Chapter 1 Systemic Response to Injery

8/13/2019 Chapter 1 Systemic Response to Injery

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CHAPTER 1 - The Systemic Response to Injury

Edward Lin

Stephen F Lowry

Ste!e E Ca"!anoINTRODUCTION

The host response to injurysurgical, traumatic, or infectiousis characterized y

!arious endocrine, metaolic, and immunologic alterations" If the inciting injury is

minor and of limited duration, #ound healing and restoration of metaolic 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 metaolic 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 theacti!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 metaolic alterations characteristic of the injured

patient" This chapter discusses concepts related to macroendocrine and

microendocrine contriutions to the asic metaolic and immunological conse&uences

of injury and also the current concepts of metaolism and nutritional support for the

surgical patient as a practical and readily applicale adjunct for the pro!ision of

essential sustrates" The dynamics of hormonal and immunologic influences on the

metaolic and sustrate 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 'Tale )*)+" Theinteraction et#een these origins form the asis of the hypothalamic*pituitary a%is,

#hich represents a series of signaling and feedac5 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 'Tales )*3 and )*4+" Central to the hormone*

mediated response at the cellular le!el is the hormone 'ligand+6receptor interaction

and suse&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 nucleotide6inding or 9 protein6coupled receptors that are acti!ated y


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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$/+" Receptoroccupation y stimulatory hormones induces a cell memrane 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" .ustances that decrease c$/ generally e%ert an influence opposite to those

oser!ed for sustances 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 immunogloulins 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" $anyprolonged hormone*mediated responses to injury increase intracellular c$/ le!els

through a direct action on memrane receptors or y increasing the sensiti!ity of

leu5ocytes to sustances 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" )*


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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 feedac5 signals to the

hypothalamus and ha!e demonstrated in animal models an aility to reduce CR2

mRN transcription" Con!ersely, adrenalectomized animals demonstrate ele!ated

CR2 mRN transcriptional acti!ities that are re!ersed #ith e%ogenous administrationof 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 contriute 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 largerprecursor 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 oliterated in injured sujects" $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 /*


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phosphoenol pyru!ate caro%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!ailale lactate and amino acids has the net effect of shifting sustrates for hepatic

gluconeogenesis" Cortisol also stimulates lipolysis and inhiits 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 moilization ser!e as a!ailale energy sources and

additional sustrates 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 gloulin 'C:9+ and

alumin" ;ith injury, total plasma cortisol concentrations increase, ut C:9 and

alumin 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" Ojecti!e findings include hypoglycemia

from decreased gluconeogenesis, hyponatremia from impaired renal tuular 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 contriutes to electrolyte anormalities"

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 omnius inhiitors 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 Inhiitory (actorInitially identified as a T lymphocyte6deri!ed inhiitor of macrophage migration,

macrophage inhiitory 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( antiodies #ere administered to endoto%emic mice, sur!i!al

increased presumaly 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 thesynthesis, storage, and release of thyroid*stimulating hormone 'T.2+ in the anterior


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pituitary" T.2 in turn stimulates thyro%ine 'T


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amino acid le!els" Conditions that inhiit 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

moilization of fat stores" (at moilization 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 inhiits insulin release and decreasesglucose 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 thatinterleu5in*)a, tumor necrosis factor*alpha 'TN(* a+, and interleu5in*? can inhiit 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 oser!ed negati!e nitrogen alance

is attriuted 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

contriute 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 cataolic effects after surgical insults"

eu5ocytes 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 anormalities" Normal sujects 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 )


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immunoinhiitory 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+ issynthesized 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%tracereral 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 inhiited y alpha*adrenergic agonists, and atrial natriuretic

peptide 'N/+"

In the 5idney, >/ promotes reasorption of #ater from the distal tuules andcollecting ducts" /eripherally, >/ mediates !asoconstriction" This effect in the

splanchnic circulation may cause the trauma*induced ischemiareperfusion

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 contriutes 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 '.ID2+ 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 estalished, a plasma osmolality

elo# 3B= mOsm5g 23O and a urine osmolality ao!e )AA mOsm5g 23O is

indicati!e of .ID2" .ID2 is commonly seen in patients #ith head trauma and

urns"

