1 Systemic Response to Injury and Metabolic Support

hormonal, immunologic, and cellular responses to injury.

Alterations of metabolism and nutrition in injury states are
discussed in continuum because the utilization of fuel substrates
during
injury also is subject to the infuences of hormonal and infammatory
mediators.
!" S#S"MI$ I%&'AMMA(R# R"S)(%S" S#%*R(M"
+1, a proinfammatory phase characterized by acti-ation of cellular
processes
designed to restore tissue function and eradicate in-ading
microorganisms,
and
+., an antiinfammatory +counterregulatory phase, that is important
for pre-enting e/cessi-e proinfammatory acti-ities and restoring
homeostasis
in the indi-idual +able 101,.
$"%RA' %"R1(2S S#S"M R"32'AI(% (& I%&'AMMAI(%
Refe/ Inhibition of Infammation
he central ner-ous system +$%S,, -ia autonomic signaling, has an
integral
role in regulating the infammatory response that is primarily
in-oluntary.
he autonomic system regulates heart rate, blood pressure, respiratory
rate,
gastrointestinal +3I, motility, and body temperature. he autonomic
ner-ous
system also regulates infammation in a refe/ manner, much li4e the
patellar
tendon refe/. he site of infammation sends a5erent signals to the
hypothalamus,
6hich in turn rapidly relays opposing antiinfammatory messages to
reduce infammatory mediator release by immunocytes.
A5erent Signals to the 7rain
1. circulation
tumor necrosis factor +%&,08 0 de-oid of blood9brain barrier admit the
passage
&e-ers, anore/ia, and depression
.. neural path6ays +$holinergic Antiinfammatory )ath6ays,
-agal sensory input from from the site of injury:
cyto4ines +e.g., %&08 and interleu4in ;I'<01,,
baroreceptors,
chemoreceptors,
thermoreceptors
reduces heart rate, increases gut motility, dilates arterioles, and
causes pupil constriction, and regulates infammation
signals discharged from the -agus ner-e are targeted at the site
of injury or infection
0Acetylcholine +primary % for parasympathetic system,
0reduces tissue macrophage acti-ation 6ith +nicotinic, receptors
0directly reduces tissue macrophage release of the proinfammatory
mediators
%&08, I'01, I'01=, and high mobility group protein +!M301,, but not the
antiinfammatory cyto4ine I'01>.
0rapidly
A7'" 101 $linical Spectrum of Infection and Systemic Infammatory
Response Syndrome +SIRS,
erm *e?nition
Infection
0Identi?able source of microbial insult
SIRS
06o or more of follo6ing criteria
0emperature @A=B$ or CADB$
0!eart rate @E> beatsFmin
0Respiratory rate @.> breathsFmin or
0)aco. CA. mm !g or mechanical -entilation
0Ghite blood cell count @1.,>>>FH' or CI>>>FH' or @1>J band
forms
Sepsis
0Identi?able source of infection K SIRS
Se-ere sepsis
0Sepsis K organ dysfunction
Septic shoc4
0Sepsis K cardio-ascular collapse +reLuiring -asopressor support,
systemic infammatory response syndrome +SIRS, to injury, follo6ed by
a period of con-alescence mediated by the counterregulatory anti0
infammatory response syndrome +$ARS,. Se-ere infammation may
lead to acute multiple organ failure +M(&, and early death follo6ing
injury +gray solid arro6,. A lesser infammatory response follo6ed by
e/cessi-e $ARS may induce a prolonged immunosuppressed state that
can also be deleterious to the host +bro4en arro6,. %ormal reco-ery
after injury reLuires a period of systemic infammation follo6ed by a
return to homeostasis
Hormonal Response to Injury
polypeptides (e.g., cytokines, glucagon, and insulin)
amino acids (e.g., epinephrine, serotonin, and histamine),
fatty acids (e.g., glucocorticoids, prostaglandins, and leukotrienes).
Hormone Signaling Pathways
Most hormone receptors generate signals y one o! three major pathways, which o"erlap.
(#) receptor kinases such as insulin and insulin$like growth !actor receptors,
(%) guanine nucleotide-binding or G-protein receptors such as neurotransmitter and
prostaglandin receptors
(&) ligand-gated ion channels which permit ion transport when acti"ated
'() Intracellular *+ receptors are maintained in the cytosol y linking to the stress$
induced protein, heat shock protein (HSP). ,hen the glucocorticoid ligand inds to the
*+ receptor, the dissociation o! HSP !rom the receptor acti"ates the receptor$ligand
comple( and is transported to the nucleus.
-irtually e"ery hormone o! the hypothalamic$pituitary$adrenal (HP.) a(is in!luences the
physiologic response to injury and stress (/ale #$%), ut some with direct in!luence on
the in!lammatory response or immediate clinical impact will e highlighted.
Hypothalamic Regulation
+orticotropin$releasing hormone
/hyrotropin$releasing hormone
*rowth hormone$releasing hormone
0uteini1ing hormone$releasing hormone
Anterior Pituitary Regulation
.drenocorticotropic hormone
+ortisol
/hyroid$stimulating hormone
/hyro(ine
/riiodothyronine
*rowth hormone
*onadotrophins
Se( hormones
Insulin$like growth !actor
Somatostatin
Prolactin
'ndorphins
Posterior Pituitary Regulation
-asopressin
2(ytocin
Autonomic System
3orepinephrine
'pinephrine
.ldosterone
Renin$angiotensin system
Insulin
*lucagon
'nkephalins
Hormonal Response to Injury
.+/H
+ortisol (glucocorticoid)
*H
I*4$#
+atecholamines
.05
Insulin
.cute phase proteins
Inflammatory mediators
Histamine
Serotonin
6allikrein$kinin
4atty acid metaolites
Heat shock proteins
'icosanoids
+ytokines
R2S
Adrenocorticotropic Hormone
$synthesi1ed and released y the anterior pituitary
$regulated y circadian signals such that the greatest ele"ation o! .+/H occurs late at
night until the hours immediately e!ore sunrise (altered or oliterated in the injured)
$injury 7ele"ations in corticotropin$releasing hormone and .+/H
$Pain, an(iety, "asopressin, angiotensin II, cholecystokinin, "asoacti"e intestinal
polypeptide (-IP), catecholamines, and proin!lammatory cytokines are all prominent
mediators o! .+/H release in the injured patient.
$,ithin the 1ona !asciculata o! the adrenal gland, .+/H signaling acti"ates intracellular
pathways that lead to glucocorticoid production
$e(cess .+/H will result in adrenal cortical hypertrophy.
Cortisol and Glucocorticoids
$+ortisol is the major glucocorticoid
is ele"ated depending on the type o! systemic stress
$potentiates the actions o! glucagon and epinephrine 7hyperglycemia
$gluconeogenesis (protein degradation as well as the release o! lactate that ser"e as
sustrates)
insulin resistance in muscles and adipose tissue
release o! !ree !atty acids, triglycerides, and glycerol !rom adipose tissue as a means o!
pro"iding additional energy sources.
.cute adrenal insu!!iciency (..I) can e a li!e$threatening complication most commonly
seen in acutely ill patients with adrenal suppression !rom e(ogenously administered
glucocorticoids with conse8uent atrophy o! the adrenal glands.
$present with weakness, nausea, "omiting, !e"er, and hypotension.
$2jecti"e !indings) hypoglycemia !rom decreased gluconeogenesis,
hyponatremia !rom impaired renal tuular sodium resorption
hyperkalemia !rom diminished kaliuresis.
