%ed" Discussions of the inflammatory response should not e dissociated from these cellular entities" The cyto5ine cascade acti!ated in response to injury consists of a comple% net#or5 #ith di!erse effects on all aspects of physiological regulatory mechanisms" Cyto5ines are pi!otal determinants of the host response after injury and a proper perspecti!e of their immuno iologic se&uelae can ha!e important applications in the comprehensi!e care of the surgical patient" The num er of cyto5ines identified has e%panded to nearly 4A, ut their functions and elicited responses, particularly in injury, are incompletely understood largely ecause of the pleiotropic, redundant, and mutual interactions among these mediators" The cyto5ines descri ed here represent a limited list of etter*characterized mediators related to injury and the inflammatory response" Tumor Necrosis (actor*alpha The inflammatory response to se!ere cross*sectional tissue injury or infectious agents e!o5es a comple% cascade of proinflammatory cyto5ines" ,mong these, tumor necrosis factor*alpha 'TN(* a+ is the earliest and one of the most potent mediators of the su se&uent host response" The sources of TN(*a synthesis include monocytesCmacrophages and T cells, #hich are a undant in the peritoneum and splanchnic tissues" Gupffer cells represent the single largest concentrated population of macrophages in the human ody" .urgical or traumatic injuries to the !iscera may ha!e profound influences on the generation of inflammatory mediators and homeostatic responses such as acute phase protein production '(ig" )*@+" The release of TN(*a in response to acute injury is rapid and short*li!ed" -%periments simulating an acute inflammatory response y means of endoto%in challenge in human su jects ha!e demonstrated a monophasic tumor necrosis factor 'TN(+ appearance cur!e, pea5ing at appro%imately @A min and follo#ed y a return to undetecta le le!els #ithin < h '(ig" )* )A+" -!en #ith a half*life of )= to )E min, the rief appearance of TN( can induce mar5ed meta olic and hemodynamic changes and acti!ate cyto5ines distally in the cascade" The a re!iated production of TN( implies the presence of effecti!e endogenous modulators, #hich ser!e to pre!ent any propagation of unregulated TN(*a acti!ity" This has een pro!ed ecause se!eral natural mechanisms that antagonize TN( production or acti!ity ha!e een identified" -ndogenous inhi itors in the form of clea!ed e%tracellular domains of the transmem rane TN( receptors 'solu le TN( receptors, sTN(Rs+ are readily detecta le in the circulation" These receptors may ser!e a protecti!e role y

competiti!ely se&uestering e%cess circulating TN(, ut are pro a ly only capa le of doing so against lo# le!els of TN( acti!ity and for rief periods" TN(*a also is a major cyto5ine related to muscle cata olism and cache%ia during stress" ,mino acids are mo ilized from s5eletal muscles and shunted to#ard the hepatic circulation as fuel su strates" .tudies ha!e demonstrated that TN(*a6induced muscle cata olism occurs through a u i&uitin*proteasome proteolytic path#ay #ith increased e%pression of the u i&uitin gene" Other associated functions of TN(*a include coagulation acti!ation and promoting the release of prostaglandin -3 '/9-3+, platelet*acti!ating factor '/,(+, glucocorticoids, and eicosanoids" Interleu5in*) TN(*a also induces the iosynthesis and release of interleu5in*) 'ID*)+ from macrophages and endothelial cells" There are t#o 5no#n proinflammatory species of ID*), ID*)a and ID*) " ID*)a is predominantly cell mem rane6associated and e%erts its influence !ia cellular contacts" The more detecta le form released in the circulation is ID*) , #hich is produced in greater &uantities than ID*)a and capa le of inducing the characteristic systemic derangements after injury" The potency and effects of ID*) reflect those of TN(*a, eliciting similar physiologic and meta olic alterations" ,t high doses of ID*) and TN(*a, these cyto5ines independently initiate a state of hemodynamic decompensation" ,t lo# doses, they can produce the same response only if administered simultaneously"These o ser!ations emphasize the synergism of TN(*a and ID*) in eliciting some proinflammatory responses" The half*life of ID*) is appro%imately ? min, #hich, along #ith its primary role as a local inflammatory mediator, ma5es its detecta ility in acute injury or illness e!en less li5ely than that of TN(*a" ,mong its effects, ID*) induces the classic inflammatory fe rile response to injury y stimulating local prostaglandin acti!ity in the anterior hypothalamus" ,ssociated #ith the hypothalamic acti!ity is the induction of anore%ia y an ID*) effect on the satiety center" This cyto5ine also augments T cell proliferation y enhancing the production of ID*3 and also may influence s5eletal muscle proteolysis, characteristic of cache%ia" ,ttenuated pain perception after surgery can e mediated y ID*) y promoting the release of *endorphins from the pituitary gland and increasing the num er of central opioid*li5e receptors" Di5e TN(, ID*) is a potent stimulant for ,CT2 and glucocorticoid release !ia its actions on the hypothalamus and pituitary gland" , non*agonist ID*) species, 5no#n as ID*) receptor antagonists 'ID*)ra+, also is released during injury" This molecule effecti!ely competes for inding to ID*) receptors yet e%acts no o!ert signal transduction" ID*)ra, #hich is often detecta le during inflammation or injury, ser!es as a potent regulator of ID*) acti!ity" Distal cyto5ine mediators, released as part of the inflammatory cascade initiated y TN(*a and ID*), include ID*3, ID*<, ID*?, ID*E, granulocyteCmacrophage colony* stimulating factor '9$*C.(+, and interferon* g 'I(N* g+" Interleu5in*3 ,lthough necessary as an inflammatory mediator in promoting T lymphocyte proliferation, immunoglo ulin production, and gut arrier integrity, ID*3 has not een readily detecta le in the circulation during acute injury" .imilar to ID*), its short half* life of less than )A min adds to the difficulty in detecting it after injury" ID*3 secretion y lymphocytes is impaired after acute injury and se!eral disease states, nota ly cancer and ac&uired immunodeficiency syndrome ',ID.+" /erioperati!e lood

transfusions also are associated #ith reduced ID*3 production" ,ttenuated ID*3 e%pression contri utes to the transient immunocompromised state of the surgical patient" , lo# point in gut arrier ID*3 acti!ity resulting from injuries can predispose the patient to enteric organism acti!ation of the inflammatory cyto5ine cascade" There is e!idence for accelerated lymphocyte programmed cell death 'apoptosis+, in association #ith diminished ID*3 acti!ity, mediated y the proapoptotic (asCCD@= cell receptor in the early postoperati!e period" The com ined diminution of lymphocyte sur!i!al and ID*3 acti!ity may contri ute to the immunocompromised phenotype of the injured patient" .tudies ha!e demonstrated a population density shift from type ) T helper cells 'T2), cell*mediated and opsonizing anti ody immune responses, including ID*3, ID*)3, and I(N*g production+ to type 3 T helper cells 'T23, Ig- anti ody6mediated immune response, including ID*<, ID*?, ID*)A, ID*)4 production+ after surgical stress" The immune acti!ities of the T23 response usually are less effecti!e against microorganisms, and they accentuate the ris5s for postoperati!e infections '(ig" )*))+" Interleu5in*< ID*< is a glycoprotein molecule, produced y acti!ated T23 cells, #ith di!erse iologic effects on hemopoietic cells, including induction of : lymphocyte proliferation" Of particular importance in its role in anti ody* mediated immunity is the capacity to enhance macrophage major histocompati ility comple% class II '2D,* DR and 2D,*D/+ e%pression and adhesion molecules, ma5ing them efficient antigen* presenting cells" ID*< also induces class s#itching in differentiating : lymphocytes to produce predominantly Ig9< and Ig-, #hich are important immunoglo ulins in allergic and antihelminthic responses" ,s a potent antiinflammatory cyto5ine, ID*< do#n*regulates se!eral functions associated #ith acti!ated human macrophages, namely, the effects of ID*) , TN(*a, ID*?, ID*E, and supero%ide production" These antiinflammatory effects of ID*< are not seen in resting monocytes" The importance of this cyto5ine is the capacity to do#n* regulate the response of inflammatory macrophages e%posed to stimuli such as acterial endoto%in or proinflammatory cyto5ines" ID*< can induce programmed cell death in inflammatory macrophages, ut this effect is a rogated y I(N*g" ID*< and I(N*g antagonize one anotherFs effects on : cells" ID*< also appears to increase macrophage suscepti ility to the antiinflammatory effects of glucocorticoids" ID*)4 may share se!eral properties #ith ID*<" Interleu5in*? :ecause of the ele!ated lood le!els of ID*? often o ser!ed during acute injury or stress, it is used fre&uently as an indicator of the systemic inflammatory response and a predictor of preoperati!e mor idity" TN(*a and ID*) are major inducers of ID*?" ID* ? can e produced y !irtually all cell types, including the intestines" ,fter injury, ID* ? le!els in the circulation are detecta le y ?A min, pea5 et#een < to ? h, and can persist for as long as )A days" The relati!ely long half*life partially e%plains its ease of detecta ility" ID*? le!els appear to e proportional to the e%tent of tissue injury during an operation rather than the duration of the surgical procedure itself" -!idence suggests a comple% role for ID*? in mediating proinflammatory and antiinflammatory acti!ities" ID*) and ID*? are important mediators of the hepatic acute*phase protein response during injury and appear to enhance C*reacti!e protein, fi rinogen, haptoglo in, amyloid ,, a*)* antitrypsin, and complement production 'see (ig" )*@+" ID*? not only induces /$N acti!ation during injury and inflammation ut

also may delay the phagocytic disposal of senescent or dysfunctional /$Ns during injury" The persistence of inflammatory /$Ns after injury might e%plain the injurious effects on distant tissues, such as the pulmonary or renal system" ID*? mediates the antiinflammatory path#ay during injury through different mechanisms" It is capa le of attenuating TN( and ID*) acti!ity #hile promoting the release of sTN(Rs and ID*)ra" /rolonged and persistent e%pression of ID*? is associated #ith immunosuppression and postoperati!e infectious mor idity" -le!ated ID*? le!els postoperati!ely can impair glutaminase acti!ity, causing a reduction in plasma glutamine" Interleu5in*E The appearance of ID*E acti!ity is temporally associated #ith ID*? after injury and has een proposed as an additional iomar5er for the ris5 of multiple organ failure" ID*E does not produce the hemodynamic insta ility characteristic of TN(*a and ID*) ut rather ser!es as a /$N acti!ator and potent chemoattractant" ID*E is eing esta lished as a major contri utor to organ injury such as the acute lung injury" Interleu5in*)A ID*)A is an important endogenous regulatory mediator during the inflammatory response8 it acts primarily y modulating TN(*aacti!ity" Its appearance in the circulation during endoto%emia closely follo#s the appearance TN(*a" .upporting e%periments ha!e demonstrated that neutralization of ID*)A during endoto%emia increases monocyte TN(*a production and mortality, ut restitution of ID*)A reduces TN(*ale!els and the associated deleterious effects" ID*)A may ha!e additional protecti!e roles after injury*induced inflammation y promoting ID*)ra and sTN(R production" In animal e%periments, the sustained systemic production of ID*)A during septic peritonitis modulates the systemic inflammatory response" $urine e%periments ha!e demonstrated rapid induction of ID*)A messenger RN, 'mRN,+ acti!ity after cecal ligation and puncture, and higher mortality #hen this acti!ity is loc5ed #ith anti*ID*)A" This immunomodulatory effect also may a rogate the proinflammatory response necessary for local clearance of in!ading organisms" Interleu5in*)3 The capacity of ID*)3 to promote the differentiation of T2) cells and the production of I(N*g ma5es it a pi!otal molecule in cell*mediated immunity after injury or infection" In mice #ith fecal peritonitis, sur!i!al increases #ith ID*)3 administration" ID*)3 also is implicated in pre!enting programmed cell death 'apoptosis+ in certain T lymphocyte populations after their acti!ation" Interleu5in*)4 ID*)4 is a pleiotropic cyto5ine that shares many of the properties of ID*< as #ell as a modest amino acid se&uence 'a out 4A percent+" ID*)4 is produced during T23 responses" ID*< and ID*)4 modulate macrophage function, ut ID*)4 has no identifia le effect on T lymphocytes and only has influence on su populations of : lymphocytes" ID*< and ID*)4 receptors share a common signaling component" ID*)4 can up*regulate macrophage major histocompati ility comple% class I and II antigens and other surface antigens, such as CD34" ID*)4 can inhi it nitric o%ide production and the e%pression of proinflammatory cyto5ines, and it can enhance the production of ID*)ra" The net effect of ID*)4, along #ith ID*< and ID*)A, is antiinflammatory"