In the asence of >/, central diaetes insipidus occurs and there is !oluminous

output of dilute urine" (re&uently seen in comatose patients, the polyuria in untreated

diaetes 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 andinjury" The hypermetaolic state oser!ed after se!ere injury has een attriuted to


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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 ao!e aseline immediately after injury, reaching their pea5 in 3< to


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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 toa decrease in lood pressure y increasing renin secretion" The macula densa detects

changes in chloride concentration in the renal tuules"

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 capale 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!oussystem" 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 sustrates, autonomic neural input, and other hormones" In normal

metaolism, glucose is the major stimulant of insulin secretion" Other sustrate

stimulants include amino acids, free fatty acids, and 5etone odies" 2ormonal and

neural influences during stress alter this response" -pinephrine and sympathetic

stimulation inhiit 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 cataolic state"

Insulin e%erts a gloal anaolic 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 oser!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 aperipheral 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 diaetics 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 sustrates, autonomic neural input, and otherhormones" ;hereas insulin is an anaolic hormone, glucagon ser!es more of a


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cataolic 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 indispensale in tissue healing and in theimmune response generated against microial in!asions" s mounting e!idence

suggests, the acti!ities of these cyto5ine mediators are integrally related to classic

hormone function and metaolic responses to injury"

Cyto5ine*$ediated Response

/atients #ith injuries or infections e%hiit hemodynamic, metaolic, 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 'Tale )*=+" 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 thismechanism, 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 'Tale )*?+" 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 thatis responsile for the hemodynamic instaility characteristic of septic shoc5" The


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chronic and e%cessi!e production of these cyto5ines is partly responsile for the

metaolic derangements of the injured patients, such as deilitating muscle #asting

and cache%ia" /ree%isting cyto5ine production can contriute 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 cyto5inesmay render the patient immunocompromised and increase susceptiility 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 identifiale infectious process" Central to the insult suffered y the host and the

suse&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 immunoiologic se&uelae can ha!e important applications in the comprehensi!e

care of the surgical patient" The numer 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 descried 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 suse&uent host response" The sources of TN(*a synthesis include

monocytesmacrophages and T cells, #hich are aundant 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" -%perimentssimulating an acute inflammatory response y means of endoto%in challenge in

human sujects 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

undetectale le!els #ithin < h '(ig" )* )A+" -!en #ith a half*life of )= to )E min, the

rief appearance of TN( can induce mar5ed metaolic and hemodynamic changes

and acti!ate cyto5ines distally in the cascade" The are!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 inhiitors in the form of clea!ed e%tracellular domains of the

transmemrane TN( receptors 'solule TN( receptors, sTN(Rs+ are readilydetectale in the circulation" These receptors may ser!e a protecti!e role y


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competiti!ely se&uestering e%cess circulating TN(, ut are proaly only capale 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 cataolism and cache%ia during

stress" mino acids are moilized from s5eletal muscles and shunted to#ard the

hepatic circulation as fuel sustrates" .tudies ha!e demonstrated that TN(*a6induced

muscle cataolism occurs through a ui&uitin*proteasome proteolytic path#ay #ithincreased e%pression of the ui&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*) 'I*)+ from

macrophages and endothelial cells" There are t#o 5no#n proinflammatory species of

I*), I*)a and I*)" I*)a is predominantly cell memrane6associated and e%erts

its influence !ia cellular contacts" The more detectale form released in the circulation

is I*), #hich is produced in greater &uantities than I*)a and capale of inducingthe characteristic systemic derangements after injury" The potency and effects of I*)

reflect those of TN(*a, eliciting similar physiologic and metaolic alterations" t high

doses of I*) 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 oser!ations emphasize the synergism of

TN(*a and I*) in eliciting some proinflammatory responses" The half*life of I*) is

appro%imately ? min, #hich, along #ith its primary role as a local inflammatory

mediator, ma5es its detectaility in acute injury or illness e!en less li5ely than that of