$In addition to cortisol de!iciency, insu!!icient mineralocorticoid (aldosterone) acti"ity
also contriutes to hyponatremia and hyperkalemia.
*lucocorticoids ha"e long een employed as e!!ecti"e immunosuppressi"e agents.
$thymic in"olution
$depressed cell$mediated immune responses re!lected y decreases in /$killer and natural
killer cell !unctions,
$/$lymphocyte lastogenesis
$mi(ed lymphocyte responsi"eness
$gra!t$"ersus$host reactions
$delayed hypersensiti"ity responses
$monocytes lose the capacity !or intracellular killing ut appear to maintain normal
chemotactic and phagocytic properties
$in neutrophils, glucocorticoids inhiit intracellular supero(ide reacti"ity, suppress
chemota(is, and normali1e apoptosis signaling mechanisms. Howe"er, neutrophil
phagocytosis !unction remains unchanged.
$downregulates proin!lammatory cytokine production (/34$, I0$#, and I0$9) and
increases the production o! the anti$in!lammatory mediator I0$#: (an important negati"e
regulatory !unction in the in!lammatory response)
Macrophage Inhibitory Factor
$ a glucocorticoid antagonist !rom the anterior pituitary ; / lymphocytes situated at the
sites o! in!lammation that potentially re"erses the immunosuppressi"e e!!ects o!
glucocorticoids.
$proin!lammatory mediator that potentiates gram$negati"e and gram$positi"e septic
shock.
Groth Hormones and Insulin!"i#e Groth Factors
$ promotes protein synthesis and also enhances the moili1ation o! !at stores.
$/he protein synthesis are mediated y the secondary release o! insulin$like growth
!actor$# (I*4$#) !rom the li"er. 4ormerly called somatomedin +, promotes amino acid
incorporation and cellular proli!eration and attenuates proteolysis.
I*4 #$ protein synthesis and glycogenesis.
$increases glucose uptake and !at utili1ation.
$increases glucose uptake and protein synthesis.
$skeletal growth y promoting the incorporation o! sul!ate and proteoglycans into
cartilage.
$inhiited y interleukin (I0)$#, /34$, and I0$9
$stimulate leukocyte !unction and cell proli!eration
Catecholamines $%PI& '%(
$hypermetaolic state
$increased three$ to !our!old in plasma immediately !ollowing injury, with ele"ations
lasting %< to <= hours
$glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis
$ decreased insulin release, ut increases glucagon secretion
$ insulin resistance in skeletal muscle
$ stress$induced hyperglycemia, not unlike the e!!ects o! cortisol on lood sugar.
$inc secretion o! thyroid and parathyroid hormones, /<, /&, and renin, ut inhiit the
release o! aldosterone.
$0ike cortisol, enhances leukocyte demargination with resultant neutrophilia and
lymphocytosis.
$inc (c.MP) and ultimately decreases lymphocyte responsi"eness to mitogens.
Aldosterone
$mineralocorticoid synthesi1ed, stored, and released in the adrenal 1ona glomerulosa.
$.+/H is the most potent stimulant o! aldosterone release.
$major !unction to maintain intra"ascular "olume y conser"ing sodium and eliminating
potassium and hydrogen ions in the early distal con"oluted tuules o! the nephrons.
$de!iciency)hypotension and hyperkalemia
$e(cess) edema, hypertension, hypokalemia, and metaolic alkalosis.
Insulin
$inhiited release in in!lammation ; there is peripheral insulin resistance !ollowing
injury
$result) in stress$induced hyperglycemia
$ anaolic) glycogenesis and glycolysis, glucose transport into cells, lipogenesis, and
protein synthesis.
$In the injured patient, two phases o! release) #.suppresses o"erall insulin release and
occurs within a !ew hours a!ter injury. %. later phase is a return to normal or e(cessi"e
insulin production, ut with persistent hyperglycemia, consistent with peripheral
resistance to insulin.
$.cti"ated lymphocytes e(press insulin receptors, and acti"ation enhances /$cell
proli!eration and cytoto(icity.
$increased !unctional >$ and /$lymphocyte populations
Acute Phase Proteins
$ nonspeci!ic iochemical markers produced y hepatocytes in response to tissue injury,
in!ection, or in!lammation.
$I0$9 is a potent inducer o! acute phase proteins that can include proteinase inhiitors,
coagulation and complement proteins, and transport proteins.
$only +$reacti"e protein (+RP) has een consistently used as a marker o! injury response
due to its dynamic re!lection o! in!lammation. It does not show diurnal "ariations and are
not a!!ected y !eeding.
$a use!ul iomarker o! in!lammation as well as response to treatment. Its accuracy
surpasses that o! the erythrocyte sedimentation rate.
Mediators o! In!lammation
Cyto#ines
$ most potent mediators o! the in!lammatory response
$eradicate in"ading microorganisms and promote wound healing
$ can cause hemodynamic instaility (i.e., septic shock) or metaolic derangements (i.e.,
muscle wasting). ?ncontrolled7end$organ !ailure and death
$o"erlapping ioacti"ity
Cyto#ine Source Comment
/34$ Macrophages/monocytes .mong earliest responders !ollowing injury@ hal!$
li!e A%: min@ acti"ates /34$receptor$# and $%@
induces signi!icant shock and cataolism
6up!!er cells
3eutrophils
36 cells
.strocytes
'ndothelial cells
/ lymphocytes
.drenal cortical cells
.dipocytes
6eratinocytes
2steolasts
Mast cells
5endritic cells
I0$# Macrophages/monocytes /wo !orms (I0$ and I0$)@ similar physiologic
e!!ects as /34$@ induces !e"ers through
prostaglandin acti"ity in anterior hypothalamus@
promotes $endorphin release !rom pituitary@ hal!$
li!e A9 min
> and / lymphocytes
36 cells
'ndothelial cells
'pithelial cells
6eratinocytes
4irolasts
2steolasts
5endritic cells
.strocytes
.drenal cortical cells
Megakaryocytes
Platelets
3eutrophils
3euronal cells
I0$% T lymphocytes Promotes lymphocyte proli!eration,
immunogloulin production, gut arrier integrity@
Cyto#ine Source Comment
hal!$li!e A#: min@ attenuated production !ollowing
major lood loss leads to immunocompromise@
regulates lymphocyte apoptosis
I0$& T lymphocytes
Macrophages
'osinophils
Mast cells
I0$< T lymphocytes Induces >$lymphocyte production o! Ig*< and
Ig', mediators o! allergic and anthelmintic
response@ downregulates /34$, I0$#, I0$9, I0$=
Mast cells
>asophils
Macrophages
> lymphocytes
'osinophils
Stromal cells
I0$B T lymphocytes Promotes eosinophil proli!eration and airway
in!lammation
'osinophils
Mast cells
>asophils
I0$9 Macrophages 'licited y "irtually all immunogenic cells@ long
hal!$li!e@ circulating le"els proportional to injury
se"erity@ prolongs acti"ated neutrophil sur"i"al
> lymphocytes
3eutrophils
>asophils
Mast cells
4irolasts
'ndothelial cells
.strocytes
Syno"ial cells
.dipocytes
2steolasts
Megakaryocytes
+hroma!!in cells
Cyto#ine Source Comment
6eratinocytes
I0$= Macrophages/monocytes +hemoattractant !or neutrophils, asophils,
eosinophils, lymphocytes
/ lymphocytes
>asophils
Mast cells
'pithelial cells
Platelets
I0$#: T lymphocytes Prominent anti$in!lammatory cytokine@ reduces
mortality in animal sepsis and .R5S models
> lymphocytes
Macrophages
>asophils
Mast cells
6eratinocytes
I0$#% Macrophages/monocytes Promotes /H# di!!erentiation@ synergistic acti"ity
with I0$%