Interferon*g $uch of ID*)3 iology is mediated through the production and acti!ities of I(N*g" 2uman T helper 'T2+ cells acti!ated y the acterial antigens ID*3 or ID*)3 readily produce I(N*g" Con!ersely, I(N*g can induce the production of ID*3 and ID*)3 y T helper cells" ;ith its release from acti!ated T cells, I(N* g is detecta le in !i!o y ? h and has a half*life of appro%imately 4A min" I(N*g le!els pea5 at <E to B3 h and may persist for B to E days" Injured tissues, such as operati!e #ounds, also demonstrate the presence of I(N*g production = to B days after injury" Natural 5iller cells are potent inducers of ID*)3 production" I(N*g has important roles in acti!ating circulating and tissue macrophages" ,l!eolar macrophage acti!ation mediated y I(N*g may induce acute lung inflammation after major surgery or trauma" 9ranulocyteC$acrophage6Colony .timulating (actor 9ranulocyteCmacrophage*colony stimulating factor '9$*C.(+ production is induced y ID*3 and endoto%in" In !itro studies ha!e demonstrated a prominent role for 9$* C.( in delaying apoptosis of macrophages and /$Ns" This gro#th factor is effecti!e in promoting the maturation and recruitment of functional leu5ocytes necessary for normal inflammatory cyto5ine response, and potentially in #ound healing" The mechanisms may e the result of the suppression of ID*)A production" Results of perioperati!e 9$*C.( administration in patients undergoing major oncologic procedures ha!e demonstrated augmentation of neutrophil num ers and function" Regulation of Inflammatory Cell Death /rogrammed Cell Death During systemic inflammation, the response mounted y the host to injury and infection manifests the collecti!e acti!ities of circulating and tissue*fi%ed immunocytes and endothelial cell populations" In the normal host, programmed cell death 'apoptosis+ is the principal mechanism y #hich senescent or dysfunctional cells, including macrophages and /$Ns, are systematically disposed of #ithout acti!ating other immunocytes or the release of proinflammatory contents" The signals inducing normal apoptosis differ from cell to cell ut most li5ely con!erge at a common final path#ay" These signals arise from the e%tracellular en!ironment and may include hormonal and paracrine acti!ities '(ig" )*)3+" The inflammatory milieu disrupts the normal apoptotic machinery in dysfunctional or aging cells, conse&uently delaying the disposal of acti!ated macrophages and /$Ns" .e!eral proinflammatory cyto5ines delay the normal temporal se&uence of macrophage and /$N apoptosis in !itro" These include TN(, ID*), ID*4, ID*?, 9$* C.(, granulocyte colony6stimulating factor '9*C.(+, and I(N*g" :y contrast, ID*< and ID*)A accelerate apoptosis in acti!ated monocytes" The prolonged sur!i!al of inflammatory immunocytes may perpetuate and augment the inflammatory response to injury and infection, precipitating multiple organ failure and e!entual death in se!erely injured and critically ill patients" TN( Receptor6$ediated /rogrammed Cell Death Tumor necrosis factor receptors 'TN(Rs+ elong to a superfamily of appro%imately )= transmem rane proteins that are present on !irtually all cells, including immunocytes" $em ers of this family, #hich are lin5ed y their conser!ed e%tracellular se&uences, also include lymphoto%in* receptor, (asCCD@= ',/O*)+, ner!e gro#th factor receptors 'N9(R+, CD3B, CD4A, OH<A, <*)::, DR4 ';.D*), ,/O*4, TR,$/+,

and DR< ',/O*3+" ,cti!ation of these receptors induce specific cell responses that may include initiation of programmed cell death" There are t#o specific transmem rane TN(Rs 'type I, p==8 and type II, pB=+, ut they ha!e distinct intracellular domains" The p== TN(R induces apoptosis, cytoto%icity, e%pression of adhesion molecules on endothelial cells, and acti!ation of the sphingomyelin path#ay and nuclear factor65appa : 'N(*5:+" The pB= TN(R induces proliferation of T cells, fi ro lasts, natural 5iller cells, and proinflammatory cyto5ine release" The p== TN(R has the dominant role in triggering apoptosis, ut the concurrent participation of type I and type II TN(Rs is necessary for initiating this process" The participation of oth receptors is re&uired, ecause acti!ated intracellular pB= TN(R*related protein transducers are shared y the p== TN(R signaling comple%" During sepsis and e%perimental endoto%emia, do#n*regulation of macrophage and /$N TN(R acti!ity is o ser!ed" This attenuation in TN(R acti!ity may delay apoptosis of inflammatory macrophages and /$Ns, prolonging the inflammatory response '(ig" )*)4+" The p== TN(R and (as receptors e%hi it similar cytoplasmic se&uence motifs, 5no#n as the Ideath domain"J These death domains interact #ith other intracellular proteins to propagate do#nstream signaling for programmed cell death" ;hile TN(R I is found on !irtually all cell types, (as 'CD@=, ,/O*)+ e%pression in murine models is predominantly e%pressed in the li!er, lung, heart, intestine, s5in, and lymphocytes" In human eings, (as e%pression also is tissue*specific" ;hen triggered y its specific ligand, (asD, (as induces its only 5no#n function, #hich is to initiate apoptosis" $utations of (as or (asD are implicated as a cause for lymphoproliferati!e disorders and delayed disposal of inflammatory macrophages" (asCCD@= Receptor6$ediated /rogrammed Cell Death The only 5no#n role of the (as receptor is to initiate programmed cell death" :ecause of the intracellular homology of (as to p== TN(R, they oth induce apoptosis !ia similar mechanisms, ut (as*mediated apoptosis occurs #ith greater speed '#ithin hours+ than that mediated y p== TN(R" This may indicate a more direct 'i"e", less comple%+ path#ay for (as* mediated apoptosis than that of the TN(R type I path#ay" ;hile the induction of apoptosis !ia (asC(asD cross*lin5ing in acti!ated immunocytes may e ad!antageous during systemic inflammation, this acti!ity at the tissue le!el may e detrimental to the host" (as*mediated acti!ity in the li!er during inflammation may precipitate or e%acer ate ongoing hepatic injury" There is hepatic parenchymal up*regulation of (as receptors #ith acute to%ic injury simultaneously enhanced y (asD e%pression of infiltrating lymphocytes" .tudies also suggest a role for (asC(asD interaction in thyroid gland destruction and thyroiditis" Therapeutic strategies deri!ed from (asC(asD interaction re&uires selecti!ity to minimize inad!ertent organ injury" Immunocyte Receptor ,cti!ity in Inflammation $em rane TN(R In human endoto%emia, TN(R e%pression in macrophages and /$Ns is do#n* regulated" In macrophages, the decrease in surface TN(R reaches a lo# point 3h after endoto%in infusion and reco!ers to normal le!els in ?h '(ig" )*)<+" This receptor reco!ery continues to supranormal le!els at 3< h" /$Ns e%hi it a more sustained decrease in surface TN(Rs under the same conditions" ,mong signs such as fe!ers, leu5ocytosis, and chills, macrophage TN(R e%pression pattern is the most sensiti!e correlate identified for human response to endoto%in e%posure" There is a reduction of cell*surface TN(Rs in septic patients" Nonsur!i!ing patients #ith se!ere sepsis ha!e

an immediate reduction in cell*surface TN(R e%pression, #hile sur!i!ing patients ha!e almost normal receptor le!els from the outset" TN(R e%pression can potentially e used as an indicator of outcome in patients #ith se!ere sepsis" .olu le TN(R .olu le TN(Rs, proteolytically clea!ed e%tracellular domains of mem rane* associated TN(Rs, also are ele!ated in patients #ith se!ere sepsis" sTN(Rs retain their affinity for TN( and therefore compete #ith the cellular receptors for the inding of free TN(" This represents a counterregulatory response to e%cessi!e systemic TN( acti!ity" In contrast to macrophage mem rane TN(Rs, nonsur!i!ing septic patients demonstrate a significant ele!ation only in the p== sTN(R compared to sur!i!ing patients" Cell*associated TN(R e%pression is more relia le than sTN(R as an early predictor of ris5 and outcome in human sepsis '(ig" )*)=+" 2ormones and Cyto5ine Interactions CortisolC9lucocorticoids 2ypercortisolemia differentially influences leu5ocyte counts and cyto5ine e%pression in a temporal fashion" 9lucocorticoid administration immediately efore or concomitantly #ith endoto%in infusion in healthy human eings is a le to attenuate the symptoms 'e"g", fe!er, tachycardia+, catecholamine response, and acute phase response, ut it increases ID*)A release" Increased ID*)A release may contri ute to the acute antiinflammatory effect of glucocorticoids" 2ypercortisolemia induced y ? h or more of glucocorticoid administration efore endoto%in infusion does not attenuate the responses that are seen from endoto%in infusion alone" Infusion of cortisol for more than )3 h efore endoto%in infusion increases TN( and ID*? release" This may e%plain the !aried systemic responses to infection in critically ill or se!erely injured patients #ho ha!e associated hypercortisolemia" .uch responses are influenced y antecedent e!ents that alter the hormonal milieu" 9lucocorticoids also can influence the regulation of T lymphocyte proliferation or programmed cell death, as demonstrated y in !itro de%amethasone*induced apoptosis of human T lymphocytes" CDEK T cells are more sensiti!e to glucocorticoid*induced apoptosis than CD<Kcells" 9lucocorticoid*induced apoptosis of T lymphocytes re&uires ele!ations of intracellular c,$/" ID*3, ID*<, and ID*)A protects these T lymphocytes from glucocorticoid*induced apoptosis" The proinflammatory cyto5ine ID*) and, pro a ly, TN( and ID*? can acti!ate the hypothalamus*pituitary*adrenal a%is and induce the release of CR2 and ,CT2, leading to increased circulatory glucocorticoid le!els" 9lucocorticoids, in turn, inhi it endoto%in*induced production of TN( at the le!el of mRN, translation" De%amethasone also inhi its neutrophil apoptosis and prolongs their functional responsi!eness" This can e detrimental to the patient ecause the delay in clearance from tissues may perpetuate the injurious effects of acti!ated neutrophils" Catecholamines Catecholamines inhi it endoto%in*induced macrophage production of TN(*a in !itro and in human #hole lood e% !i!o" In normal human su jects, short*term pree%posure to epinephrine effecti!ely inhi its endoto%in* induced TN( production" Concurrently, this short*term pree%posure to epinephrine increases the production of the antiinflammatory cyto5ine ID* )A" Donger pree%posure, 3< h, had a less pronounced antiinflammatory effect" -ndogenous epinephrine or e%ogenous administration as a

component of sepsis treatment may ser!e to limit e%cessi!e proinflammatory effects of the cyto5ine net#or5 during the early phase of systemic infection" -pinephrine attenuates endoto%in*induced do#n*regulation of TN(R e%pression on human monocytes in !i!o, an effect that is eta*receptor mediated and c,$/ dependent" The use of catecholamines in treatment may ha!e the potential for influencing immune cell function" OT2-R $-DI,TOR. O( IN0UR1 R-./ON.-ndothelial Cell $ediators -ndothelial Cell (unction In addition to modulating coagulation and !asomotor acti!ities, mediators ela orated y the !ascular endothelium in response to injury are #ell* documented contri utors to the inflammatory process" In a paracrine fashion, local mediators such as TN(*a, ID*), endoto%in, throm in, histamine, and I(N*g are capa le of stimulating or acti!ating the endothelial cell during local tissue injury" In response, the endothelial cell releases se!eral mediators, including ID*), platelet*acti!ating factor '/,(+, prostaglandins '/9I3 and /9-3+, 9$*C.(, gro#th factors, endothelin, nitric o%ide, and small amounts of throm o%ane ,3 'T%,3+" ,cti!ated endothelial cells also release collagenases capa le of autodigesting their o#n asement mem ranes" This permits neo!ascularization and !ascular remodeling at sites of injury in order to facilitate ade&uate o%ygen supply and immunocyte transport" ,ngiotensin*con!erting enzymes ',C-+ con!ert angiotensin I to angiotensin II on the surface of endothelial cells, ma5ing it a potent regulator of !ascular tone" -ndothelial cell mediators can modulate cardio!ascular and renal function and influence the hypothalamus*pituitary* adrenal a%is '(ig" )*)?+" The acti!ated endothelial cell up*regulates its e%pression of leu5ocyte adhesion receptor molecules such as -*selectin 'formerly referred to as endothelial*leu5ocyte adhesion molecule*), -D,$*)+, /*selectin, and intercellular adhesion molecules 'IC,$*), IC,$*3+" The adhesion of leu5ocytes and platelets to the endothelial surface occurs early in the endothelial*deri!ed inflammatory process" In cultured endothelial cells, asal e%pression of -*selectin during inflammation re&uires the stimulation of TN(*a and ID*)" ;ithin ) h after treatment #ith either of these t#o cyto5ines, mRN, acti!ity for -*selectin is detecta le" The e%pression of -* selectin on endothelial cell surfaces is ma%imal at < to ? h" Reco!ery from the inflammatory process also is characterized y internalization of these adhesion molecules #ithin the endothelial cell" Neutrophil adhesion to the endothelium during injury has important clinical implications for increasing !ascular permea ility and passage of leu5ocytes into injured tissues" These are important in the etiology of conditions such as acute lung and ischemia*reperfusion injuries" In the nonstressed state, the endothelium possesses little capacity to recognize and ind circulating leu5ocytes" Docal injuries and inflammatory mediator stimulation promote the margination of circulating /$Ns to the endothelial surfaces" These marginated /$Ns are deforma le and tra!el along the endothelial surfaces at mar5edly reduced !elocities, #hich is referred to as rolling" Rolling represents a process of transient attachment and detachment et#een receptors of /$Ns and the endothelium" The su se&uent de!elopment of stronger receptor adhesions, /$N acti!ation y the endothelial mediators, and release of /$N proteinases at endothelial junctions precedes the migration of /$Ns out of the !ascular compartment, a process referred to as diapedesis" ,lthough necessary for local tissue inflammation and eradication of micro es, acti!ated /$Ns and the

su se&uent release of inflammatory mediators and reacti!e o%ygen meta olites are implicated in capillary lea5age, acute lung injury, and postischemic injury '(ig" )*)B+" The release of mediators y the endothelium and their su se&uent influence on neigh oring and distant tissues ascri es endocrine properties to endothelial cells during injury" The a ility to attract leu5ocytes and produce inflammatory mediators ma5es endothelial cells important participants in the immune response to injury" -ndothelium*Deri!ed Nitric O%ide -ndothelium*deri!ed nitric o%ide or rela%ing factor '-DNO or -DR(+ can e released in response to acetylcholine stimulation, hypo%ia, endoto%in, cellular injury, or mechanical shear stress from circulating lood" Its !asodilatory acti!ity has een demonstrated in large 'conduit+ arteries and in resistance !essels of most mammalian species, including human eings" Induction of !ascular smooth muscle rela%ation y -DNO re&uires the acti!ation of solu le guanylate cyclase and an increase in cytosolic cyclic guanosine monophosphate 'c9$/+ #ithin the myocytes" $ethylene lue inhi its guanylate cyclase, pre!ents the production of c9$/, and inhi its !ascular rela%ation" c9$/ also is present in platelets and can e acti!ated y -DNO" Increased c9$/ in platelets is associated #ith reduced adhesion and aggregation" -DNO induces !asodilation and platelet deacti!ation '(ig" )*)E+" -DNO also mediates protein synthesis in hepatocytes and electron transport in hepatocyte mitochondria" It is a readily diffusi le su stance #ith a half*life of a fe# seconds" -DNO spontaneously decomposes into nitrate and nitrite" -DNO is formed from o%idation of l*arginine, a process catalyzed y nitric o%ide synthase 'NO*synthase+" Cofactors of NO*synthase acti!ity include calmodulin, ionized calcium, and N,D/2" In addition to the endothelium, this enzymatic acti!ity also is present in /$Ns, macrophages, renal cells, Gupffer cells, and cere ellar neurons" In normal !asculature, e%periments loc5ing -DNO acti!ity induce a state of !asoconstriction that is readily re!ersed #ith l*arginine administration" This demonstrates that the !asculature is in a constant state of !asodilation ecause of the continuous asal release of -DNO" -ndogenous inhi itors of -DNO ha!e een identified that are autoregulators of endothelial tone" -le!ations of -DNO in septic shoc5 and trauma, as measured y its nitrite and nitrate meta olites, are e!idenced in association #ith lo# systemic !ascular resistance and ele!ated endoto%in le!els" /rostacyclin /rostacyclin '/9I3+ is an important endothelium*deri!ed !asodilator synthesized in response to !ascular shear stress and hypo%ia" It has functions similar to those of -DNO" /rostacyclin is deri!ed from arachidonic acid and causes rela%ation and platelet deacti!ation y increasing c,$/" It has een used to reduce pulmonary hypertension, particularly in pediatric patients" -ndothelins -ndothelins '-T+ are ela orated y !ascular endothelial cells in response to injury, throm in, transforming gro#th factor* 'T9(* +, ID*), angiotensin II, arginine !asopressin, catecholamines, and ano%ia" .tructurally formed from a 4E6amino acid precursor molecule, -T is a 3)6amino acid peptide #ith potent !asoconstrictor properties" ,mong the peptides in this family '-T*), -T*3, -T*4+, endothelial cells produce only -T*)" -T*) is the most iologically acti!e and potent !asoconstrictor