TN(*a"

mong its effects, I*) induces the classic inflammatory ferile 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 I*) effect on the satiety

center" This cyto5ine also augments T cell proliferation y enhancing the production

of I*3 and also may influence s5eletal muscle proteolysis, characteristic of cache%ia"

ttenuated pain perception after surgery can e mediated y I*) y promoting the

release of *endorphins from the pituitary gland and increasing the numer of central

opioid*li5e receptors" i5e TN(, I*) is a potent stimulant for CT2 and

glucocorticoid release !ia its actions on the hypothalamus and pituitary gland"

non*agonist I*) species, 5no#n as I*) receptor antagonists 'I*)ra+, also is

released during injury" This molecule effecti!ely competes for inding to I*)

receptors yet e%acts no o!ert signal transduction" I*)ra, #hich is often detectaleduring inflammation or injury, ser!es as a potent regulator of I*) acti!ity"

Distal cyto5ine mediators, released as part of the inflammatory cascade initiated y

TN(*a and I*), include I*3, I*


14/46

transfusions also are associated #ith reduced I*3 production" ttenuated I*3

e%pression contriutes to the transient immunocompromised state of the surgical

patient" lo# point in gut arrier I*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 I*3 acti!ity, mediated y the proapoptotic (asCD@=cell receptor in the early postoperati!e period" The comined diminution of

lymphocyte sur!i!al and I*3 acti!ity may contriute 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 antiody immune responses, including I*3, I*)3, and

I(N*g production+ to type 3 T helper cells 'T23, Ig- antiody6mediated immune

response, including I*


15/46

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"

I*? mediates the antiinflammatory path#ay during injury through different

mechanisms" It is capale of attenuating TN( and I*) acti!ity #hile promoting the

release of sTN(Rs and I*)ra" /rolonged and persistent e%pression of I*? isassociated #ith immunosuppression and postoperati!e infectious moridity" -le!ated

I*? le!els postoperati!ely can impair glutaminase acti!ity, causing a reduction in

plasma glutamine"

Interleu5in*E

The appearance of I*E acti!ity is temporally associated #ith I*? after injury and has

een proposed as an additional iomar5er for the ris5 of multiple organ failure"

I*E does not produce the hemodynamic instaility characteristic of TN(*a and I*)

ut rather ser!es as a /$N acti!ator and potent chemoattractant" I*E is eing

estalished as a major contriutor to organ injury such as the acute lung injury"

Interleu5in*)A

I*)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 I*)A during endoto%emia

increases monocyte TN(*a production and mortality, ut restitution of I*)A reduces

TN(*ale!els and the associated deleterious effects" I*)A may ha!e additional

protecti!e roles after injury*induced inflammation y promoting I*)ra and sTN(R

production" In animal e%periments, the sustained systemic production of I*)A during

septic peritonitis modulates the systemic inflammatory response" $urine e%periments

ha!e demonstrated rapid induction of I*)A messenger RN 'mRN+ acti!ity after

cecal ligation and puncture, and higher mortality #hen this acti!ity is loc5ed #ith

anti*I*)A" This immunomodulatory effect also may arogate the proinflammatory

response necessary for local clearance of in!ading organisms"

Interleu5in*)3

The capacity of I*)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 I*)3 administration"

I*)3 also is implicated in pre!enting programmed cell death 'apoptosis+ in certain T

lymphocyte populations after their acti!ation"

Interleu5in*)4

I*)4 is a pleiotropic cyto5ine that shares many of the properties of I*< as #ell as a

modest amino acid se&uence 'aout 4A percent+" I*)4 is produced during T23

responses" I*< and I*)4 modulate macrophage function, ut I*)4 has no

identifiale effect on T lymphocytes and only has influence on supopulations of :

lymphocytes" I*< and I*)4 receptors share a common signaling component" I*)4

can up*regulate macrophage major histocompatiility comple% class I and II antigens

and other surface antigens, such as CD34" I*)4 can inhiit nitric o%ide production

and the e%pression of proinflammatory cyto5ines, and it can enhance the production

of I*)ra" The net effect of I*)4, along #ith I*< and I*)A, is antiinflammatory"