3eutrophils
6eratinocytes
5endritic cells
> lymphocytes
I0$#& T lymphocytes Promotes >$lymphocyte !unction@ structurally
similar to I0$<@ inhiits nitric o(ide and
endothelial acti"ation
I0$#B Macrophages/monocytes .nti$in!lammatory e!!ect@ promotes lymphocyte
acti"ation@ promotes neutrophil phagocytosis in
!ungal in!ections
'pithelial cells
I0$#= Macrophages Similar to I0$#% in !unction@ ele"ated in sepsis,
particularly gram$positi"e in!ections@ high le"els
!ound in cardiac deaths
6up!!er cells
6eratinocytes
.drenal cortical cells
2steolasts
Cyto#ine Source Comment
I43$ T lymphocytes Mediates I0$#% and I0$#= !unction@ hal!$li!e, days@
!ound in wounds BCD days a!ter injury@ promotes
.R5S
36 cells
Macrophages
*M$+S4 T lymphocytes Promotes wound healing and in!lammation
through acti"ation o! leukocytes
4irolasts
'ndothelial cells
Stromal cells
I0$%# T lymphocytes Pre!erentially secreted y /H% cells@ structurally
similar to I0$% and I0$#B@ acti"ates 36 cells, >
and / lymphocytes@ in!luences adapti"e immunity

HM*>$I Monocytes/lymphocytes High moility group o( chromosomal protein@
53. transcription !actor@ late (downstream)
mediator o! in!lammation (.R5S, gut arrier
disruption)@ induces Esickness eha"iorE
.R5S 7 acute respiratory distress syndrome@ *M$+S4 7 granulocyte$macrophage
colony$stimulating !actor@ I43 7 inter!eron@ Ig' 7 immunogloulin '@ Ig* 7
immunogloulin *@ I0 7 interleukin@ 36 7 natural killer@ /H# 7 / helper suset cell #@
/H% 7 / helper suset cell %@ /34 7 tumor necrosis !actor.
Heat Shoc# Proteins
$Stimuli)hypo(ia, trauma, hea"y metals, local trauma, and hemorrhage
$intracellular protein modi!iers and intracellular transport o! steroid molecules protect
cells !rom traumatic stress.
$production seems to decline with age.
Reacti)e *+ygen Metabolites
$short$li"ed, highly reacti"e.
$/hey cause tissue injury y o(idation o! unsaturated !atty acids within cell memranes.
$.cti"ated leukocytes are potent generators o! reacti"e o(ygen metaolites
$cells are protected y glutathione and catalases
$?pon restoration o! lood !low and o(ygen supply, large 8uantities o! reacti"e o(ygen
metaolites are produced that lead to reper!usion injury.
%icosanoids
$prosta$ glandins (P*), thromo(anes (/F), leukotrienes (0/), hydro(y$ eicosatetraenoic
acids (H'/'), and lipo(ins (0F)
$o(idation deri"ati"es o! the memrane phospholipid arachidonic acid (eicosatetraenoic
acid)
$secreted y "irtually all nucleated cells e(cept lymphocytes
$ cycloo(ygenase) prostaglandins and thromo(anes.
$lipo(ygenase pathway) leukotrienes and H'/'.
$not stored, ut synthesi1ed rapidly upon stimulation y hypo(ic injury, direct tissue
injury, endoto(in, norepinephrine, "asopressin, angiotensin II, radykinin, serotonin,
acetylcholine, cytokines, and histamine.
$ P*'% increases !luid leakage !rom lood "essels, ut a rising P*'% le"el o"er se"eral
hours e"entually !eeds ack to +2F$% and induces the !ormation o! the anti$
in!lammatory lipo(in !rom neutrophils.
$ 3S.I5s acetylate +2F$%, which conse8uently reduces the P*'% le"els and increases
lipo(in production. +2F$% acti"ity also can e inhiited y glucocorticoids.
$ deleterious e!!ects are implicated in acute lung injury, pancreatitis, and renal !ailure.
$0eukotrienes are #::: times more potent than histamines in promoting capillary leakage.
$0eukotrienes promote leukocyte adherence, neutrophil acti"ation, ronchoconstriction,
and "asoconstriction.
/ale #$< Systemic Stimulatory and Inhiitory .ctions o! 'icosanoids
*rgan,Function Stimulator Inhibitor
Pancreas
*lucose$stimulated insulin secretion #%$HP'/' P*'%

*lucagon secretion P*5%, P*'%


Liver
*lucagon$stimulated glucose
production
P*'%


Fat
Hormone$stimulated lipolysis P*'%


Bone
Resorption P*'%, P*'$m, 9$6$P*'# , P*4#,
P*I%


Pituitary
Prolactin P*'#


0H P*'# , P*'%, B$H'/'


/SH P*.#, P*>#, P*'# , P*'#


*H P*'#


Parathyroid
P/H P*'%

P*4%

Pulmonary
>ronchoconstriction P*4%, /F.%, 0/+<, 0/5<, 0/'<

P*'%

enal
Stimulate renin secretion P*'%, P*I%


Gastrointestinal
+ytoprotecti"e e!!ect P*'%


!mmune esponse
*rgan,Function Stimulator Inhibitor
Suppress lymphocyte acti"ity P*'%