5no#n, estimated to e ten times more potent than angiotensin II" Three endothelin receptors, referred to as -T,, -T:, -TC, function y the 9 protein6coupled receptor mechanism" -T: receptors are lin5ed to the formation of -DNO and /9I3, #hich are negati!e feed ac5 mechanisms" This may e%plain the transient !asodilation o tained #ith lo#*dose administration of -T*) and the need for -DNO and -T to maintain physiologic tone in !ascular smooth muscles" The !asoconstrictor acti!ity of -T can e re!ersed y the administration of acetylcholine, #hich stimulates -DNO production" Increased serum le!els of -T are correlated #ith the se!erity of injury after major trauma, major surgical procedures, and in cardiogenic or septic shoc5" /latelet*,cti!ating (actor ,nother endothelium*deri!ed product is /,(, a phospholipid constituent of cell mem ranes that can e induced y TN(, ID*), ,>/, and angiotensin II" This potent inflammatory mediator stimulates production of T%,3through the cycloo%ygenase path#ay and promotes platelet aggregation" T%,3 is also a potent !asoconstrictor" -%perimentally, /,( has increased glucagon and catecholamine acti!ity" It can induce hypotension, increase !ascular permea ility, hemoconcentration, pulmonary hypertension, ronchoconstriction, primed /$N acti!ity, eosinophil chemota%isCdegranulation, and throm ocytopenia" It induces a general leu5ocytopenia y #ay of margination" ,dministration of antagonists to /,( in e%perimental human endoto%emia demonstrates partial attenuation of symptoms such as myalgias and rigors, ut these inhi itors are ineffecti!e in re!ersing hemodynamic derangements" /,( alters the shape of endothelial cells, causing them to contract and increase permea ility" In cultured endothelial cells, cell contraction permits the passage of macromolecules, such as al umin, across cell junctions" /,( is a chemotactant for leu5ocyte adherence to the !ascular #all and facilitates migration out of the !ascular compartment" The disparity et#een /,(*induced !ascular permea ility and /,(* induced !asoconstriction is most li5ely the result of differential receptor types and affinity found in different !ascular segments" Other cells that secrete /,( include macrophages, /$Ns, asophils, mast cells, and eosinophils" ,trial Natriuretic /eptides ,trial natriuretic peptides ',N/s+ are peptides released y the central ner!ous system and y specialized endothelium found in atrial tissues in response to #all tension" ,N/s are potent inhi itors of aldosterone secretion and pre!ent rea sorption of sodium" In rats, the myocardial endothelium*deri!ed nitric o%ide '-DNO+ inhi its the release of ,N/, #hile -T*) is a potent secretagogue of ,N/" The role of ,N/ in human response to injury is un5no#n" Intracellular $ediators 2eat*.hoc5 /roteins In addition to heat stimulation, stimuli such as hypo%ia, trauma, hea!y metals, local trauma, and hemorrhage induce the production of intracellular heat*shoc5 proteins '2./s+" These proteins are presumed to protect cells from the deleterious effects of traumatic stress" 2./s function intracellularly in the assem ly, disassem ly, sta ility, and transport of proteins" The classic e%ample of 2./ acti!ity is the intracellular transport of steroid molecules" The formation of 2./s re&uire gene induction y the heat*shoc5 transcription factor '2.(+" 9ene e%pression occurs in parallel #ith hormonal acti!ities of the hypothalamus*pituitary*adrenal a%is" This response may e ,CT2*sensiti!e, and the production may decline #ith age" ,lthough 2./s are

important intracellular effectors, their rele!ance in the human response to injury can only e inferred from animal data" Reacti!e O%ygen $eta olites Reacti!e o%ygen meta olites 'RO$s+ are short*li!ed, highly reacti!e molecular o%ygen species #ith an unpaired outer or it" They cause tissue injury y pero%idation of cell mem rane unsaturated fatty acids" RO$s are produced y comple% processes that in!ol!e anaero ic glucose o%idation coupled #ith the reduction of o%ygen to supero%ide anion" .upero%ide anion is a potent RO$ ut can e meta olized to other reacti!e species such as hydrogen pero%ide and hydro%yl radical" Cells are not immune to damage y their o#n RO$s ut are generally protected y o%ygen sca!engers that include glutathione and catalases" In ischemic tissues, the intracellular mechanisms for production of RO$s ecome fully acti!ated ut are nonfunctional ecause of a lac5 of o%ygen supply" ;ith restoration of lood flo# and o%ygen supply, large &uantities of RO$s are produced that induce reperfusion injury" In response to a stimulus, acti!ated leu5ocytes are potent generators of reacti!e o%ygen meta olites" RO$s also can induce apoptosis" .tudies using T lymphocytes ha!e demonstrated a major apoptotic mechanism mediated y depletion of intracellular glutathione or RO$ sca!enger" The proapoptotic (asCCD@= receptor acti!ation is implicated in depleting 9.2 #ith resultant intracellular RO$ accumulation and cell death" Repletion of 9.2 in these cells can re!erse these effects" Other Inflammatory $ediators -icosanoids The eicosanoid class of mediators, #hich encompasses prostaglandins '/9+, throm o%anes 'T%+, leu5otrienes 'DT+, hydo%yeicosatetraenoic acids '2-T-+, and lipo%ins 'D%+, are o%idation deri!ati!es of the mem rane phospholipid, arachidonic acid 'eicosatetraenoic acid+" They are secreted y !irtually all nucleated cells e%cept lymphocytes" The synthesis of arachidonic acid from phospholipids re&uires enzymatic acti!ation of phospholipase ,3 '(ig" )*)@+" The cycloo%ygenase and the lipo%ygenase path#ays are t#o major routes y #hich arachidonic acid is o%ygenated" $ost eicosanoids generated from the cycloo%ygenase path#ay are gi!en the su script designation of 3 'e"g", T%,3+, #hile products of the lipo%ygenase path#ay are designated < 'e"g", DT-<+" These su scripts indicate the num er of car on dou le onds present in the side chains" /roducts of the cycloo%ygenase path#ay include all of the prostaglandins and throm o%anes" The formation of prostacyclin '/9I3+ re&uires further enzymatic acti!ity y prostacyclin synthetase, and the formation of T%,3 re&uires the acti!ity of throm o%ane synthetase" The lipo%ygenase path#ay generates the leu5otrienes and 2-T-" Initial phospholipase ,3 acti!ation can e achie!ed y compounds such as epinephrine, angiotensin II, rady5inin, histamine, and throm in" Con!ersely, phospholipase ,3 can e inhi ited y lipocortin, #hich is induced y cortisol" The synthesis of prostaglandins and throm o%anes also are inhi ited y nonsteroidal antiinflammatory drugs and salicylates, #hich are cycloo%ygenase inhi itors" -icosanoids are not stored in cells ut are synthesized rapidly upon stimulation y hypo%ic and ischemic injury, direct tissue injury, endoto%in, norepinephrine, ,>/, angiotensin II, rady5inin, serotonin, acetylcholine, and histamine" $any of these stimuli also induce a second cycloo%ygenase enzyme, referred to as COH*3, that enhances the production of arachidonic acid meta olites" COH*3 acti!ity can e

inhi ited y glucocorticoids, #hich pro!ide specific inhi ition of cycloo%ygenase meta olites, as opposed to lipocortin, #hich inhi its production of arachidonic acid meta olites" The products of arachidonic acid meta olism are functionally cellCtissue specific" >ascular endothelium primarily synthesizes /9I3, #hich causes !asodilation and platelet deacti!ation" Throm o%ane synthetase con!erts platelet prostaglandins to T%,3, a potent !asoconstrictor and platelet aggregator" $acrophages are capa le of synthesizing cycloo%ygenase and lipo%ygenase products" .econd messengers mediate much of eicosanoid acti!ity" (or e%ample, /9compounds, in a manner similar to ,CT2, T.2, and D2, inhi it ,>/ acti!ity and hormone*stimulated lipolysis y acti!ating adenylate cyclase acti!ity and generating intracellular c,$/" Throm o%ane and leu5otrienes ha!e opposite effects from /9y increasing intracellular free calcium !ia the phosphatidylinositol path#ay" -icosanoids ha!e di!erse effects systemically on endocrine and immune function, neurotransmission, and !asomotor regulation 'Ta le )*B+" -icosanoids are major components of the inflammatory response in injured tissue, characterized y !ascular permea ility, leu5ocyte migration, and !asodilation" Collecti!ely, their deleterious effects are implicated in acute lung injury, pancreatitis, and renal failure" Deu5otrienes are produced y cells of the lung, connecti!e tissue, smooth muscle, macrophages, and mast cells that mediate the reactions characteristic of anaphyla%is" Deu5otrienes are ),AAA times more potent than histamines in promoting capillary lea5age" They also are effecti!e promoters of leu5ocyte adherence, neutrophil acti!ation, ronchoconstriction, and !asoconstriction" The role of lipo%ins is not #ell understood ut they are elie!ed to induce neutrophil acti!ation and production of supero%ides and degranulation" The meta olic effects of eicosanoids are #ell recognized" In the regulation of glucose, products of the cycloo%ygenase path#ay inhi it pancreatic eta cell release of insulin #hile products of the lipo%ygenase path#ay promote eta cell acti!ity" 2epatocytes also e%press specific receptors for /9-3 that, #hen acti!ated, inhi it gluconeogenesis" /9-3inhi its hormone* stimulated lipolysis" -icosanoids modulate the immune response in multiple #ays" .mall amounts of /9-3 suppress proliferation of human T lymphocytes y mitogens, an effect mediated y do#n*regulation of ID*3 production" -nhanced lymphocyte acti!ation y mitogens can e achie!ed #ith the administration of indomethacin, a /9-3inhi itor" During phagocytosis, /$Ns release eicosanoids such as DT:< to ser!e as chemoattractants for other leu5ocytes" /9-3 and DTD< are commonly present in local areas of injury and are elie!ed to ha!e a direct influence on the inflammatory response" Galli5rein*Ginin .ystem :rady5inins are potent !asodilators produced through 5ininogen degradation y the serine protease 5alli5rein" Galli5rein e%ists in lood and tissues as inacti!e pre5alli5rein and is acti!ated y !arious chemical and physical factors" ,mong these are 2ageman factor, trypsin, plasmin, factor HI, glass surfaces, 5aolin, and collagen" Ginins are rapidly meta olized y 5inase I and II" Ginase I degrades the anaphylato%ins C4a, C<a, and C=a" Ginase II is identical to angiotensin*con!erting enzyme" The use of angiotensin*con!erting enzyme inhi itors ',C- inhi itors+ in controlling hypertension may ser!e partially to loc5 5inin degradation in some patients and enhance the 5inin*induced injurious effects on the ronchial tree" Ginins increase capillary permea ility and tissue edema, e!o5e pain, and increase ronchoconstriction" They also increase renal !asodilation and conse&uently reduce