16/46

Interferon*g

$uch of I*)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 I*3 or I*)3 readily

produce I(N*g" Con!ersely, I(N*g can induce the production of I*3 and I*)3 y T

helper cells" ;ith its release from acti!ated T cells, I(N* g is detectale in !i!o y ? h

and has a half*life of appro%imately 4A min" I(N*g le!els pea5 at


17/46

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 transmemrane 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 inducesproliferation of T cells, firolasts, 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 oser!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%hiit similar cytoplasmic se&uence motifs, 5no#n

as the death domain"J These death domains interact #ith other intracellular proteinsto 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, (as, (as induces its only 5no#n function, #hich is to initiate apoptosis"

$utations of (as or (as are implicated as a cause for lymphoproliferati!e disorders

and delayed disposal of inflammatory macrophages"

(asCD@= 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 (as(as 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%acerate ongoing hepatic injury" There is hepatic parenchymal

up*regulation of (as receptors #ith acute to%ic injury simultaneously enhanced y

(as e%pression of infiltrating lymphocytes" .tudies also suggest a role for (as(as

interaction in thyroid gland destruction and thyroiditis" Therapeutic strategies deri!edfrom (as(as interaction re&uires selecti!ity to minimize inad!ertent organ injury"

Immunocyte Receptor cti!ity in Inflammation

$emrane 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" )*)


18/46

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"

.olule TN(R

.olule TN(Rs, proteolytically clea!ed e%tracellular domains of memrane*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 memrane 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 reliale than sTN(R as

an early predictor of ris5 and outcome in human sepsis '(ig" )*)=+"

2ormones and Cyto5ine Interactions

Cortisol9lucocorticoids

2ypercortisolemia differentially influences leu5ocyte counts and cyto5ine e%pressionin a temporal fashion" 9lucocorticoid administration immediately efore or

concomitantly #ith endoto%in infusion in healthy human eings is ale to attenuate

the symptoms 'e"g", fe!er, tachycardia+, catecholamine response, and acute phase

response, ut it increases I*)A release" Increased I*)A release may contriute 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 I*? 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


19/46

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 $-DITOR. O( IN0UR1 R-./ON.-

-ndothelial Cell $ediators

-ndothelial Cell (unction

In addition to modulating coagulation and !asomotor acti!ities, mediators elaorated

y the !ascular endothelium in response to injury are #ell* documented contriutors

to the inflammatory process" In a paracrine fashion, local mediators such as TN(*a,

I*), endoto%in, thromin, histamine, and I(N*g are capale of stimulating or

acti!ating the endothelial cell during local tissue injury" In response, the endothelial

cell releases se!eral mediators, including I*), platelet*acti!ating factor '/(+,

prostaglandins '/9I3 and /9-3+, 9$*C.(, gro#th factors, endothelin, nitric o%ide,and small amounts of thromo%ane 3 'T%3+" cti!ated endothelial cells also

release collagenases capale of autodigesting their o#n asement memranes" 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*), -$*)+, /*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 I*)" ;ithin ) h after treatment #ith either of these t#o

cyto5ines, mRN acti!ity for -*selectin is detectale" 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 permeaility and passage of leu5ocytes intoinjured 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" ocal injuries and

inflammatory mediator stimulation promote the margination of circulating /$Ns to

the endothelial surfaces" These marginated /$Ns are deformale 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 suse&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 forlocal tissue inflammation and eradication of microes, acti!ated /$Ns and the


20/46

suse&uent release of inflammatory mediators and reacti!e o%ygen metaolites are

implicated in capillary lea5age, acute lung injury, and postischemic injury '(ig" )*)B+"

The release of mediators y the endothelium and their suse&uent influence on

neighoring and distant tissues ascries endocrine properties to endothelial cells

during injury" The aility 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 solule guanylate cyclase and an increase in

cytosolic cyclic guanosine monophosphate 'c9$/+ #ithin the myocytes" $ethylene

lue inhiits guanylate cyclase, pre!ents the production of c9$/, and inhiits

!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 diffusile sustance #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 ND/2" In addition to the endothelium, this enzymatic acti!ity

also is present in /$Ns, macrophages, renal cells, Gupffer cells, and cereellar

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 inhiitors 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

metaolites, 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 inresponse 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 elaorated y !ascular endothelial cells in response to injury,

thromin, transforming gro#th factor*'T9(*+, I*), 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 cellsproduce only -T*)" -T*) is the most iologically acti!e and potent !asoconstrictor