"ematologic
Platelet aggregation /F.%

P*I%

*H 7 growth hormone@ B$H'/' 7 B$hydro(yeicosatetraenoic acid@ #%$H'/' 7 #%$
hydro(ypero(y$eicosatetraenoic acid@ 9$6$P*'# 7 9$keto$prostaglandin '#@ 0H 7
luteini1ing hormone@ 0/+< 7 leukotriene +<@ 0/5< 7 leukotriene 5<@ 0/'< 7 leukotriene
'<@ P*.# 7 prostaglandin .#@ P*># 7 prostaglandin >#@ P*5% 7 prostaglandin 5%@ P*'#
7 prostaglandin '#@ P*'# 7 prostaglandin '#@ P*'% 7 prostaglandin '% @ P*'$m 7 #&,#<$
dihydro$#B$keto$P*'% (major urine metaolite o! P*'%)@ P*4 7 prostaglandin 4@ P*4# 7
prostaglandin 4#@ P*4% 7 prostaglandin 4%@ P*I 7 prostaglandin I@ P*I% 7 prostaglandin
I%@ P/H 7 parathyroid hormone@ /SH 7 thyroid$stimulating hormone@ /F.% 7
thromo(ane .%.
$cycloo(ygenase pathway inhiit pancreatic $cell release o! insulin, while products o! the
lipo(ygenase pathway promote $cell acti"ity.
$P*'% inhiit gluconeogenesis ; hormone$stimulated lipolysis.
Fatty Acid Metabolites
$2mega$9 !atty acids also ser"e as precursors o! in!lammatory mediators) leukotrienes,
prostaglandins, and platelet$acti"ating !actor.
$ anti$in!lammatory e!!ects o! omega$& !atty acids y dec metaolic rate, normali1es
glucose metaolism, attenuates weight loss, and impro"es nitrogen alance, minimi1es
ischemiaGreper!usion injury, ameliorates endoto(in$induced acute lung injury y
suppressing the le"els o! proin!lammatory eicosanoids and reducing pulmonary
neutrophil accumulation.
-alli#rein!-inin System
>radykinins are potent "asodilators produced through kininogen degradation y the
serine protease kallikrein
$6allikrein acti"ated y Hageman !actor, trypsin, plasmin, !actor FI, glass sur!aces,
kaolin, and collagen.
$6inins increase capillary permeaility and tissue edema, e"oke pain, inhiit
gluconeogenesis, and increase ronchoconstriction. /hey also increase renal "asodilation
and conse8uently reduce renal per!usion pressure. /he resulting increase in renin
!ormation acti"ates sodium and water retention "ia the renin$angiotensin system.
$>radykinin release is stimulated y hypo(ic and ischemic injury. Increased kallikrein
acti"ity and radykinin le"els are oser"ed !ollowing hemorrhage, sepsis, endoto(emia,
and tissue injury.
$>radykinin reduce the deleterious se8uelae o! septic shock ha"e only demonstrated
modest re"ersal in gram$negati"e sepsis, ut no o"erall impro"ement in sur"i"al.
Serotonin
$(B$hydro(ytryptamine, B$H/) a tryptophan deri"ati"e that is !ound in chroma!!in cells o!
the intestine and in platelets.
$midgut carcinoid tumors o!ten secrete B$H/ in e(cess.
$"asoconstriction, ronchoconstriction, and platelet aggregation, myocardial chronotrope
and inotrope.
Histamine
$!rom histidine and stored in neurons, skin, gastric mucosa, mast cells, asophils, and
platelets.
$acti"ated y increased calcium le"els
$two receptor) H# stimulates ronchoconstriction, intestinal motility, and myocardial
contractility.
$H% inhiits histamine release.
$>oth H# and H% receptor acti"ation induce hypotension, peripheral pooling o! lood,
increased capillary permeaility, decreased "enous return, and myocardial !ailure.
$Inc in hemorrhagic shock, trauma, thermal injury, endoto(emia, and sepsis.
Cyto#ine Response to Injury
/umor 3ecrosis 4actor
4ollowing acute injury or during in!ections, /34$ is among the earliest and most potent
mediators o! suse8uent host responses. /he primary sources o! /34$ synthesis include
monocytesGmacrophages and / cells, which are aundant in the peritoneum and
splanchnic tissues. 4urthermore, 6up!!er cells represent the single largest concentrated
population o! macrophages in the human ody. /here!ore, surgical or traumatic injuries to
the adominal "iscera undoutedly ha"e pro!ound in!luence on the generation o!
in!lammatory mediators and homeostatic responses such as acute phase protein
production. .lthough the hal!$li!e o! /34$ is less than %: minutes, this rie! appearance
is su!!icient to e"oke marked metaolic and hemodynamic changes and acti"ate
mediators distally in the cytokine cascade. /34$ is also a major inducer o! muscle
cataolism and cache(ia during stress y shunting a"ailale amino acids to the hepatic
circulation as !uel sustrates. 2ther !unctions o! /34$ include coagulation acti"ation,
promoting the e(pression or release o! adhesion molecules, prostaglandin '% , platelet$
acti"ating !actor (P.4), glucocorticoids, and eicosanoids.
Solule (i.e., circulating) /34 receptors (s/34Rs) are proteolytically clea"ed
e(tracellular domains o! memrane$associated /34Rs that are ele"ated and readily
detectale in acute in!lammation. s/34Rs retain their a!!inity !or the inding o! /34$
and there!ore compete with the cellular receptors !or the inding o! !ree /34$. /his
potentially represents an endogenous counterregulatory response to e(cessi"e systemic
/34$ acti"ity. Howe"er, it should e noted that the !unctional iology o! s/34Rs may
not e limited to /34$ antagonism, ut may also ser"e as a carrier (e.g., transporter) or as
a storage pool o! ioacti"e /34$ in the circulation.
Interleukin$#
I0$# is primarily released y acti"ated macrophages and endothelial cells. /here are two
known species o! I0$#) I0$# and I0$#. I0$# is predominantly cell memrane associated
and e(erts its in!luence "ia cellular contacts. I0$# is more readily detectale in the
circulation and capale o! eliciting similar physiologic and metaolic alterations as /34$.
,ith high doses o! either I0$# or /34$, these cytokines independently initiate a state o!
hemodynamic decompensation. .t low doses, they can produce the same response only i!
administered simultaneously. /hese oser"ations emphasi1e the synergistic roles o! /34$
and I0$# in the in!lammatory response. I0$# is predominantly a local mediator with a
hal!$li!e o! appro(imately 9 minutes, making its aility to e detected in acute injury or
illness e"en less likely than that o! /34$. I0$# induces the classic in!lammatory !erile
response to injury y stimulating local prostaglandin acti"ity in the anterior
hypothalamus. .ttenuated pain perception a!ter surgery can e mediated y I0$# y
promoting the release o! $endorphins !rom the pituitary gland and increasing the numer
o! central opioid$like receptors.
'ndogenous I0$# receptor antagonists (I0$#ra) also are released during injury and ser"e
as an endogenous autoregulator o! I0$# acti"ity. /his molecule e!!ecti"ely competes !or