renal lood flo#" The resulting increase in renin formation acti!ates sodium and #ater retention !ia the renin*angiotensin system" :rady5inin release is stimulated y hypo%ic and ischemic injury" Increased 5alli5rein acti!ity and rady5inin le!els ha!e een detected after hemorrhage, sepsis, endoto%emia, and tissue injury" These o ser!ations are positi!ely correlated #ith the magnitude of injury and mortality" Clinical trials using rady5inin antagonists in attempts to reduce the deleterious se&uelae of septic shoc5 ha!e demonstrated only modest re!ersal in gram* negati!e sepsis and no o!erall impro!ement in sur!i!al" $eta olically, 5inins increase glucose clearance y inhi iting gluconeogenesis" :rady5inin infusion also may increase nitrogen retention" .erotonin The neurotransmitter serotonin '=*hydro%ytryptamine, =*2T+ is a tryptophan deri!ati!e that is found in enterochromaffin cells of the intestine and in platelets" /atients #ith midgut carcinoid tumors often secrete e%cessi!e =*2T" This neurotransmitter stimulates !asoconstriction, ronchoconstriction, and platelet aggregation" It also is capa le of acting as a myocardial chronotrope and inotrope" ,lthough it is released at sites of injury, its role in the injury response is unclear" 2istamine 2istamine is deri!ed from histidine and stored in neurons, s5in, gastric mucosa, mast cells, asophils, and platelets" Its release is acti!ated y increased calcium le!els" There are t#o receptor types for histamine inding" 2) inding mediates increased histamine precursor upta5e, l* histidine, and stimulates ronchoconstriction, intestinal motility, and myocardial contractility" 23 inding inhi its histamine release" 2) and 23 receptor acti!ation induces !asodilation and increases !ascular permea ility" 2istamine administration causes hypotension, peripheral pooling of lood, increased capillary permea ility, decreased !enous return, and myocardial failure" 2istamine is released in hemorrhagic shoc5, trauma, thermal injury, endoto%emia, and sepsis" 2istamine le!els are correlated #ith mortality from septic shoc5" $-T,:ODIC R-./ON.- TO IN0UR1 The description of human iochemical responses to injury and the classification of such responses into an e and flo# phase y Cuth ertson and others pro!ides a useful model y #hich the meta olic response to injury may e characterized '(ig" )* 3A+" The e phase corresponds to the earliest moments to hours after injury, often in association #ith hemodynamic insta ility or reductions in effecti!e circulating lood !olume" The meta olic conse&uences of this phase are less #ell studied ut are generally associated #ith reductions in total ody energy e%penditure and losses of urinary nitrogen" The e phase is characterized y an early enhancement of neuroendocrine hormone appearance, including catecholamines and cortisol" Dess is 5no#n a out the microendocrine mediator response" It is difficult to analyze the immune cell mediator response engendered during the e phase separately from that occurring in response to fluid or !olume resuscitation, and the resultant tissue reperfusion and reo%ygenation that initiates the onset of the flo# phase" -%cept #ith the most minor injury, the flo# phase is ushered in y compensatory mechanisms resulting from !olume repletion and cessation of initial injury conditions" The meta olic response associated #ith the flo# phase ser!es to direct energy and protein su strates so as to preser!e critical organ function and repair damaged tissues" This includes an increase in #hole* ody o%ygen consumption and meta olic rate,

enhancement of critical enzyme path#ays for readily o%idiza le su strates such as glucose, and stimulation of immune system functions re&uired for repair of tissue destruction and protection from additional rea5s in epithelial arriers" , reprioritization of su strate processing occurs to support the production of acute* phase reactants, immunoreacti!e proteins, and coagulation factors" The iologic priority of #ound healing also is esta lished during the early flo# phase" $eta olic Response to (asting , comparison et#een the meta olic physiology of injury to that of unstressed fasting is useful for assessing the relati!e magnitudes of altered physiology under these #idely !arying conditions" (actors such as antecedent health status, age, and lean ody mass also influence the a solute rates of su strate turno!er after fasting and injury" .u strate $eta olism , healthy adult of BA 5g ody #eight e%pends )BAA to )EAA 5calCday of energy o tained from lipid, car ohydrate, and protein sources '(ig" )*3)+" O ligate glycolytic cells, such as neurons, leu5ocytes, and erythrocytes, re&uire )EA g glucose per 3< h for asal energy needs" During acute star!ation, glucose is deri!ed from e%isting storage pools, including appro%imately B= g glucose stored as hepatic glycogen" .5eletal muscle cannot directly release free glucose, ecause it lac5s the glucose*?* phosphatase necessary for free glucose release" The reduction of circulating glucose during prolonged fasting ser!es as a primary stimulus to hormonal release that modulates gluconeogenesis and su strate su stitution for those tissues that re&uire glucose for energy" 9lucose concentration falls #ithin hours after the onset of fasting in association #ith decreases in insulin release and sustained increases of circulating glucagon and more transient ele!ations of 92, catecholamines, ,>/, and angiotensin II" 9lucagon and epinephrine enhance c,$/ to promote glycogenolysis, and cortisol and glucagon promote gluconeogenesis" The actions of norepinephrine, ,>/, and angiotensin II are mediated y the intracellular signals of phosphatidylinositol and calcium to promote glycogenolysis" Cortisol and epinephrine limit pyru!ate use" The effect of these actions is an increase in glucose production" .ustained glucose production depends on presentation of amino acids, glycerol, and fatty acids to the li!er '(igs" )*33 and )*34+" The primary gluconeogenic precursors used y the li!er and to a lesser e%tent y the 5idney for gluconeogenesis are lactate, glycerol, and amino acids such as alanine and glutamine" .5eletal muscle releases lactate y rea5do#n of endogenous glycogen stores and y glycolysis of transported glucose" Dactate also is released y erythrocytes and #hite lood cells after aero ic glycolysis and release of ne#ly formed lactate into the circulation" This lactate is recon!erted to glucose in the li!er y the Cori cycle '(ig" )*3<+" The &uantity of glucose made from lactate produced y s5eletal muscle is not sufficient to maintain glucose homeostasis" Conse&uently, appro%imately B= g of protein must e degraded daily during fasting and star!ation to pro!ide gluconeogenic amino acids to the li!er" /roteolysis, #hich results primarily from decreased insulin and increased cortisol, is associated #ith an increase in urinary nitrogen e%cretion from the normal ? to E gCday to appro%imately E to )) g #ithin the initial = days of fasting" /rotein mo ilized in star!ation is deri!ed primarily from s5eletal muscle, ut the loss of protein from other organs also occurs" The amino nitrogen load resulting from deamination of amino acids for gluconeogenesis increases urinary ammonia e%cretion" The renal e%cretion of

ammonium ion ecomes the primary route of elimination of alpha*amino nitrogen during star!ation ecause the normally acti!e hepatic enzymes are diminished" Renal gluconeogenesis increases through meta olism of glutamine and glutamate" The 5idney may account for up to <= percent of glucose production during late star!ation" ,fter appro%imately = days, the rate of #hole* ody proteolysis diminishes to a le!el of )= to 3A gCday and urinary nitrogen e%cretion sta ilizes at 3 to = gCday for se!eral #ee5s" This reduction in proteolysis occurs as the ner!ous system and other pre!ious glucose*utilizing tissues adapt to 5etone o%idation as the predominant energy source" During star!ation, transport systems in the lood* rain arrier increase the rate of 5etone ody transport, and meta olism of 5etone odies y the rain increases" Conse&uently, the amount of protein re&uired for gluconeogenesis is significantly reduced 'see (ig" )*34+" , reduction in ana olic gro#th factors such as I9(*) 'formerly somatomedin C+ also is o ser!ed during the first se!eral days of fasting '(ig" )*3=+" The reduction in this factor and its associated inding proteins reduces an important signal for transcellular amino acid transport" Tissue protein synthesis also falls correspondingly #ith reduced proteolysis" -nergy re&uirements for gluconeogenesis and asal enzymatic and muscular function, such as neural transmission and cardiac contraction, can e met y the mo ilization of appro%imately )?A g of triglycerides from adipose tissue in the form of free fatty acids and glycerol in a resting, fasting BA*5g su ject '(ig" )*3?+" (ree fatty acid release is stimulated y a reduction in the serum insulin concentration" Increased glucagon may participate in this alteration, as do catecholamines" The free fatty acids and 5etone odies generated y the li!er are used as a source of energy y tissues such as the heart, 5idney, muscle, and li!er" Dipid stores pro!ide up to <A percent of the caloric e%penditure during star!ation" Dipid o%idation during star!ation diminishes the a solute glucose re&uirement to sustain tissue and ody energy e%penditure" (atty acid use occurs at a rate that is proportional to serum fatty acid concentration" Getone odies spare glucose y inhi ition of pyru!ate dehydrogenase in most tissues" The use of fat as a main fuel source decreases the amount of mandatory glycolysis, #hich diminishes the re&uirements for gluconeogenesis and protein degradation" Once the initial o ligatory neuroendocrine stress hormone response recedes, #hole* ody energy e%penditure also decreases during prolonged fasting" This reduction in resting energy e%penditure is a conse&uence of decreased sympathetic ner!ous system acti!ity and reduced s5eletal muscle acti!ity" Reduced secretory enzyme production and intestinal meta olic demands contri ute to this adjustment" $eta olism ,fter Injury The meta olic conse&uences of injury differ in many fundamental #ays from those of simple star!ation" ;ell*defined changes in hormone le!els and associated su strates accompany injury" These changes can reflect the degree of underlying injury '(ig" )* 3B+" , useful construct in the attendant changes in interorgan su strate flu% has een proposed y Cahill '(ig" )* 3E+" It is the sustained acti!ities of macroendocrine hormones in conjunction #ith immune cell acti!ation that pro!ides the signals that differentiate injury meta olism from unstressed star!ation" -nergy :alance Injury of any magnitude eyond the most tri!ial is associated #ith an increase in energy e%penditure and increases in o%ygen consumption that !ary directly #ith the se!erity of injury '(ig" )*3@+ or urn surface area '(ig" )*4A+" , linear relationship

et#een ody cell mass and resting energy e%penditure often is o ser!ed in injured patients" The increase in energy e%penditure o ser!ed after injury results initially from the increased acti!ity of the sympathetic ner!ous system and increased circulating concentrations of catecholamines" Increases in energy e%penditure can e replicated y the administration of catecholamines to healthy su jects" Con!ersely, glucocorticoid e%cess does not significantly enhance energy e%penditure" The mechanism for this catecholamine effect may e related to influences on cell mem rane sodium permea ility and the energy re&uired for ion pump action to maintain normal transmem rane concentrations" This influence is o ser!ed during the endoto%inCcyto5ine interacti!ity, in #hich reductions in muscle resting transmem rane potential are readily o ser!ed" Under these conditions, increases in circulating catecholamines occur #ith restoration of mem rane potential and efore changes in energy e%penditure" 1oung estimated that such cellular ion pumping and transport acti!ities may account for o!er <A percent of total ody energy e%penditure" Dipid $eta olism (ree fatty acids are a principal source of energy after injury" Dipolysis is enhanced y the immediate ele!ations in ,CT2, cortisol, catecholamines, glucagon, and gro#th hormone le!els, reduction in insulin le!el, and increased sympathetic ner!ous system acti!ity" Catecholamines are the chief stimulus to hormone*sensiti!e lipase" The sympathetic ner!ous system and circulating catecholamines are important in the lipolytic response to stress" In!estigations into the mechanism of catecholamine* induced posttraumatic lipolysis suggest that lipolysis may e increased y changes in adrenergic postreceptor 'protein 5inase hormone6sensiti!e lipase+ response after electi!e operation" Dipolysis o ser!ed during the e phase results in ele!ated le!els of plasma free fatty acids and glycerol" Increased reesterification of fatty acids, such as that seen in the presence of high concentrations of lactate, may decrease net free fatty acid release" This e%planation is supported y the o ser!ed rise in plasma glycerol le!el noted after injury, #hich suggests that lipolysis is occurring, and y increased concentrations of lactate in studies in #hich there is no change in free fatty acid concentration" ,cidosis, hyperglycemia, and anesthetic agents also alter lipid mo ilization after injury" (or e%ample, lipolysis is directly inhi ited y pento ar ital anesthesia, and hemorrhage in the presence of pento ar ital usually results in a fall in the plasma free fatty acid and 5etone ody concentrations" -%perimental hemorrhage using other anesthetic agents or in a#a5e animals increases free fatty acid and 5etone ody concentrations" During the flo# phase, net lipolysis continues, as reflected y increased concentrations and clearance of plasma free fatty acids" In the presence of o%ygen, the released fatty acids can e o%idized y cardiac and s5eletal muscle to produce energy" The precise role of fatty acids in the inhi ition of glycolysis after injury is contro!ersial" -!idence suggests that fatty acid6induced inhi ition of glycolysis may e a major mechanism for reduced glycolysis during the flo# phase after minor to moderate injury" This mechanism may not operate in se!ere injury, hemorrhage, or sepsis, conditions in #hich persistent glycolysis and net proteolysis are o ser!ed" Dipoprotein lipase, the endothelial cell mem rane enzyme responsi le for clearing plasma triglycerides, is suppressed in adipose tissue after trauma, ut not in muscle" In sepsis this enzyme acti!ity is suppressed in oth muscle and adipose tissue" The roles of cyto5ines, such as TN( '#hich inhi its lipogenesis and decreases lipoprotein lipase acti!ity+, ID*), and /9-, in fat meta olism are not fully understood"

The high concentrations of intracellular fatty acids and the ele!ated concentration of glucagon during the e and flo# phases inhi it fatty acid synthesis" In hepatocytes, this also stimulates the transport of acyl coenzyme , 'acyl Co,+ into the mitochondria for o%idation and 5etogenesis" Getogenesis is !aria le and is in!ersely correlated #ith the se!erity of injury" Getogenesis is decreased after major injury, se!ere shoc5, and sepsis and is suppressed y increases in le!els of insulin and other energy su strates, y increased upta5e and o%idation of free fatty acids, and y an associated counterregulatory hormone response" ,fter minor injury or mild infection, 5etogenesis increases ut to a lesser e%tent than that seen during nonstressed star!ation" Injuries that are associated #ith minor 5etone ody formation also appear to e associated #ith a small or a sent increase in plasma free fatty acid concentrations" Car ohydrate $eta olism .ystemic glucose intolerance is #ell documented in injured patients" :y contrast, asal insulin le!els are ele!ated y se!eral times during the early flo# phase, indicating a state of relati!e insulin resistance" Regional tissue catheterization and isotope dilution studies pro!ide a more precise description of this insulin resistance" , =A to ?A percent increase in net splanchnic glucose output is o ser!ed in septic patients, and a =A to )AA percent increase is noted in thermally injured patients" The associated macroendocrine hormone milieu contri utes to this net gluconeogenic response and is elie!ed to e largely under the acti!e control of glucagon #ith permissi!e re&uirement for cortisol" The precise contri utions of other macroendocrine hormones are unclear, although there is e!idence to suggest that proinflammatory mediators such as ID*? also may e%ert an influence on hepatic glucose production" Defina le acute changes in su strate turno!er are associated #ith the proinflammatory mediator acti!ity induced y endoto%in administration or TN( infusion 'Ta le )*E+" Increases in plasma glucose le!els are proportional to the se!erity of injury and to some e%tent are correlated #ith sur!i!al" ;ith the presence of hyperglycemia, resulting largely from increased hepatic production, a ready source of su strate is pro!ided to tissues such as those of the ner!ous system, #ound, and red lood cells, #hich do not re&uire insulin for glucose transport" -le!ated concentrations of glucose and of some amino acids may e necessary for leu5ocyte energy re&uirements in inflamed tissues and in defense of epithelial arriers or other sites of micro ial in!asion" Insulin resistance is of teleologic enefit to the host in that the accompanying neuroendocrine hormone response precludes the adaptation to 5etone ody production" To a large e%tent, the depri!ation of glucose to nonessential organs such as s5eletal muscle and adipose tissues is mediated y catecholamines" This relationship is suggested y a close correlation et#een plasma glucose and pre!ailing catecholamine le!els '(ig" )*4)+" /eripheral insulin resistance has een noted in isolated catecholamine e%cess in healthy su jects, as has een increased hepatic glucose production" Con!ersely, glucocorticoids do not alter these parameters '(ig" )*43+" ,lthough the mechanisms for reduced glucose o%idation are not fully understood, a mediator*induced reduction of s5eletal muscle pyru!ate dehydrogenase acti!ity diminishes the con!ersion of glucose to acetyl Co, and su se&uent entry into the tricar o%ylic acid cycle" The conse&uent accumulation and shunting of three car on s5eletons to the li!er pro!ides su strate for gluconeogenesis" 9lucose must e pro!ided to inflammatory and healing cells in the #ound en!ironment" 9lucose upta5e and lactate production in #ounded tissue are