21/46

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 feedac5 mechanisms" This may e%plain the transient !asodilation otained

#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 cane 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

memranes that can e induced y TN(, I*), >/, 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 permeaility, hemoconcentration, pulmonaryhypertension, ronchoconstriction, primed /$N acti!ity, eosinophil

chemota%isdegranulation, and thromocytopenia" 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 inhiitors are ineffecti!e in re!ersing hemodynamic derangements"

/( alters the shape of endothelial cells, causing them to contract and increase

permeaility" In cultured endothelial cells, cell contraction permits the passage of

macromolecules, such as alumin, 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 permeaility 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 inhiitors of aldosterone secretion and pre!ent reasorption of

sodium" In rats, the myocardial endothelium*deri!ed nitric o%ide '-DNO+ inhiits 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 assemly, disassemly, staility,

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 eCT2*sensiti!e, and the production may decline #ith age" lthough 2./s are


22/46

important intracellular effectors, their rele!ance in the human response to injury can

only e inferred from animal data"

Reacti!e O%ygen $etaolites

Reacti!e o%ygen metaolites 'RO$s+ are short*li!ed, highly reacti!e molecular

o%ygen species #ith an unpaired outer orit" They cause tissue injury y pero%idationof cell memrane unsaturated fatty acids"

RO$s are produced y comple% processes that in!ol!e anaeroic glucose o%idation

coupled #ith the reduction of o%ygen to supero%ide anion" .upero%ide anion is a

potent RO$ ut can e metaolized 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!eo%ygen metaolites" 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 (asCD@= 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+,

thromo%anes 'T%+, leu5otrienes 'T+, hydo%yeicosatetraenoic acids '2-T-+, and

lipo%ins '%+, are o%idation deri!ati!es of the memrane 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 suscript

designation of 3 'e"g", T%3+, #hile products of the lipo%ygenase path#ay are

designated < 'e"g", T-/,

angiotensin II, rady5inin, serotonin, acetylcholine, and histamine" $any of these

stimuli also induce a second cycloo%ygenase enzyme, referred to as COH*3, thatenhances the production of arachidonic acid metaolites" COH*3 acti!ity can e


23/46

inhiited y glucocorticoids, #hich pro!ide specific inhiition of cycloo%ygenase

metaolites, as opposed to lipocortin, #hich inhiits production of arachidonic acid

metaolites" The products of arachidonic acid metaolism are functionally celltissue

specific" >ascular endothelium primarily synthesizes /9I3, #hich causes !asodilation

and platelet deacti!ation" Thromo%ane synthetase con!erts platelet prostaglandins to

T%3, a potent !asoconstrictor and platelet aggregator" $acrophages are capale ofsynthesizing cycloo%ygenase and lipo%ygenase products"

.econd messengers mediate much of eicosanoid acti!ity" (or e%ample, /9-

compounds, in a manner similar to CT2, T.2, and 2, inhiit >/ acti!ity and

hormone*stimulated lipolysis y acti!ating adenylate cyclase acti!ity and generating

intracellular c$/" Thromo%ane and leu5otrienes ha!e opposite effects from /9-

y 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 'Tale )*B+" -icosanoids are major

components of the inflammatory response in injured tissue, characterized y !ascular

permeaility, leu5ocyte migration, and !asodilation" Collecti!ely, their deleterious

effects are implicated in acute lung injury, pancreatitis, and renal failure" eu5otrienesare produced y cells of the lung, connecti!e tissue, smooth muscle, macrophages,

and mast cells that mediate the reactions characteristic of anaphyla%is" eu5otrienes

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 metaolic effects of eicosanoids are #ell recognized" In the regulation of glucose,

products of the cycloo%ygenase path#ay inhiit 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, inhiit

gluconeogenesis" /9-3inhiits 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 I*3 production" -nhanced lymphocyte acti!ation y

mitogens can e achie!ed #ith the administration of indomethacin, a /9-3inhiitor"