inding to I0$# receptors, yet e(acts no o"ert signal transduction.
Interleukin$%
I0$% is a primary promoter o! /$lymphocyte proli!eration, immunogloulin production,
and gut arrier integrity. Partly due to its circulation hal!$li!e o! less than #: minutes, I0$
% has not een readily detectale !ollowing acute injury. .ttenuated I0$% e(pression
associated with major injuries or perioperati"e lood trans!usions potentially contriute
to the transient immunocompromised state o! the surgical patient. /here is e"idence to
suggest that accelerated lymphocyte apoptosis (i.e., lymphocyte depletion) e(acerates
the injury$induced immunocompromise as a result o! diminished I0$% stimulation.
Interleukin$<
I0$< is produced y acti"ated type % /$helper (/H%) lymphocytes and possesses di"erse
in!luence on hematopoietic cell proli!eration. It is particularly important in antiody$
mediated immunity and in antigen presentation. I0$< also induces class switching in
di!!erentiating > lymphocytes to produce predominantly Ig*< and Ig', which are
important immunogloulins in allergic and anthelmintic responses. I0$< has potent anti$
in!lammatory properties against acti"ated macrophages y downregulating the e!!ects o!
I0$#, /34$, I0$9, and I0$=, as well as o(ygen radical production. I0$< also appears to
increase macrophage susceptiility to the anti$in!lammatory e!!ects o! glucocorticoids.
Interleukin$9
/34$ and I0$# are potent inducers o! I0$9 production !rom "irtually all cells and tissues,
including the gut. .!ter injury, I0$9 le"els in the circulation are detectale y 9: minutes,
peak etween < and 9 hours, and can persist !or as long as #: days. +irculating I0$9
le"els appear to e proportional to the e(tent o! tissue injury during an operation, more so
than the duration o! the surgical procedure itsel!. Recent e"idence has demonstrated oth
a proin!lammatory role and an anti$in!lammatory role !or I0$9. I0$9 is an important
mediator o! the hepatic acute phase response during injury and con"alescence. I0$9 not
only induces neutrophil acti"ation during injury and in!lammation ut also may delay the
disposal o! such neutrophils, therey prolonging the injurious e!!ects mediated y these
cells. I0$9 also possesses anti$in!lammatory properties during injury y attenuating /34$
and I0$# acti"ity while promoting the release o! solule tumor necrosis !actor receptors
(s/34Rs) and I0$# receptor antagonists.
Interleukin$=
I0$= e(pression and acti"ity is similar to that o! I0$9 a!ter injury and has een proposed
as an additional iomarker !or the risk o! multiple organ !ailure. I0$= does not produce
the hemodynamic instaility characteristic o! /34$ and I0$#, ut is a chemoattractant and
a potent acti"ator o! neutrophils.
Interleukin$#:
I0$#: has emerged as a modulator o! /34$ acti"ity. '(perimental e"idence has
demonstrated that neutrali1ation o! I0$#: during endoto(emia increases monocyte /34$
production and mortality, ut restitution o! I0$#: reduces /34$ le"els and the associated
deleterious e!!ects. I0$#: is also capale o! attenuating I0$#= messenger rionucleic acid
(mR3.) e(pression in monocytes. In animal e(periments, induction o! I0$#:
transcription has een shown to attenuate the systemic in!lammatory response and reduce
mortality during septic peritonitis. Howe"er, e(cessi"e rI0$#: administration in similar
animal models has een associated with increased acterial load and mortality.
Interleukin$#%
I0$#% has a primary role in cell$mediated immunity and promotes the di!!erentiation o!
/H# cells. In mice with !ecal peritonitis as well as those with urn injury, sur"i"al
increases with I0$#% administration, while I0$#% neutrali1ation results in high mortality.
I0$#% administration in nonhuman primates is capale o! inducing an in!lammatory
response !or up to <= hours, independently o! /34$ and I0$#. I0$#% promotes neutrophil
and coagulation acti"ation, as well as the e(pression o! oth proin!lammatory and anti$
in!lammatory mediators. 4urthermore, I0$#% to(icity appears to e synergistic with I0$%.
.lthough I0$#% detection !ollowing injury or se"ere in!ections is "ariale, most e"idence
would suggest that this cytokine contriutes to the o"erall proin!lammatory response.
Interleukin$#&
I0$#& shares many structural and !unctional properties o! I0$<. I0$< and I0$#& modulate
macrophage !unction, ut unlike I0$<, I0$#& has no identi!iale e!!ect on / lymphocytes
and only has in!luence on selected >$lymphocyte populations. I0$#& can inhiit nitric
o(ide production and the e(pression o! proin!lammatory cytokines and can enhance the
production o! I0$#ra. 4urthermore, I0$#& attenuates leukocyte interaction with acti"ated
endothelial sur!aces. /he net e!!ect o! I0$#&, along with I0$< and I0$#:, is anti$
in!lammatory.
Interleukin$#B
I0$#B is a macrophage$deri"ed cytokine with potent autocrine regulatory properties. .s a
result o! shared receptor signaling components, oth I0$#B and I0$% possess similar
ioacti"ity in promoting lymphocyte acti"ation and proli!eration. In neutrophils, I0$#B
induces I0$= production and nuclear !actor$> (34$>) acti"ation and enhances phagocytic
!unction against !ungal in!ections.
Interleukin$#=
I0$#=, !ormerly inter!eron (I43)$$inducing !actor, is a proin!lammatory cytokine product
o! acti"ated macrophages. Structurally similar to I0$# and !unctionally similar to I0$#%,
I0$#= promotes early resolution o! acterial in!ections in mice. >acterial products I0$<
and I43$ can stimulate I0$#= production !rom monocytes. I0$#= signaling is associated
with 34$> and c$Hun 3$terminal kinase (H36) pathway acti"ation, as well as the
e(pression o! !unctionally acti"e intercellular adhesion molecule$# (I+.M$#).
4urthermore, murine endoto(emia models indicate that I0$#= is a downstream mediator
o! oth /34$ and 4as ligandCinduced hepatoto(icity. Preliminary data ha"e demonstrated
signi!icant ele"ations o! circulating I0$#= during sepsis !or as long as %# days. /his
ele"ation in I0$#= is particularly pronounced in gram$positi"e sepsis.
Inter!eron$
Much o! interleukin (I0)$#% and I0$#= iology is mediated "ia inter!eron (I43)$. Human
/ helper lymphocytes acti"ated y acterial antigens, I0$%, I0$#%, or I0$#= readily
produce I43$. +on"ersely, I43$ can induce the production o! I0$%, I0$#%, and I0$#=.
,hen released into the circulation, I43$ is detectale in vivo y 9 hours and may e