significantly increased" ;ound inflammatory cells re&uire glucose as an energy su strate and accelerated glucose upta5e in #ounded and urned tissue is correlated #ith the inflammatory cellular infiltrate" The increase in glucose upta5e in #ounded tissue is associated #ith an increase in the acti!ity of phosphofructo5inase, a major rate*limiting enzyme in glycolysis" Despite the increase in glucose upta5e and phosphofructo5inase acti!ity, #ounded and urned tissues demonstrate decreased insulin sensiti!ity and fail to normally increase glucose upta5e or glycogenesis in response to insulin" /rotein and ,mino ,cid $eta olism The inta5e of protein for a healthy young adult is appro%imately EA to )3A g, or )4 to 3A g of nitrogen per day" Daily fecal and urinary e%cretion of nitrogen is 3 to 4 g and )4 to 3A g, respecti!ely" ,fter injury, daily nitrogen e%cretion in the urine increases to 4A to =A g as urea nitrogen and represents net proteolysis" The increased e%cretion of urea after injury also is associated #ith the urinary loss of sulfur, phosphorus, potassium, magnesium, and creatinine, #hich indicates rea5do#n of intracellular compounds" Isotope dilution studies suggest that decreases in cell mass are responsi le for the increased loss of these meta olites" .ophisticated methods of ody mass assessment, such as neutron acti!ation analysis, confirm a loss of lean tissues after significant injury" , predominant loss of s5eletal muscle protein is suggested y increased urinary 4* methylhistidineCcreatinine ratios" Radiola eled amino acid incorporation studies and protein analyses confirm that s5eletal muscle is depleted #hile !isceral tissues, such as li!er and 5idney, are relati!ely preser!ed" The mechanisms for this !isceral protein preser!ation are unclear, ut animal studies suggest that proinflammatory cyto5ine acti!ity may contri ute to this process" Data on total ody protein turno!er suggest that after injury the net changes in cata olism and synthesis depend on the se!erity of the injury" -lecti!e operations and minor injuries result in decreased protein synthesis and normal rates of protein rea5do#n" .e!ere trauma, urns, and sepsis are associated #ith increased #hole* ody protein turno!er and increased net protein cata olism 'Ta le )*@+" ,ccelerated proteolysis and gluconeogenesis persist after major injury and during sepsis" The rise in urinary nitrogen and negati!e nitrogen alance egins shortly after injury, reaches a pea5 a out the first #ee5 and may continue for 4 to B #ee5s" The magnitude of nitrogen loss also is related to the age, se%, and physical condition of the patient" 1oung healthy males lose more protein in response to an injury than do #omen or the elderly, presuma ly ecause they ha!e a higher lean ody mass than the latter t#o patient su sets" The amino acid composition of normal human eings !aries according to tissue origin" ,fter trauma, su strate cycling occurs et#een s5eletal muscle, li!er, and the #ound 'see (ig" )*3E+" Luantitati!ely, the major source of amino acids is s5eletal muscle, in #hich the proportions of specific amino acids as protein and free intracellular components !aries dramatically from that in normal plasma '(ig" )*44+" Increases y se!eral times in the splanchnic upta5e of alanine and glutamine in conjunction #ith similar trends for peripheral tissue efflu% are o ser!ed after injury" ,lthough the precise mechanisms for the net increase in s5eletal muscle protein rea5do#n remain unclear, the com ined e%tracellular hormonal milieu of relati!e insulin resistance, cortisol e%cess, and proinflammatory cyto5ine acti!ity e%ert a synergistic influence" ;ithin the cell, enhanced o%idati!e species and diminished antio%idant acti!ities, such as glutathione, all enhance the potential for protein insta ility" $any of these same mediators ser!e to increase u i&uitin*dependent

proteolytic path#ays '(ig" )*4<+, one of se!eral potential path#ays for degradation of cellular proteins" The u i&uitin*proteasome path#ay may not e operati!e in all cata olic conditions" (or e%ample, this path#ay is of major importance for muscle protein degradation during sepsis, ut it is only partly responsi le for the protein cata olism seen after urn injury" The intracellular muscle concentrations of se!eral essential amino acids decrease at the same time that net efflu% is occurring from s5eletal muscle" The release of glutamine and alanine are greater than can e predicted from its relati!e a undance in muscle tissue protein, indicating their net synthesis in muscle efore release" 9lutamine is a major energy source for lymphocytes, fi ro lasts, and the gastrointestinal tract, especially during conditions of increased stress" 9lutamine may act as a conditional essential amino acid during periods of cata olism, since depletion of this su strate has pronounced negati!e effects on enterocytes and mucosal integrity and since administration of glutamine re!erses these effects" ,lthough it is hypothesized that pro!ision of this amino acid might preser!e or enhance immune cell and enterocyte function during stress, clinical studies documenting such eneficial effects during injury in human su jects are lac5ing" NUTRITION IN T2- .UR9IC,D /,TI-NT $ost patients undergoing electi!e surgical operations #ithstand the rief period of cata olism and star!ation #ithout noticea le difficulty" $aintaining an ade&uate nutritional regimen may e of critical importance in managing seriously ill surgical patients #ith pree%isting #eight loss and depleted energy reser!es" :et#een these t#o e%tremes are patients for #hom nutritional support is not essential for life ut may ser!e to shorten the postoperati!e reco!ery phase and minimize the num er of complications" (re&uently, a patient may ecome ill or e!en die from complications secondary to star!ation rather than the underlying disorder" It is essential that the surgeon ha!e a sound grasp of the fundamental meta olic changes associated #ith surgery, trauma, and sepsis and an a#areness of the methods a!aila le to re!erse or ameliorate these e!ents" .urgery, Trauma, .epsis In contrast to the #hole* ody and tissue*specific energy and protein conser!ation response e%hi ited during unstressed star!ation, the injured patient manifests !aria le, ut o ligatory, increases in energy e%penditure and nitrogen e%cretion '(ig" )*4=+" ;hile the e%tent and duration of this response to injury are modified y a !ariety of factors, including the ade&uacy of resuscitation, infection, and medication, the ina ility to do#n* regulate ody energy e%penditure and nitrogen losses may rapidly deplete la ile and functional energy stores" The postinjury meta olic en!ironment precludes the efficient o%idation of fat and 5etone production, there y promoting the continued erosion of protein pools" This enhanced net protein cata olic process, if unchec5ed y effecti!e disease*specific therapy and allo#ed to progress for an e%tended period #ithout nutritional inter!ention, e!entuates in critical organ failure" The se&uence of flo# phase meta olic and endocrine e!ents occasioned y injury may e di!ided into se!eral phases" The magnitude of the changes and the duration of each phase !ary considera ly and are directly related to the se!erity of the injury" The enefits of e%ogenous nutritional support in each of these reco!ery phases is contro!ersial" Ne!ertheless, the integrati!e iology of endocrine and immune system interactions #ould predict a greater li5elihood of achie!ing lean tissue restoration and su strate* dependent immune competence during periods of attenuated mediator

acti!ity" .uch o ser!ations do not preclude a rationale for earlier efforts at nutritional inter!ention" Rather, they pro!ide a iologic asis for reasona le e%pectations of therapy and for the design of future therapeutic adjuncts" Cata olic /hase Once patients ha!e recei!ed initial resuscitation and sta ilization of #ounds, the earliest defina le meta olic response is one of cata olism" This phase has een termed the adrenergic*corticoid phase, ecause it corresponds to the period during #hich changes induced y adrenergic and adrenal corticoid hormones are most stri5ing" It is also li5ely that components of the micromediator systems e%ert significant influences during this phase" The detection of proinflammatory mediators or their surrogate mar5ers 'such as solu le receptors+ usually is noted to pea5 during this period, and the ma%imum changes in su strate turno!er are o ser!ed during this period 'see Ta le )*@+" To !aria le degrees, rates of gluconeogenesis, acute phase protein production, and immune cell acti!ity are all altered during the cata olic phase" The administration of moderate amounts of glucose to these indi!iduals produces little or no change in the rate of protein cata olism, although e!idence using isotopic determinations suggests that pro!ision of sufficient nonprotein calories in com ination #ith amino acids may reduce the rate of ody protein rea5do#n 'Ta le )*)A+" In the cata olic phase, glucose turno!er is increased, #hile Cori cycle acti!ity is stimulated and three*car on intermediates are con!erted ac5 to glucose in the li!er y pyru!ate car o%ylase and phosphoenolpyru!ate car o%ylase" Increased synthesis of these t#o enzymes occurs in the presence of ele!ated le!els of glucagon, glucocorticoids, and catecholamines and lo# concentration of insulinthe hormonal en!ironment present during the cata olic phase of injury" Dipolysis also is stimulated y this hormonal milieu, and an o ligatory o%idation of fatty acids is e!ident" -fforts directed at interruption of afferent neurogenic stimuli y e%tradural anesthesia ha!e met #ith partial success in attenuating some of these a normalities of energy su strate turno!er" The impact of such therapy on nitrogen loss has een far less dramatic, suggesting that circulating or tissue paracrine factors other than classical neuroendocrine hormones are of major importance in early postinjury meta olic responses" It has een #idely speculated that one or more proinflammatory cyto5ine mediators are major determinants of increased rates of energy e%penditure and su strate turno!er after injury, ut no clear e!idence of this influence in human eings has een presented" :loc5ade of TN( and ID*) acti!ities during conditions of human endoto%inemia does not pre!ent the characteristic increase in meta olic rate and glucose or protein turno!er" -arly ,na olic /hase Depending on the se!erity of injury, the ody turns from a cata olic to an ana olic phase" This may occur #ithin 4 to E days after uncomplicated electi!e surgery or after #ee5s in patients #ith e%tensi!e cross*sectional tissue injury, sepsis, or ungrafted thermal injury" This turning point, also 5no#n as the corticoid*#ithdra#al phase, is characterized y a sharp decline in nitrogen e%cretion and restoration of appropriate potassium* nitrogen alance" This phase is also iochemically characterized y a reprioritization of acute phase reactants, as early inflammatory response proteins are supplanted y tissue repair and ana olic factors, such as I9(* )" Clinical manifestations of this transition period are rief and coincide #ith initial diuresis of retained #ater and rene#ed interest in oral nutrition"

The early ana olic phase may last from a fe# #ee5s to a fe# months depending on the capacity to ingest ade&uate nutrition and the e%tent to #hich erosion of protein stores has occurred" Nitrogen alance is positi!e, indicating synthesis of proteins, and there is a rapid and progressi!e gain in #eight and muscular strength" /ositi!e nitrogen alance reaches a ma%imum of appro%imately < gCday, #hich represents the synthesis of appro%imately 3= g of protein and the gain of o!er )AA g of lean ody massCday" The total amount of nitrogen gain ultimately e&uals the amount lost during the cata olic phase, although the rate of gain #ill e much slo#er than the rate of initial loss" Date ,na olic /hase The final period of con!alescence or the late ana olic phase may last from se!eral #ee5s to se!eral months after a se!ere injury" This phase is associated #ith the gradual restoration of adipose stores as the pre!iously positi!e nitrogen alance declines to#ard normal" ;eight gain is much slo#er during this phase ecause of the higher caloric content of fat and can e realized only if inta5e is in e%cess of caloric e%penditure" In most indi!iduals, the phase ends #ith a gradual return to the pre!iously normal ody #eight" The patient #ho is partially immo ilized during this period of time, ho#e!er, may e%hi it a mar5ed gain in #eight as a result of decreased energy e%penditure" ,ssessment and Re&uirements Nutritional homeostasis assumes that proper timing and administration of nutrients has a fa!ora le impact on the outcome of therapy" Nutritional assessment is underta5en to determine the se!erity of nutrient deficiencies or e%cesses and to aid in predicting nutritional re&uirements '(ig" )*4?+" Important information is o tained y determining the presence of #eight loss and of chronic illnesses or dietary ha its influencing the &uantity and &uality of food inta5e" .ocial ha its predisposing to malnutrition and the use of medications that may influence food inta5e or urination should e in!estigated" /hysical e%amination see5s to assess loss of muscle and adipose tissues, organ dysfunction, and su tle change in s5in, hair, or neuromuscular function reflecting an impending nutritional deficiency" ,nthropometric data '#eight change, s5in fold thic5ness, and arm circumference muscle area+ and iochemical determinations 'le!els of creatinine e%cretion, al umin, and transferrin+ can e used to su stantiate the patientFs history and physical findings" It is imprecise to rely on any single or fi%ed com ination of these findings to assess nutritional status or mor idity" ,ppreciation for the stresses and natural history of the disease process, in com ination #ith nutritional assessment, is the asis for identifying patients in acute or anticipated need of nutritional support" The caloric and nitrogen re&uirements necessary to maintain an indi!idual in alance after se!ere injury depend on the e%tent of injury, the source and route of administered nutrients, and, to some e%tent, the degree of antecedent malnutrition" , fundamental goal of nutritional support is to meet the energy re&uirements for meta olic processes, core temperature maintenance, and tissue repair" (ailure to pro!ide ade&uate nonprotein energy sources leads to dissolution of lean tissue stores" The re&uirements for energy may e measured y indirect calorimetry or estimated from urinary nitrogen e%cretion, #hich is proportional to resting energy e%penditure" :asal energy e%penditure ':--+ also can e estimated y the e&uations of 2arris and :enedict7 :-- 'men+