During phagocytosis, /$Ns release eicosanoids such as T:< to ser!e as

chemoattractants for other leu5ocytes" /9-3 and TD< 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 metaolized y 5inase I and II" Ginase I degrades the

anaphylato%ins C4a, C


24/46

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 oser!ations are positi!ely correlated #ith the

magnitude of injury and mortality" Clinical trials using rady5inin antagonists inattempts 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"

$etaolically, 5inins increase glucose clearance y inhiiting 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 capale 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 inhiits histamine release" 2) and

23 receptor acti!ation induces !asodilation and increases !ascular permeaility"

2istamine administration causes hypotension, peripheral pooling of lood, increased

capillary permeaility, 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:OIC 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 Cuthertson and others pro!ides a

useful model y #hich the metaolic 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 instaility or reductions in effecti!e circulating lood

!olume" The metaolic conse&uences of this phase are less #ell studied ut aregenerally 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" ess is

5no#n aout 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 metaolic response associated #ith the flo# phase ser!es to direct energy and

protein sustrates so as to preser!e critical organ function and repair damaged tissues"This includes an increase in #hole*ody o%ygen consumption and metaolic rate,


25/46

enhancement of critical enzyme path#ays for readily o%idizale sustrates 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 sustrate processing occurs to support the production of acute*

phase reactants, immunoreacti!e proteins, and coagulation factors" The iologic

priority of #ound healing also is estalished during the early flo# phase"

$etaolic Response to (asting

comparison et#een the metaolic 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 asolute rates of sustrate turno!er after fasting and

injury"

.ustrate $etaolism

healthy adult of BA 5g ody #eight e%pends )BAA to )EAA 5calday of energy

otained from lipid, carohydrate, and protein sources '(ig" )*3)+" Oligate glycolyticcells, 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 sustrate sustitution 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" actate also is released y erythrocytes and #hite lood cells after aeroicglycolysis 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


26/46

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 metaolism of glutamine and glutamate" The

5idney may account for up to


27/46

et#een ody cell mass and resting energy e%penditure often is oser!ed in injured

patients" The increase in energy e%penditure oser!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 sujects" Con!ersely,

glucocorticoid e%cess does not significantly enhance energy e%penditure" Themechanism for this catecholamine effect may e related to influences on cell

memrane sodium permeaility and the energy re&uired for ion pump action to

maintain normal transmemrane concentrations" This influence is oser!ed during the

endoto%incyto5ine interacti!ity, in #hich reductions in muscle resting

transmemrane potential are readily oser!ed" Under these conditions, increases in

circulating catecholamines occur #ith restoration of memrane potential and efore

changes in energy e%penditure" 1oung estimated that such cellular ion pumping and

transport acti!ities may account for o!er


28/46

The high concentrations of intracellular fatty acids and the ele!ated concentration of

glucagon during the e and flo# phases inhiit 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 !ariale 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 otherenergy sustrates, 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 asent increase in plasma free fatty acid

concentrations"

Carohydrate $etaolism

.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 andisotope dilution studies pro!ide a more precise description of this insulin resistance"

=A to ?A percent increase in net splanchnic glucose output is oser!ed in septic

patients, and a =A to )AA percent increase is noted in thermally injured patients" The

associated macroendocrine hormone milieu contriutes 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 contriutions of other

macroendocrine hormones are unclear, although there is e!idence to suggest that

proinflammatory mediators such as I*? also may e%ert an influence on hepatic

glucose production" Definale acute changes in sustrate turno!er are associated #ith

the proinflammatory mediator acti!ity induced y endoto%in administration or TN(

infusion 'Tale )*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 sustrate 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 microial

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 organssuch 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 sujects, 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 suse&uent entry into

the tricaro%ylic acid cycle" The conse&uent accumulation and shunting of three

caron s5eletons to the li!er pro!ides sustrate for gluconeogenesis"

9lucose must e pro!ided to inflammatory and healing cells in the #ounden!ironment" 9lucose upta5e and lactate production in #ounded tissue are


29/46

significantly increased" ;ound inflammatory cells re&uire glucose as an energy

sustrate 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 urnedtissues demonstrate decreased insulin sensiti!ity and fail to normally increase glucose

upta5e or glycogenesis in response to insulin"