persistently ele"ated !or as long as = days. Injured tissues, such as operati"e wounds, also
demonstrate the presence o! I43$ production B to D days a!ter injury. I43$ has important
roles in acti"ating circulating and tissue macrophages. .l"eolar macrophage acti"ation
mediated y I43$ may induce acute lung in!lammation a!ter major surgery or trauma.
*ranulocyte$Macrophage +olony$Stimulating 4actor
In "itro studies ha"e demonstrated a prominent role !or granulocyte$macrophage colony$
stimulating !actor (*M$+S4) in delaying apoptosis (programmed cell death) o!
macrophages and neutrophils. /his process may contriute to organ injury such as that
!ound in acute respiratory distress syndrome (.R5S). /his growth !actor is e!!ecti"e in
promoting the maturation and recruitment o! !unctional leukocytes necessary !or normal
in!lammatory cytokine response, and potentially in wound healing. Results o!
perioperati"e *M$+S4 administration in patients undergoing major oncologic procedures
and in patients with major urns ha"e demonstrated enhanced neutrophil numers and
!unction.
High Moility *roup >o($#
High moility group o($# (HM*>$#) is a 53. transcription !actor that is e(pressed %<
to <= hours a!ter the initial injurious e"ent. Its peak has een associated with deleterious
outcomes such as ad"anced .R5S and death. /he appearance o! this mediator is in
contrast to the early appearances o! /34$, I0$#, I0$9, and I0$=, which peak within
minutes o! injury and there!ore are di!!icult to lock. HM*>$# is associated with weight
loss, !ood a"ersion, shock, and the general Esickness eha"iorE seen in sepsis and the
systemic in!lammatory response syndrome. .s a late mediator o! the in!lammatory
response, anti$HM*>$# strategies might e used in e!!orts to control the progression o!
the deleterious e!!ects o! in!lammation and sepsis.
Cellular Response to Injury
*ene '(pression and Regulation
. road reiteration o! terminology is used to characteri1e gene regulation. Identical 53.
chains are !ound in e"ery cell o! the ody@ howe"er, each o! these cells e(presses distinct
structural and !unctional characteristics. >y the acti"ation and deacti"ation o! certain
genes in a stem cell, the highly organi1ed process o! differentiation leads to the ultimate
!unction o! the cell.
In humans, most genes are regulated at the stage o! 53. transcription (i.e., intranuclear)
(4ig. #$9). /here!ore, whether a gene is e(pressed or not in a disease is o!ten determined
y the production o! corresponding messenger rionucleic acid (mR3.). R3. !rom the
original transcript can e !urther modi!ied, termed splicing, to produce related ut
dissimilar mR3. and resultant proteins. In cytokine production in which R3. is
re8uired !or rapid translation (i.e., protein synthesis) upon demand, protein caps at the BI
and &I ends ensure R3. staility and pre"ent splicing. 2nce out o! the nucleus, the
mR3. can e inacti"ated or translated to !orm proteins. /hese proteins can !urther e
modi!ied !or speci!ic !unctions. In essence, these cytosolic modi!ications supplement the
primary regulatory mechanisms within the nucleus.
4I*. #$9.
*ene e(pression and protein synthesis can occur within a %<$hour period. /he process
can e regulated at "arious stages) transcription, mR3. processing, or protein
packaging. .t each stage, it is possile to inacti"ate the mR3. or protein, rendering
these molecules non!unctional.
How a particular gene is acti"ated depends on the orderly assemlage o! transcription
!actors (i.e., regulatory proteins) to speci!ic 53. se8uences immediately upstream to the
target gene, known as the promoter region. /he 53. inding sites are the enhancer
se#uences, and proteins that inhiit the initiation o! transcription are repressors.
/ranscription !actors ecome important during the in!lammatory response ecause the
aility to control the pathways leading to their acti"ation means the aility to regulate the
manner and magnitude y which a cell can respond to an injury stimulus.
+ell Signaling Pathways
Heat Shock Proteins
Heat shock proteins (HSPs), also known as stress proteins, are produced y cells in
response to injury or tissue ischemia. HSPs are essential !or the aility o! cells to
o"ercome stress. +ytosolic heat shock !actors (HS4s) are the transcription !actors that are
acti"ated y con!ormational changes upon injury, which translocate into the nucleus and
ind to the HSP promoter regions. /he o"erarching role o! HSPs is to attenuate the
in!lammatory response. Major mechanisms include reduction o! o(ygen metaolites,
promoting /H% cell proli!eration, and inhiiting 34$> acti"ation.
*$Protein Receptors
*/P$inding proteins (*$proteins) are the largest !amily o! signaling receptors !or cells
and include many o! the pathways associated with the in!lammatory response. *$protein
receptor acti"ation turns on an adjacent e!!ector protein, leading to downstream signaling.
/he two major second messengers o! the *$protein pathway are (#) !ormation o! cyclic
adenosine monophosphate (c.MP), and (%) calcium, released !rom the endoplasmic
reticulum (4ig. #$D). .n increase in cellular c.MP can acti"ate gene transcription. 4or
e(ample, inding o! epinephrine and norepinephrine acti"ates the adrenergic receptor,
leading to signaling through the *$proteinGc.MP signaling pathways.
4I*. #$D.
*$proteinCcoupled receptors are transmemrane proteins. /he *$protein receptors
respond to ligands such as adrenaline and serotonin. ?pon ligand inding to the receptor
(R), the *$protein undergoes a con!ormational change through */P$*5P con"ersion,
and in turn acti"ates the e!!ector (') component. /he ' component suse8uently
acti"ates second messengers. /he role o! IP& is to induce release o! calcium !rom the
endoplasmic reticulum ('R).
*$proteinGcalcium acti"ation re8uires acti"ation o! the e!!ector phospholipase + and
phosphoinositols. ,hen calcium is not needed, it is pumped into the mitochondria and
the endoplasmic reticulum !or storage. 4urther downstream in *$protein signaling is the
acti"ation o! protein kinase + (P6+), which can acti"ate 34$> as well as other
transcription !actors.
0igand$*ated Ion +hannels
/hese receptor channels, when acti"ated y a ligand, permit rapid !lu( o! ions across the
cell memrane. 3eurotransmitters !unction y this pathway, and an e(ample o! such a