M ??"<B K )4"B=';+ K ="A'2+ 6 ?"B?',+ 5calCday :-- '#omen+ M ?==") K @"=?';+ K )"E='2+ *<"?E',+ 5calCday #here ; M #eight, 5g 2 M height, cm , M age, years These e&uations are suita le for estimating energy re&uirements in at least EA percent of hospitalized patients" Nonprotein calories are supplied in e%cess of energy e%penditure ecause the use of e%ogenous nutrients is decreased and energy su strate demands are increased after traumatic or septic insult" ,ppropriate nonprotein caloric needs are )"3 to )"= times resting energy e%penditure 'R--+ during enteral nutrition and )"= to 3"A times R-- during intra!enous nutrition" It is seldom, if e!er, appropriate to e%ceed this le!el of nonprotein energy inta5e during the height of the cata olic phase" .ome authorities ha!e suggested that targeted underfeeding might e a more appropriate strategy in such patients" The second o jecti!e of nutritional support is to meet the su strate re&uirements for protein synthesis" $aintenance of protein synthesis depends on many factors, including the nature and degree of the insult, the source and amount of e%ogenous protein, and pre!ious nutritional status" Conse&uently, no single nutritional formulation is appropriate for all patients" ,n appropriate calorie*nitrogen ratio ')=A to 3AA7)+ should e maintained, ut e!idence suggests that increased protein inta5e 'and a lo#er calorie*nitrogen ratio+ may e efficient in selected hypermeta olic patients" In the a sence of se!ere renal or hepatic dysfunction precluding the use of standard nutritional regimens, appro%imately A"3= to A"4= g of nitrogenC5g of ody #eight should e pro!ided daily" .pecialized nutritional formulations designed to impro!e nitrogen use in organ dysfunction such as acute renal and hepatic failure are targeted either to supplement deficiencies associated #ith the disease process or to correct characteristic amino acid a normalities" The re&uirements for !itamins and essential trace minerals can e easily met in the typical patient #ith an uncomplicated postoperati!e course" >itamins usually are not gi!en in the a sence of preoperati!e deficiencies" /atients maintained on elemental diets or parenteral hyperalimentation re&uire complete !itamin and mineral supplementation" The commercial defined*formula enteral diets contain !arying amounts of essential minerals and !itamins 'Ta le )*))+" It is necessary to ensure that ade&uate replacement is a!aila le in the diet or y supplementation" Numerous commercial !itamin preparations are a!aila le for intra!enous or intramuscular use, although most do not contain !itamin G and some do not contain !itamin :)3 or folic acid" .upplemental trace minerals may e gi!en intra!enously" -ssential fatty acid supplementation also may e necessary, especially in patients #ith depletion of adipose stores" /atients recei!ing intra!enous feeding re&uire all the a o!e micronutrients to pre!ent the de!elopment of deficiencies" Indications and $ethods for Nutritional .upport The selection of patients #ho re&uire partial or complete nutritional support has ecome increasingly important as constraints on hospitalization and resource management escalate" The a ility to pro!ide nutritional support to stressed patients

and to attenuate nitrogen losses in cata olic states is an important adjunct to surgical care" The need for nutritional support should e assessed during the preoperati!e and postoperati!e courses of all ut the most routine cases" $ost surgical patients, ho#e!er, do not re&uire special nutritional regimens" The reasona ly #ell*nourished and other#ise healthy indi!idual #ho undergoes an uncomplicated major operati!e procedure has sufficient ody fuel reser!es to #ithstand the cata olic insult and partial star!ation for at least ) #ee5" ,de&uate &uantities of parenteral fluids #ith appropriate electrolyte composition and a minimum of )AA g glucose daily to minimize protein cata olism #ill e all that is necessary in most patients" ,ssuming that the patient has a relati!ely uncomplicated postoperati!e course and resumes normal oral inta5e at the end of this period, defined*formula diets or parenteral alimentation are unnecessary and inad!isa le ecause of the associated ris5s" During the early ana olic phase, the patient needs an ade&uate caloric inta5e of proper composition to meet the energy needs of the ody and to allo# protein synthesis" , high calorie*to*nitrogen ratio 'optimally appro%imately )=A 5calCg nitrogen+ and an ade&uate supply of !itamins and minerals are necessary for ma%imum ana olism during this period" In contrast to this group, there are populations of surgical patients for #hom an ade&uate nutritional regimen can e of critical importance for a successful outcome" These include some patients #ho are chronically de ilitated preoperati!ely from their diseases or from malnutrition and patients #ho ha!e suffered trauma, sepsis, or surgical complications and cannot maintain an ade&uate caloric inta5e" In many cases the need for nutritional therapy during the early cata olic phase is apparent" This most certainly includes patients for #hom there is a high e%pectation of prolonged hospitalization and diminished capacity for !oluntary nutrient inta5e, such as patients #ith e%tensi!e urns or those #ith other se!ere injuries and incipient or o!ert organ failure" Despite the intuiti!ely o !ious decision to initiate nutritional support in such populations, documentation of nutrition*specific enefits or impro!ements in outcome are generally lac5ing" Ne!ertheless, such highly stressed and at*ris5 patients should recei!e consideration of nutritional support early" The dilemma more commonly presented to the clinician is the identification of other patients in #hom a reasona le e%pectation of enefit from nutritional inter!ention can e met" /rospecti!e, randomized trials ha!e significantly narro#ed the populations in #hom this e%pectation might e met" In general, the indications for preoperati!e nutritional support, at least in hospitalized patients, appear largely confined to patients #ith e!idence of more se!ere erosion of lean ody mass and adipose tissue stores" This does not preclude the possi ility that nutritional support in the am ulatory setting or those #ith e!idence of organ failure or immunosuppression might achie!e enefit from specialized nutritional support efore electi!e surgery" .pecialized nutritional support can e gi!en enterally, or enterally #ith supplements !ia peripheral !ein, or y central !enous routes" The enteral route should al#ays e used #hen possi le ecause it is considered to e more economical and #ell tolerated in many patients, including those ha!ing undergone recent a dominal surgery" Nasopharyngeal, gastrostomy, and jejunostomy tu e feedings may e considered for alimentation in patients #ho ha!e a relati!ely normal gastrointestinal tract ut cannot or #ill not eat" -lemental diets may e administered y similar routes #hen ul5 and fat* free nutrients re&uiring minimal digestion are indicated" /arenteral alimentation may e used for supplementation in the patient #ith limited oral inta5e or, more commonly, for complete nutritional management in the a sence of oral inta5e" Clinical studies demonstrate that parenteral feeding potentially enhances the

magnitude of macroendocrine 'stress hormones+ and microendocrine 'cyto5ine+ mediator responses to an antigenic challenge '(ig" )*4B+" ;hile the mechanisms for amplification of counterregulatory hormone and proinflammatory mediator le!els in parenterally fed su jects remain to e fully elucidated, a loss of intestinal arrier function permitting acute or chronic host e%posure to luminal to%ins has een proposed" In human eings, it has not een clearly determined #hether parenteral nutrition significantly alters intestinal arrier function instead of intracellular and intercellular anatomy" The incidence of systemic immune compromise resulting from parenteral nutrition has pro!ed difficult to document" ;hile se!eral studies suggest a higher incidence of infectious complications in parenterally fed su jects compared #ith an enterally fed cohort, this o ser!ation is largely confined to traumatically injured populations 'Ta le )*)3+" Despite the failure to document clinical differences et#een the enteral and parenteral feeding routes for e%ogenous nutrients, the gastrointestinal tract ser!es a num er of synthetic and immunologic functions that ear consideration in the design of nutritional support regimens" , num er of approaches for preser!ing gastrointestinal mucosal integrity and gut mass, including luminal stimulation y digesti le or nondigesti le su strates, and infusion of critical intestinal fuel sources such as glutamine or short*chain fatty acids, are undergoing clinical trials" To date, these products ha!e not een clearly documented to impro!e outcome in the majority of populations studied" The patientFs a ility to tolerate and a sor enteral feedings is determined y the rate of infusion, the osmolality, and the chemical nature of the product" -nteral feedings often are egun at a rate of 4A to =A mDCh and are increased y )A to 3= mDCh per day until the optimal !olume is deli!ered" ,fter full !olume is attained, the concentration of the solution is increased slo#ly to the desired strength" If esophageal or gastric feedings are gi!en, residual gastric !olume should e monitored to reduce the ris5 of a major aspiration episode" If a dominal cramping or diarrhea occurs, the rate of administration or the concentration of the solution should e decreased" ,ll feeding tu es should e thoroughly irrigated clear of solutions if feedings are interrupted or medications are gi!en y this route" -nteral (eeding Nasoenteric Tu e (eeding The use of feeding tu es that tra!erse the gastroesophageal junction should normally e used only in alert patients" ;hile some e%ceptions might transiently e%ist, prolonged use of such feeding tu es should e discouraged" The foremost contraindication for nasoesophageal or gastric tu e feeding is unconsciousness or lac5 of protecti!e laryngeal refle%es, #hich may result in life*threatening pulmonary complications from aspiration" -!en #ith a tracheostomy, it is inad!isa le to feed mentally o tunded patients !ia such route, since feedings often can e reco!ered from tracheostomy suction, indicating continued aspiration of gastric contents" -sophageal feedings are seldom permissi le" The nasojejunal tu e may allo# feeding eyond dysfunctional gastric stomas and high gastrointestinal fistulas" In such cases it may e possi le to maintain nutrition #ithout a jejunostomy tu e until stomal dysfunction relents or the fistula heals" .uch tu es may e positioned in the upper small intestine y positioning the patient in a manner that promotes passage of the mercury*#eighted tu e into the desired intestinal segment" If this techni&ue is unsuccessful, placement may e accomplished #ith fluoroscopic guidance or y an e%perienced endoscopist" /roper position of the tu e must e confirmed radiographically"

;hene!er dietary preparations are administered into the gastrointestinal tract !ia tu es, it is ad!isa le to use edside infusion pumps to ensure a constant rate of deli!ery o!er each 3<*h period" The use of such pumps decreases the incidence of gastrointestinal side effects induced y o!erly rapid deli!ery of hyperosmolar solutions, and it allo#s safer administration of larger daily !olumes of nutrients, ecause gastric distention is minimized" In!estigation is re&uired for all a dominal complaints in such patients in !ie# of reports of intussusception around feeding tu es placed more distally in the small intestine" 9astrostomy Tu e (eeding The administration of lended food through a gastrostomy tu e is a good method for feeding patients #ith a !ariety of chronic gastrointestinal lesions arising at or a o!e the cardioesophageal junction" 9astrostomy tu e feeding is contraindicated for mentally o tunded patients #ith inade&uate laryngeal refle%es" This feeding method should e used only in alert patients or in patients #ith total o struction of the distal esophagus" .urgically constructed gastrostomies of the .tamm 'serosa*lined, temporary+ or the modified 9lassman 'mucosa*lined, permanent+ type are an accepta le means of pro!iding enteral feedings, although percutaneous endoscopic gastrostomies '/-9s+ ha!e pro!ed to e safe and e&ually effecti!e" The feeding mi%ture may e ordinarily prepared food con!erted y a lender into a semili&uid consistency" 2yperosmolarity of the feeding formula is not generally a pro lem as long as the pylorus is intact" 0ejunostomy Tu e (eeding 0ejunostomy tu e feedings usually are re&uired for patients in #hom nasoesophageal or gastrostomy tu e feedings are contraindicated" This includes comatose patients, patients #ith high gastrointestinal fistulas or o structions, and patients in #hom a nasojejunal feeding tu e cannot e placed" The jejunostomy may e of the Rou%*en*1 'permanent+ or the ;itzel 'temporary+ type" The latter is constructed y inserting a num er )E (rench ru er catheter into the pro%imal jejunum appro%imately 4A cm distal to the ligament of Treitz" The #all of the jejunum is in!erted o!er the tu e for a out 4 cm as it emerges from the o#el to create a serosa*lined tunnel that allo#s rapid sealing of the jejunal opening #hen the tu e is remo!ed" ,n alternati!e procedure is the placement of a smaller* ore polyethylene or .ilastic catheter" The tu e is rought out through a sta incision in the left upper &uadrant of the a domen" The jejunum is sutured to the anterior a dominal #all at the point of tu e entry to seal it from the peritoneal ca!ity" It is accepta le to place jejunostomy tu es concomitantly #ith major or trauma*related a dominal operations if prolonged nutritional support is anticipated in such patients" Under some circumstances, #hen the need for postoperati!e enteral feedings is e!ident or li5ely, the placement of a needle*catheter feeding tu e may o !iate the need for more e%tensi!e procedures" The a ility to secure jejunal feeding tu es endoscopically ma5es this a reasona le alternati!e to surgically constructed jejunostomies" In a large series, $aurer and colleagues reported the feasi ility, safety, and cost* effecti!eness of fluoroscopically guided percutaneous insertion of jejunostomy tu es in a di!erse population of patients #ho #ould other#ise ha!e re&uired intraoperati!e or endoscopic feeding*tu e placement" If the jejunostomy tu e is inad!ertently remo!ed, lind attempts at reinsertion should not e attempted" If disco!ered #ithin a fe# hours, the tu e may e reinserted under fluoroscopic guidance to e certain that it is in the o#el efore feedings are resumed"