/rotein and mino cid $etaolism

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 areresponsile for the increased loss of these metaolites" .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* methylhistidinecreatinine ratios" Radiolaeled 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 contriute to this process"

Data on total ody protein turno!er suggest that after injury the net changes in

cataolism 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 cataolism 'Tale )*@+" 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 aout 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, presumaly ecause they ha!e a higher lean ody mass than the latter t#o

patient susets"

The amino acid composition of normal human eings !aries according to tissueorigin" fter trauma, sustrate 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 oser!ed after injury"

lthough the precise mechanisms for the net increase in s5eletal muscle protein

rea5do#n remain unclear, the comined 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 proteininstaility" $any of these same mediators ser!e to increase ui&uitin*dependent


30/46

proteolytic path#ays '(ig" )*4


31/46

acti!ity" .uch oser!ations do not preclude a rationale for earlier efforts at nutritional

inter!ention" Rather, they pro!ide a iologic asis for reasonale e%pectations of

therapy and for the design of future therapeutic adjuncts"

Cataolic /hase

Once patients ha!e recei!ed initial resuscitation and stailization of #ounds, theearliest definale metaolic response is one of cataolism" 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 solule receptors+ usually is noted to pea5 during

this period, and the ma%imum changes in sustrate turno!er are oser!ed during this

period 'see Tale )*@+" To !ariale degrees, rates of gluconeogenesis, acute phase

protein production, and immune cell acti!ity are all altered during the cataolic phase"

The administration of moderate amounts of glucose to these indi!iduals produces

little or no change in the rate of protein cataolism, although e!idence using isotopicdeterminations suggests that pro!ision of sufficient nonprotein calories in

comination #ith amino acids may reduce the rate of ody protein rea5do#n 'Tale

)*)A+"

In the cataolic phase, glucose turno!er is increased, #hile Cori cycle acti!ity is

stimulated and three*caron intermediates are con!erted ac5 to glucose in the li!er

y pyru!ate caro%ylase and phosphoenolpyru!ate caro%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 cataolic phase of injury" ipolysis also is stimulated

y this hormonal milieu, and an oligatory 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 anormalities of energy

sustrate 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 metaolic

responses" It has een #idely speculated that one or more proinflammatory cyto5ine

mediators are major determinants of increased rates of energy e%penditure and

sustrate turno!er after injury, ut no clear e!idence of this influence in human eings

has een presented" :loc5ade of TN( and I*) acti!ities during conditions of human

endoto%inemia does not pre!ent the characteristic increase in metaolic rate and

glucose or protein turno!er"

-arly naolic /hase

Depending on the se!erity of injury, the ody turns from a cataolic to an anaolic

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 anaolic factors, such as I9(* )" Clinical

manifestations of this transition period are rief and coincide #ith initial diuresis ofretained #ater and rene#ed interest in oral nutrition"


32/46

The early anaolic 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 < gday, #hich represents the

synthesis of appro%imately 3= g of protein and the gain of o!er )AA g of lean odymassday" The total amount of nitrogen gain ultimately e&uals the amount lost during

the cataolic phase, although the rate of gain #ill e much slo#er than the rate of

initial loss"

ate naolic /hase

The final period of con!alescence or the late anaolic 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 thepre!iously normal ody #eight" The patient #ho is partially immoilized during this

period of time, ho#e!er, may e%hiit 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!orale 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 otained y

determining the presence of #eight loss and of chronic illnesses or dietary haits

influencing the &uantity and &uality of food inta5e" .ocial haits 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 sutle 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, alumin, and transferrin+ can e used to

sustantiate the patientFs history and physical findings" It is imprecise to rely on any

single or fi%ed comination of these findings to assess nutritional status or moridity"

ppreciation for the stresses and natural history of the disease process, in

comination #ith nutritional assessment, is the asis for identifying patients in acuteor 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

metaolic 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+


33/46

M ??"itamins usually are not

gi!en in the asence 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 'Tale )*))+" It is necessary to ensure thatade&uate replacement is a!ailale in the diet or y supplementation" Numerous

commercial !itamin preparations are a!ailale 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 in

Documents

Chapter 1 Systemic Response to Injery