receptor is the nicotinic acetylcholine receptor (4ig. #$=).
4I*. #$=.
0igand$gated ion channels con"ert chemical signals into electrical signals, inducing a
change in cell memrane potential. ?pon acti"ation o! the channel, millions o! ions per
second in!lu( into the cell. /hese channels are composed o! many suunits, and the
nicotinic acetylcholine receptor is one such e(ample.
Receptor /yrosine 6inases
Receptor tyrosine kinases also are known as tyrosine kinase receptors ecause o! their
signi!icant intracellular tyrosine kinase domains (4ig. #$J). '(amples o! these receptors
include insulin and "arious hormone growth !actors (e.g., platelet$deri"ed growth !actor
KP5*4L, insulin$like growth !actor KI*4L$#, epidermal growth !actor K'*4L, and "ascular
endothelial growth !actor K-'*4L). Some cytokine$receptor acti"ation also utili1es the
tyrosine kinase pathway. ,hen acti"ated, the receptors dimeri1e, undergo
phosphorylation, and recruit secondary signaling molecules. .cti"ation o! protein kinase
receptors is important !or gene transcription and cell proli!eration.
4I*. #$J.
/he receptor tyrosine kinase re8uires dimeri1ation o! monomeric units. /hese receptors
possess intrinsic en1ymatic acti"ity that re8uires multiple autophosphorylation steps to
recruit and acti"ate intracellular signaling molecules.
Hanus 6inaseGSignal /ransduction and .cti"ator o! /ranscription (S/./) Signaling
Hanus kinase (H.6) is the receptor !or o"er %: cytokines, including I43$, I0$9, I0$#:, I0$
#%, and I0$#&. ,hen ligands ind to the receptors, receptor dimeri1ation occurs and
en1ymatic acti"ation propagates through the H.6 domains o! the receptors (4ig. #$#:).
.cti"ation occurs y phosphorylation, the common currency o! most intracellular signal
transduction, which then recruits S/./ (signal transduction and acti"ator o!
transcription) proteins to the cytosolic portion o! the receptors. .cti"ated S/./ proteins
!urther dimeri1e and translocate into the nucleus as transcription !actors. S/./$mediated
transcription can acti"ate di!!erent /$cell responses during injury and in!lammation. 4or
e(ample, S/./< acti"ation promotes a /H# response, while S/./9 shi!ts towards a /H%
response.
4I*. #$#:.
/he H.6GS/./ signaling pathway also re8uires dimeri1ation o! monomeric units. S/./
(signal transducers and acti"ators o! transcription) molecules possess EdockingE sites
that allow !or S/./ dimeri1ation. /he S/./ comple(es translocate into the nucleus and
ser"e as gene transcription !actors. H.6GS/./ acti"ation occurs in response to cytokines
(e.g., I0$9) and cell stressors, and has een !ound to induce cell proli!eration and
in!lammatory !unction. Intracellular molecules that inhiit S/./ !unction, known as
S2+S (suppressors o! cytokine signaling), ha"e een identi!ied.
Suppressors o! +ytokine Signaling
Suppressors o! cytokine signaling (S2+S) speci!ically lock H.6 and S/./ acti"ation
and ultimately regulate the signaling o! certain cytokines. . de!iciency o! S2+S acti"ity
may render a cell hypersensiti"e to certain stimuli such as in!lammatory cytokines and
growth hormones. 2ne "ery clear association has een the speci!ic attenuation o! I0$9
signaling in macrophages y S2+S& through the inhiition o! S/./&.
Mitogen$.cti"ated Protein 6inases
/he mitogen$acti"ated protein kinase (M.P6) pathway is a major cellular in!lammatory
signaling pathway with regulatory roles o"er cell proli!eration and cell death (4ig. #$##).
/here are o"er %: M.P6 iso!orms, and the three major groups that alter gene e(pression
are the H36 (c$Hun 3H%$terminal kinase), 'R6 (e(tracellular regulatory protein kinase),
and p&= kinase. >roadly, these iso!orms undergo se"eral phosphorylations in order to
reach !inal acti"e !orms. +on"ersely, remo"al o! any phosphate groups signi!icantly
diminishes M.P6 acti"ity. /he H36 pathway has clear links to the in!lammatory
response, with a regulatory role in apoptosis. /34$ and I0$# can acti"ate the H36
pathway. Heat shock protein D% is one e(ample o! a H36 inhiitor. /he p&= kinase is
acti"ated in response to endoto(in, "iruses, I0$#, I0$%, I0$D, I0$#D, I0$#=, /34$, and
trans!orming growth !actor (/*4)$. /he major role o! p&=$kinase acti"ation is the
recruitment and acti"ation o! leukocytes. /hese M.P6 iso!orms do not !unction
independently, ut e(hiit appreciale Ecross$talk,E which can modulate the in!lammatory
response.
4I*. #$##.
/he M.P6 (mitogen$acti"ated protein kinase) signaling pathway re8uires multiple
phosphorylation steps. Ras, Ra!, and Mos are e(amples o! the M.P kinase kinase kinase
(M.P666), which are upstream molecules. ,ell$characteri1ed downstream kinases are
'R6 #G%, H36 or S.P6 (c$Hun 3H%$terminal kinases or stress$acti"ated protein
kinases), and p&= M.P kinases that target speci!ic gene transcription sites in the
nucleus. ./4 7 acti"ating transcription !actor@ 'R6 7 e(tracellular signal regulated
kinase@ M'4 7 myocyte$enhancing !actor.
3uclear 4actor$>
3uclear !actor (34)$> acti"ates a wide spectrum o! genes important !or the acti"ation o!
proin!lammatory cytokines and acute phase proteins (4ig. #$#%). 34$> is really a
comple( o! smaller proteins, and the pB:$p9B heterodimer comple( is the most widely
studied. In the cytosol, 34$> is maintained y inding to the inhiitor protein I$>. ,hen
a cell is e(posed to an in!lammatory stimulus (/34$ or interleukin KI0L$), a series o!
phosphorylation e"ents leads to I$> degradation. Interestingly, the rapid resynthesis o! I$
> is one mechanism y which 34$> acti"ity is inhiited. 0ow intracellular I$>
concentration is a mechanism o! prolonging the in!lammatory response, ecause the
enhanced acti"ity o! 34$> appears to delay the apoptosis o! acti"ated immune cells.
4I*. #$#%.
I$> inding to the pB:$p9B suunits o! 34$> inacti"ates the molecule. 0igand inding to
the receptor acti"ates a series o! downstream signaling molecules, o! which I$> kinase is
one. /he phosphorylated 34$> comple( !urther undergoes ui8uitini1ation and
proteosome degradation o! I$>, acti"ating 34$>, which translocates into the nucleus.
Rapid resynthesis o! I$> is one method o! inacti"ating the pB:$p9B comple(.
/oll$0ike Receptors and +5#<
More than one hal! o! the occurrences o! sepsis syndrome is the result o! gram$negati"e
in!ections mediated y lipopolysaccharide (0PS), an endoto(in. Recognition o! 0PS and