The patient is o ser!ed for signs of peritonitis for )3 to )E h after feedings are restarted" If there is any dou t a out the position of the tu e, it should e replaced surgically" (eedings are safely egun )3 to )E h after jejunostomy construction, e!en though peristalsis is not audi le" 0ejunostomy tu e feedings usually are initiated #ith one of the many commercially a!aila le defined*formula diets 'see Ta le )*))+" ;hen pro!ided y continuous infusion, such formulas usually are #ell tolerated, ut all patients must e serially e!aluated to assure efficacy" ;ith proper care, a out E= percent of jejunostomy patients tolerate their feedings" ;hen diarrhea occurs it usually can e controlled y temporarily reducing the concentration and !olume of formula" (ailing this, feeding is halted for a day, then resumed from the eginning of the feeding regimen, progressing more slo#ly than efore" In many cases symptoms are relie!ed if the rate and !olume of infusion are reduced and cold formula a!oided" (ailing control of diarrhea y these means, or as an alternati!e method to opiates, the periodic administration of ul5*forming agents might e helpful" If the patient #ith a jejunostomy has a pro%imal o#el or iliary fistula draining more than 4AA mD daily for a prolonged period, the fistular drainage may e collected y sump suction, cooled in an ice asin at edside, and promptly re*fed in small increments throughout the day" To a!oid jejunal o!erloading, the fistular fluid is re* fed et#een formula feedings" ,spirated gastric juice should not e re*fed, ecause it may cause jejunal irritation and profuse diarrhea" If the fistular drainage is profuse, it usually is not possi le to re*feed more than 3 DCday, and fluid and electrolyte losses must e replaced #ith appropriate intra!enous supplements" ,dditional #ater may e gi!en #ith the feedings or administered et#een the feedings as indicated" Occasionally an elemental diet is indicated #hen other jejunostomy formulas are not tolerated" Defined*(ormula Diets Commercial production of nutritionally complete li&uid diets, deri!ed in purified form from natural foods or from foods prepared synthetically are #idely used in acute and chronic nutritional support efforts" These diets may e used for complete nutritional support or as dietary supplements for patients #ho are una le to eat or digest enough food to meet their energy re&uirements" They may e prefera le to high*calorie parenteral feedings for patients #ho ha!e part of the small o#el a!aila le for the a sorption of simple sugars and amino acids" -lemental diets ha!e een found useful for patients #ith depleted protein reser!es secondary to gastrointestinal tract disease, such as ulcerati!e or granulomatous colitis and mala sorption syndrome, and for patients #ith only partial function of the gastrointestinal tract, such as the short o#el syndrome or gastric or small* o#el fistulas #ith feeding distal to the fistula" These diets also ha!e een used during preoperati!e o#el preparation" The commercially prepared diets also contain aseline electrolytes, #ater, fat*solu le !itamins 'e%cept !itamin G in some cases+, and trace minerals" They contain no ul5 and therefore produce a minimum of residue" They do not contain lactose and are more readily tolerated in such lactase*deficiency states as gastroenteritis, intestinal resection, radiation, or genetic predisposition" There are se!eral products #hose protein content is partially hydrolyzed or completely hydrolyzed to amino acids or dipeptides" ;hen digestion and a sorption are normal, there appears to e little therapeutic ad!antage to the use of crystalline amino acid formulas" , listing of the asic constituents for se!eral commercial preparations as #ell as the !olume

necessary to achie!e minimal daily re&uirements is gi!en in Ta le )*))" The practitioner should consult product information to ascertain further details regarding the precise composition of a prescri ed formula" .pecial products designed for use in the presence of organ dysfunction also are a!aila le 'see Ta le )*))+" (at may contri ute less than ) percent or as much as <B percent of the calories in these commercial formulas" $ost contain long*chain fats as corn oil, soy oil, or safflo#er oil" .ome include medium*chain triglycerides" :ecause the high caloric density of fat does not increase the osmolality of the formula #hen significant maldigestion or mala sorption is present, a diet lo# in fat or one supplemented #ith medium*chain triglycerides may e useful" To pre!ent the de!elopment of essential fatty acid deficiency, the clinician must e mindful of the possi le need for additional lipids #hen pro!iding such specialized diets to patients" .pecific products are limited in their o!erall clinical usefulness y !irtue of the fi%ed content of nutrients" There has een a trend to#ard preparing enteral diets in modular form #here y certain critical items, such as sodium, potassium, and fat, can e modified in concentration as needed" The amount of elemental diet re&uired to maintain #eight and nitrogen alance !aries #ith the indi!idual patient" In se!ere cata olic states, the standard diet often fails to achie!e positi!e nitrogen alance" Careful attention to #ater and electrolyte alance is mandatory, particularly #hen large &uantities of fluid are eing lost through fistulas or other routes" ,dditional sodium and potassium may e added to the mi%ture 'not to e%ceed a total of )AA m-&+, although they should e gi!en in intra!enous fluids #hen larger &uantities are needed" ;ater may e added to the mi%ture in the face of e%cessi!e pure #ater losses" Complications include nausea, !omiting, and diarrhea that de!elop ecause of the high osmolarity of the diets" This generally can e controlled y decreasing the rate andCor concentration of the mi%ture" 2ypertonic non5etotic coma may occur in the presence of e%cessi!e #ater losses or if the diets are administered at concentrations a o!e those recommended" 2yperglycemia and glycosuria can occur in any se!erely ill patient, particularly latent dia etics, and insulin may e indicated" , num er of prospecti!e trials ha!e suggested that one or more enteral nutritional regimens may reduce complications and impro!e outcome" These formulations are promoted as enhancing !arious aspects of immune or solid organ function" There is no e!idence to suggest that this is uniformly the case gi!en that other prospecti!e randomized trials failed to document any enefits" /arenteral ,limentation /arenteral alimentation in!ol!es the continuous infusion of a hyperosmolar solution containing car ohydrates, proteins, fat, and other necessary nutrients through an ind#elling catheter inserted into the superior !ena ca!a" In order to o tain the ma%imum enefit, the ratio of calories to nitrogen must e ade&uate 'at least )AA to )=A 5calCg nitrogen+ and the t#o materials must e infused simultaneously" ;hen the sources of calories and nitrogen are gi!en at different times, there is a significant decrease in nitrogen use" These nutrients can e gi!en in &uantities considera ly greater than the asic caloric and nitrogen re&uirements, and this method has pro!ed highly successful in achie!ing gro#th and de!elopment, positi!e nitrogen alance, and #eight gain in a !ariety of clinical situations" Indications for the Use of Intra!enous 2yperalimentation

It is difficult to demonstrate that parenteral feeding significantly alters the clinical course or outcome in most nonsurgical patient populations" Clinical trials and metaanalyis of parenteral feeding in the perioperati!e period ha!e, ho#e!er, suggested that preoperati!e nutritional support may enefit some surgical patients, particularly those #ith e%tensi!e malnutrition" :y contrast, definiti!e e!idence of enefit accruing from use of nutritional support in the postoperati!e setting is lac5ing" The routine use of parenteral alimentation in the critical*care en!ironment has yet to e ade&uately assessed, and so it is currently used intuiti!ely" The e!idence underlying the application of parenteral nutrition in situations of surgical rele!ance #as re!ie#ed efore the formulation of clinical practice guidelines pu lished y a recent 9eorgeto#n Uni!ersity panel" The principal indications for parenteral alimentation are found in seriously ill patients suffering from malnutrition, sepsis, or surgical or accidental trauma #hen use of the gastrointestinal tract for feedings is not possi le" It has een used in many instances in #hich it is not needed or in #hich the use of the gastrointestinal tract is more appropriate" In some instances intra!enous nutrition may e used to supplement inade&uate oral inta5e" The safe and successful use of this regimen re&uires proper selection of patients #ith specific nutritional needs, e%perience #ith the techni&ue, and an a#areness of the associated complications" The fundamental goals are to pro!ide sufficient calories and nitrogen su strate to promote tissue repair and to maintain the integrity or gro#th of lean tissue mass" Disted elo# are situations in #hich parenteral nutrition has een used in an effort to achie!e these goals" Indications ) and 3 elo# usually are e%clusi!ely used for intra!enous nutrition" Indications 4 to )4 might e appropriate for enteral or parenteral nutrition" ')+ Ne# orn infants #ith catastrophic gastrointestinal anomalies, such as tracheoesophageal fistula, gastroschisis, omphalocele, or massi!e intestinal atresia" '3+ Infants #ho fail to thri!e nonspecifically or secondarily to gastrointestinal insufficiency associated #ith the short o#el syndrome, mala sorption, enzyme deficiency, meconium ileus, or idiopathic diarrhea" '4+ ,dult patients #ith short o#el syndrome secondary to massi!e small* o#el resection or enteroenteric, enterocolic, entero!esical, or enterocutaneous fistulas" '<+ /atients #ith high alimentary tract o structions #ithout !ascular compromise, secondary to achalasia, stricture, or neoplasia of the esophagus, gastric carcinoma, or pyloric o struction" '=+ .urgical patients #ith prolonged paralytic ileus after major operations, multiple injuries, or lunt or open a dominal trauma, or patients #ith refle% ileus complicating !arious medical diseases" '?+ /atients #ith normal o#el length ut #ith mala sorption secondary to sprue, hypoproteinemia, enzyme or pancreatic insufficiency, regional enteritis, or ulcerati!e colitis" 'B+ ,dult patients #ith functional gastrointestinal disorders such as esophageal dys5inesia after cere ro!ascular accident, idiopathic diarrhea, psychogenic !omiting, or anore%ia ner!osa"

'E+ /atients #ho cannot ingest food or #ho regurgitate and aspirate oral or tu e feedings ecause of depressed or o tunded sensorium after se!ere meta olic derangements, neurologic disorders, intracranial surgery, or central ner!ous system trauma" '@+ /atients #ith e%cessi!e meta olic re&uirements secondary to se!ere trauma, such as e%tensi!e full*thic5ness urns, major fractures, or soft* tissue injuries" ')A+ /atients #ith granulomatous colitis, ulcerati!e colitis, and tu erculous enteritis, in #hich major portions of the a sorpti!e mucosa are diseased" '))+ /araplegics, &uadriplegics, or de ilitated patients #ith indolent decu itus ulcers in the pel!ic areas, particularly #hen soilage and fecal contamination are a pro lem" ')3+ /atients #ith malignancy, #ith or #ithout cache%ia, in #hom malnutrition might jeopardize successful deli!ery of a therapeutic option" ')4+ /atients #ith potentially re!ersi le acute renal failure, in #hom mar5ed cata olism results in the li eration of intracellular anions and cations, inducing hyper5alemia, hypermagnesemia, and hyperphosphatemia" Contraindications to hyperalimentation include the follo#ing7 ')+ Dac5 of a specific goal for patient management, or #hen instead of e%tending a meaningful life, ine!ita le dying is prolonged" '3+ /eriods of cardio!ascular insta ility or se!ere meta olic derangement re&uiring control or correction efore attempting hypertonic intra!enous feeding" '4+ (easi le gastrointestinal tract feeding8 in the !ast majority of instances, this is the est route y #hich to pro!ide nutrition" '<+ /atients in good nutritional status, in #hom only short*term parenteral nutrition support is re&uired or anticipated" '=+ Infants #ith less than E cm of small o#el, since !irtually all ha!e een una le to adapt sufficiently despite prolonged periods of parenteral nutrition" '?+ /atients #ho are irre!ersi ly decere rate or other#ise dehumanized" Insertion of Central >enous Infusion Catheter The successful use of intra!enous hyperalimentation generally depends on the proper placement and management of the central !enous feeding catheter" , )?*gauge, E* or )3*inch radiopa&ue catheter is introduced percutaneously through the su cla!ian or internal jugular !ein and threaded into the superior !ena ca!a" ,lthough the techni&ue for su cla!ian !ein puncture '(ig" )*4E+ has een the prefera le and more #idely used techni&ue, the internal jugular approach also may e useful '(ig" )*4@+" (or insertion of the intra!enous catheter through the su cla!ian !ein, the patient is placed supine in a )=*degree head*do#n position #ith a small pad placed et#een the

shoulder lades to allo# the shoulders to drop posteriorly" This allo#s e%pansion of the su cla!ian !ein and easier penetration" The s5in may e scru ed #ith acetone to defat the surface and then #ith an iodophor compound" Drapes are carefully placed, and scrupulous aseptic precautions are o ser!ed" Docal anesthetic is infiltrated into the s5in, forming a #heal, as #ell as into the su cutaneous tissue and periosteum at the inferior order of the midpoint of the cla!icle" $ost commercially prepared 5its for central !enous catheter insertion are e&uipped #ith a 3* to 3N*inch long, )?*gauge needle" This needle attaches to a = to )A mD syringe and is inserted, e!eled do#n through the #heal, and ad!anced to#ard the tip of the operatorFs finger, #hich is pressed #ell into the patientFs suprasternal notch" The needle should hug the inferior cla!icular surface and go o!er the first ri into the su cla!ian !ein" ;ith slight negati!e pressure applied to the syringe, entrance into the !ein #ill e noted y the appearance of lood" The needle is ad!anced a fe# millimeters further to e sure that it is entirely #ithin the lumen of the !ein" The thum is held o!er the needle hu as the syringe is remo!ed to a!oid air em olism" , fle%i le guide*#ire is then introduced into the !ein through the ore of the needle, lea!ing at least half the length of the guide*#ire !isi le a o!e the s5in to pre!ent losing the #ire in the !ein or inducing arrhythmias" ;ith control of the guide*#ire, the needle is then #ithdra#n and remo!ed o!er the guide*#ire" The puncture site can e slightly e%tended #ith a num er )) lade, and a dilator forms a tract in the soft tissue y eing passed in and out o!er the guide*#ire" , )?*gauge, E* or )3*inch radiopa&ue catheter is then introduced o!er the guide*#ire until the catheter tip reaches the superior !ena ca!a" The guide*#ire is then #ithdra#n and !enous lood return is ascertained y syringe aspiration" The catheter hu is then connected to a sterile intra!enous administration tu ing, and a slo# infusion is egun #hile the catheter is se#n to the s5in #ith a small suture" ,nti iotic ointment is routinely applied around the entrance of the catheter into the s5in, and an occlusi!e dressing is applied o!er it, including the junction of the intra!enous tu ing #ith the catheter" , chest film is immediately o tained to confirm the position of the radiopa&ue catheter in the !ena ca!a and to chec5 for a possi le pneumothora%" -!ery 3 or 4 days, the intra!enous tu ing is changed at the catheter entry site o!er a guide*#ire" The catheter site is scru ed as for an operati!e procedure, and anti iotic ointment and a ne# occlusi!e dressing are applied" ;ithdra#al or administration of lood through the catheter or the use of the catheter for central !enous pressure measurements should e a!oided, since the ris5 of contamination and catheter occlusion are significantly increased" The use of the internal jugular approach is satisfactory ut more prone to de!eloping local or systemic infection" It is un#ise, unless a solutely necessary, to place catheters into the inferior !ena ca!a from the lo#er e%tremities ecause of the greater li5elihood of sepsis and throm oem olic phenomena" Dong catheters inserted through the antecu ital cephalic or asilic !eins may e ad!anced into the superior !ena ca!a" Initial e%perience #ith poly!inyl chloride catheters #as disappointing ecause of a high incidence of throm ophle itis" The use of polyurethane catheters has decreased the incidence of such complications" Other !ascular access methods may e achie!ed y surgical cutdo#ns and passing the catheters through the su cutaneous tissue of the anterior chest #all or the nec5 '(ig" )*<A+" /reparation and ,dministration of .olutions The asic solution contains a final concentration of 3A to 3=O de%trose and 4 to =O crystalline amino acids" The solutions are usually prepared sterilely in the pharmacy

from commercially a!aila le 5its containing the component solutions and transfer apparatus" /reparation in the pharmacy under laminar flo# reduces the incidence of acterial contamination of the solution" /roper preparation #ith suita le &uality control is essential to a!oid septic complications" :ecause of the considera le !aria ility in amino acid and electrolyte concentrations among commercially a!aila le alimentation formulations, physicians must ecome familiar #ith the solutions used in their institutions" Only in this manner may additi!es, in the form of additional electrolytes, e rationally planned to meet the specific meta olic needs of the patient" -lectrolyte re&uirements may !ary considera ly from patient to patient, depending on routes of fluid and electrolyte loss, renal function, meta olic rate, cardiac function, and underlying disease state" Intra!enous !itamin preparations also should e added to parenteral formulations" >itamin deficiencies are rare occurrences if such preparations are used" In addition, phytonadione '!itamin G)+ )A mg and folic acid = mg should e administered intramuscularly once a #ee5, since these are unsta le in the hyperalimentation solution" Cyanoco alamin '!itamin :)3+ ) mg is gi!en y intramuscular injection once a month" Intramuscular administration of iron may e re&uired for patients #ith iron deficiency anemia, although ade&uate mo ilization of iron stores may occur once the patient is ana olic" During prolonged fat*free parenteral nutrition essential fatty acid deficiency may ecome apparent, manifested y a dry, scaly dermatitis and loss of hair" The syndrome may e pre!ented y periodic infusion of a fat emulsion at a rate e&ui!alent to )A to )= percent of total calories 'Ta le )*)4+" -ssential trace minerals may e re&uired after prolonged total parenteral nutrition and can e supplied y direct addition of commercial preparations of de%trose amino acids solutions" The most fre&uent presentation of trace mineral deficiencies is the eczematoid rash that de!elops diffusely and at intertriginous areas in zinc*deficient patients" Other rare trace mineral deficiencies include a microcytic anemia associated #ith copper deficiency and glucose intolerance presuma ly related to chromium deficiency" These complications are seldom seen e%cept in patients recei!ing parenteral nutrition for e%tended periods" The daily administration of commercially a!aila le trace mineral supplements o !iates most such pro lems" Depending on fluid and nitrogen tolerance, parenteral nutrition solutions usually can e increased o!er 3 to 4 days to achie!e the desired infusion rate" Insulin may e supplemented as necessary to ensure glucose tolerance" ;olf and -l#yn demonstrated that ma%imum efficiency of glucose use occurs at an infusion rate of B mgC5g ody #eight per min" De%trose infusions a o!e this le!el result in increased fat synthesis and pro!ide no additional suppression of amino acid gluconeogenesis" Rarely, additional intra!enous fluids and electrolytes might e necessary #ith continued a normal large losses of fluids" The patient should e carefully monitored for de!elopment of electrolyte, !olume, acid* ase, and septic complications" >ital signs and urinary output are regularly o ser!ed, and the patient should e #eighed daily" (re&uent adjustments of the !olume and composition of the solutions are necessary during the course of therapy" -lectrolyte determinations are made daily until sta le and e!ery 3 or 4 days thereafter, and the hemogram, li!er function chemistries, and le!els of lood urea nitrogen, phosphate, and magnesium are determined #ee5ly" The urine or capillary lood glucose le!el is chec5ed e!ery ? h and serum glucose concentration chec5ed at least once daily during the first fe# days of the infusion and at fre&uent inter!als thereafter" Relati!e glucose intolerance may occur after initiation of parenteral alimentation" Insulin may e supplemented as necessary to impro!e

car ohydrate tolerance" The response of lood glucose to e%ogenous insulin is e!aluated y fre&uent capillary lood determinations, rather than reliance on glycosuria" If the lood glucose le!els remain ele!ated or glycosuria persists, the de%trose concentration may e decreased, the infusion rate slo#ed, or regular insulin added to each ottle" The rise in lood glucose concentration o ser!ed after initiating an intra!enous alimentation program may e temporary, as the normal pancreas increases its output of insulin in response to the continuous car ohydrate infusion" In patients #ith dia etes mellitus, additional crystalline or human insulin may e re&uired" The administration of ade&uate amounts of potassium is essential to achie!e positi!e nitrogen alance and to replace depleted intracellular stores" In addition, a significant shift of potassium ion from the e%tracellular to the intracellular space can ta5e place ecause of the large glucose infusion, #ith resultant hypo5alemia, meta olic al5alosis, and poor glucose utilization" In some cases as much as 3<A m-& of potassium ion daily may e re&uired" 2ypo5alemia may cause glycosuria, #hich #ould e treated #ith potassium, not insulin" :efore gi!ing insulin, the serum potassium le!el must e chec5ed to a!oid compounding the hypo5alemia" /atients #ith insulin*dependent dia etes mellitus may e%hi it #ide fluctuations in lood glucose le!els during parenteral nutrition" /artial replacement of lipid emulsions for de%trose calories may alle!iate these pro lems in selected patients" (at -mulsions Dipid emulsions deri!ed from soy ean or safflo#er oils are #idely used as an adjuncti!e nutrient to pre!ent the de!elopment of essential fatty acid deficiency" They ha!e een used as a major energy source in parenteral alimentation, ut there is no e!idence of enhanced meta olic efficacy if greater than )A to )= percent of calories is pro!ided as lipid emulsions" (at emulsion, de%trose, and amino acid com inations are as effecti!e as car ohydrate and amino acid solutions in the repletion of nonstressed patients" The efficiency of fat as a caloric source in the traumatized, hypermeta olic patient is not #ell documented" There is a theoretic ad!antage to the use of lipid emulsions in some septic and trauma patients #hen nonsuppressi le fat o%idation and increased norepinephrine e%cretion accompany glucose infusion" /atients #ith a normal fat transport or meta olism, lipid nephrosis, coagulopathy, or serious pulmonary disease should not recei!e fat emulsions" $ost in!estigators ad!ise limitation of administered fat emulsions to et#een 3"A and 3"= gC5g of ody #eight per day" .pecial (ormulations Numerous studies ha!e documented the safety of parenteral alimentation in patients #ith renal failure" In these patients special formulations of essential amino acids may e indicated" .election of the appropriate calorie and nitrogen concentration must e judged y fluid tolerance, associated illnesses, and the fre&uency of dialysis" ,ppropriate use of dialysis is additi!e to nutritional support in impro!ing sur!i!al of these patients" .olutions for patients #ith acute, oliguric renal failure contain a final de%trose concentration of <A to <= percent and only essential l*amino acids" In patients #ith nonoliguric renal failure, it may e possi le to use essential and nonessential amino acids to promote protein synthesis" .olutions designed for patients #ith hepatic failure contain increased le!els of ranched*chain amino acids and decreased concentrations of aromatic amino acids" .uch solutions impro!e encephalopathy ut may not impro!e sur!i!al, #hich is

dictated y the underlying hepatic pathology" /atients #ith moderate hepatic reser!e and alcoholic hepatitis also may e treated #ith standard parenteral formulas to control encephalopathy and ascites" Cache%ia related to se!ere cardiac disease may e judiciously treated #ith highly concentrated de%trose and amino acid formulas that are lo# in sodium content" 9i!en the rather modest enefits demonstra le #ith nutritional support during the cata olic phase, there has een much recent in!estigation into possi le adjuncti!e therapies" -fforts to enhance ana olism !ia gro#th factor 'gro#th hormone, I9(*)+ or ana olic steroid administration generally do not appear to e of additional enefit under full*calorie feeding conditions" .ome enefit might e achie!ed in patients #ho e%hi it more chronic disease conditions in #hich #eaning from nutritional support might e indicated" Complications /ro lems may arise in the placement and maintenance of !enous access or in the formulation and deli!ery of parenteral solutions" One of the more common and serious complications associated #ith long*term parenteral feeding is sepsis secondary to contamination of the central !enous catheter" Contamination of solutions should e considered ut is rare #hen proper pharmacy protocols ha!e een follo#ed" This pro lem occurs more fre&uently in patients #ith systemic sepsis and in many cases is a conse&uence of hematogenous seeding of the catheter #ith acteria" Usually it is a result of failure to o ser!e strict aseptic precautions during preparation and administration of the solutions" One of the earliest signs of systemic sepsis may e the sudden de!elopment of glucose intolerance '#ith or #ithout temperature increase+ in a patient #ho pre!iously has een maintained on parenteral alimentation #ithout difficulty" ;hen this occurs or if fe!er de!elops #ithout o !ious cause, a diligent search for a potential septic focus is indicated" Other causes of fe!er also should e in!estigated" If fe!er persists, the infusion catheter should e remo!ed and cultured" .ome centers are no# replacing catheters considered at lo# ris5 for infection o!er a 0* #ire" .hould e!idence of infection persist o!er 3< to <E h #ithout a defina le source, the catheter should e replaced in the opposite su cla!ian !ein or into one of the internal jugular !eins and the infusion restarted" It may e ad!isa le to #ait a short period efore reinserting the catheter, especially if acteremia or hemodynamic insta ility are present" Other complications related to catheter placement include the de!elopment of pneumothora%, hemothora%, or hydrothora%8 su cla!ian artery injury8 cardiac arrhythmia if the catheter is placed into the atrium or the !entricle8 air em olism or catheter em olism8 and, rarely, cardiac perforation #ith tamponade" Clinically e!ident throm ophle itis or throm osis of the superior !ena ca!a has een rare, ut radiographically pro!ed throm ophle itis has een noted in up to 3= percent of selected patients" ,lthough the use of multiple*lumen catheters for infusion therapy and monitoring critically ill patients is occasionally indicated, the ris5s 'particularly of sepsis and of !enous throm osis+ attending the prolonged use of such catheters may e increased" -fforts should e directed to#ard replacing these catheters #ith standard single*lumen intra!enous feeding catheters as early as possi le" The acute nutritional management of surgical patients seldom re&uires the use of permanently implanted catheters 'see (ig" )*4E+" Use of these catheters should e restricted to nonseptic or high*ris5 patients re&uiring prolonged periods of nutritional or fluid therapy or for selected patients re&uiring fre&uent lood sampling"

2yperosmolar non5etotic hyperglycemia may de!elop #ith normal rates of infusion in patients #ith impaired glucose tolerance or in any patient if the hypertonic solutions are administered too rapidly" This is a particularly common complication in latent dia etics and in patients #ho ha!e had se!ere surgical stress or trauma" Treatment of the condition consists of !olume replacement #ith correction of electrolyte a normalities and the administration of insulin" This serious complication can e a!oided #ith careful attention to daily fluid alance and fre&uent determinations of urine and lood glucose le!els and serum electrolyte le!els" , num er of !olume, concentration, and compositional a normalities also may de!elop, ut these are largely a!oided y careful attention to the details of patient management" This is particularly important for elderly patients and for patients #ith significant cardio!ascular, renal, or hepatic disorders" It is important not to Io!erfeedJ the parenterally nourished patient" This is particularly true of the depleted patient in #hom e%cess calorie infusion may result in car on dio%ide retention and respiratory insufficiency" -%cess feeding also has een related to the de!elopment of hepatic steatosis or mar5ed glycogen deposition in certain patients" $ild a normalities of serum transaminase, al5aline phosphatase, and iliru in le!els may occur in many parenterally nourished patients" (ailure of the tests to plateau or return to#ard normal o!er B to )< days should suggest another cause" 2ome /arenteral Nutrition /atients #ho do not re&uire a hospital en!ironment for management of their primary disease, yet cannot tolerate ade&uate enteral or oral feeding, may e candidates for home parenteral nutrition" ,s opposed to the temporary methods of !ascular access, .ilastic catheters ha!e pro!ed to e dura le portals for long*term parenteral nutrition 'see (ig" )*<A+" ,lternati!es to this techni&ue include the placement of su cutaneous infusion ports" ,n a solute catheter*related infection rate of A"4 per year per patient is still encountered" ;hile home parenteral nutrition is more cost*effecti!e than similar inpatient methods, criteria for selection of patients must e more stringent than those listed a o!e for hospitalized patients" /atients #ith terminal illnesses, lac5 of self*care a ility, or lac5 of a supporti!e home en!ironment are candidates for this method" Inflammatory o#el disease, motility disorders, and ischemic o#el infarction are also indications" , period of inpatient training is necessary to ac&uaint the patient and family #ith appropriate methods of solution preparation and deli!ery" This is est done in a multidisciplinary setting in #hich professionals are thoroughly familiar #ith the acute and chronic complications of home parenteral nutrition" There is interest in ne# technologies that might promote the transition of parenteral nutrition6dependent patients to partial or complete enteral nutrition" .uch methods ha!e demonstrated some promise in initial trials ut #ill most li5ely pro!e inade&uate for most parenteral nutrition6dependent patients" ,c5no#ledgments .upported in part y National Institutes of 2ealth grant 9$ 4<?@=" Dr" Din is also supported y the .urgical .ociety of the Ne# 1or5 2ospital6Lueens" ':i liography omitted in /alm !ersion+ :ac5 to Contents