mounting the appropriate in!lammatory response y immune cells occurs primarily y the
toll$like receptor$< (/0R<) mechanism (4ig. #$#&). 0PS$inding proteins (0>Ps) carry
0PS to the +5#<G/0R< comple(, which sets into motion cellular mechanisms that
acti"ate M.P6, 34$>, and cytokine gene promoters. /0R< is primarily the receptor !or
gram$negati"e endoto(ins and /0R% is the counterpart !or gram$positi"e sepsis.
Receptors !or I0$# and I0$#= appear to share similar intracellular domains with toll$like
receptors, and so there are signi!icant similarities in signaling mechanisms. /he !act that
some patient populations are more susceptile to in!ectious complications than others
recently has een associated with speci!ic point mutations in the /0R gene.
4I*. #$#&.
0PS recognition y immune cells is primarily y the toll$like receptor$<G+5#<GM5$%
comple(. 0PS is transported y 0PS$inding protein (0>P) to the cell sur!ace comple(.
2ther cell sur!ace 0PS sensors include ion$gated channels, +5##G+5#=, and
macrophage sca"enger receptors.
/umor 3ecrosis 4actor and +5JB$Induced .poptosis
In the normal host, apoptosis is the principal mechanism y which senescent or
dys!unctional cells, including macrophages and neutrophils, are systematically disposed
o! without acti"ating other immunocytes or the release o! proin!lammatory contents. /he
cellular en"ironment created y systemic in!lammation disrupts the normal apoptotic
machinery in acti"ated immunocytes, conse8uently prolonging the in!lammatory
response.
Se"eral proin!lammatory cytokines (e.g., /34$, I0$#, I0$&, I0$9, *M$+S4, granulocyte
colony$stimulating !actor K*$+S4L, and I43$) and acterial products (e.g., endoto(in)
ha"e een shown to delay macrophage and neutrophil apoptosis in "itro, while I0$< and
I0$#: accelerate apoptosis in acti"ated monocytes.
In acute in!lammation, the response o! the immunocyte to /34$ is perhaps the most
widely in"estigated. /his cytokine e(erts its iologic e!!ects y inding to speci!ic
cellular receptors, tumor necrosis !actor receptor (/34R)$# (BB k5a) and /34R$% (DB
k5a) (4ig. #$#<). ?nder physiologic conditions, /34R$# mediates most known iologic
e!!ects o! solule /34$, including in!lammatory responses, 34$> acti"ation, and
apoptosis. ,hen /34R$# is e(clusi"ely acti"ated, it precipitates circulatory shock
reminiscent o! se"ere sepsis. Howe"er, e(clusi"e acti"ation o! /34R$% !ails to induce
any in!lammatory responses or shock.
4I*. #$#<.
Signaling pathway !or tumor necrosis !actor receptor (/34R)$# (BB k5a) and /34R$%
(DB k5a) occurs y the recruitment o! se"eral adapter proteins to the intracellular
receptor comple(. 2ptimal signaling acti"ity re8uires receptor trimeri1ation. /34R$#
initially recruits /34R$associated death domain (/R.55) and induces apoptosis
through the actions o! proteolytic en1ymes known as caspases, a pathway shared y
another receptor known as +5JB (4as). +5JB and /34R$# possess similar intracellular
se8uences known as death domains (55), and oth recruit the same adapter proteins
known as 4as$associated death domains (4.55) prior to acti"ating caspase$=. /34R$#
also induces apoptosis y acti"ating caspase$% through the recruitment o! RIP (receptor$
interacting protein). RIP also has a !unctional component that can initiate 34$> and c$
Hun acti"ation, oth !a"oring cell sur"i"al and proin!lammatory !unctions. /34R$%
lacks a 55 component, ut recruits adapter proteins known as /R.4# and /R.4%
(/34R$associated !actor) that interact with RIP to mediate 34$> and c$Hun acti"ation.
/R.4% also recruits additional proteins that are antiapoptotic, known as I.P (inhiitors
o! apoptosis protein). 5'5 7 death e!!ector domain@ R.I55 7 RIP$associated I+H$#$
like protein with death domain, which acti"ates proapoptotic caspases@ M'66# 7
mitogen$acti"ated proteinG'R6 kinase kinase$#@ H36 7 c$Hun 3$terminal kinase@ 3I6 7
34$>Cinducing kinase@ I$>G34$> 7 inacti"e comple( o! 34$> that ecomes acti"ated
when the I$> portion is clea"ed. K$dapted %ith permission from Lin &' (alvano )&'
Lo%ry )F* Tumor necrosis factor receptors in systemic inflammation' in +incent ,L
-ed.* /pdate in !ntensive (are and &mergency Medicine* !mmune esponse in (ritical
!llness0 Berlin* )pringer-+erlag' 1222' p 3450L
Signal transduction e(periments and studies employing receptor gene$knockout
technology ha"e consistently demonstrated intracellular signaling Ecross$talkE etween
/34R$# and /34R$% upon receptor acti"ation y /34$. /34R$# mediates most o! the
proin!lammatory e!!ects o! /34$, and it has een demonstrated that the early acti"ation
o! c$Hun 3H%$terminal kinase (H36) and p&= kinase pre"ents /34R$#Cmediated
apoptosis. /he acti"ation o! 34$> and H36 is elie"ed to e the major antiapoptotic, and
there!ore proin!lammatory, !actor@ it is signal induced y /34R$# and /34R$%. It is well$
known that /34$Cinduced 34$> acti"ation delays cell death and is associated with the
acti"ation o! di"erse genes that include proin!lammatory mediators. Inhiiting 34$>
acti"ation in endothelial cells has een shown to reduce the e(pression o! '$selectins, P$
selectins, and I0$=. '(aggerated peripheral lood monocyte 34$> acti"ation has een
associated with higher mortality rates in patients with septic shock.
Memers (i.e., homologues) o! the intracellular human oncogene product >cl$% also are
in"ol"ed in regulating immunocyte sur"i"al during systemic in!lammation. /he
intracellular e(pression o! one such memer, >!l$#, is directly dependent upon 34$>
acti"ity and is capale o! suppressing /34$Cinduced apoptosis. >!l$# mR3. is inducile
in neutrophils stimulated with agonists such as *$+S4, *M$+S4, and 0PS. In!lammatory
cytokines also can enhance neutrophil Mcl$# e(pression, another antiapoptotic >cl$%
homologue, which prolongs neutrophil sur"i"al and perpetuates in!lammation.
Monocytes acti"ated y in!lammatory stimuli such as /34$ also can ha"e prolonged
sur"i"al as a result o! upregulated >!l$# gene e(pression.
/he +5JB (4as) receptor shares much o! its intracellular structure with /34R$#. ?nlike
/34R$#, the only known !unction o! +5JB is to initiate programmed cell death.
3eutrophils and macrophages e(press +5JB, and this e(pression may ha"e important
implications in the cellular contriution to the in!lammatory response. In !act, oth
clinical sepsis and e(perimental endoto(emia ha"e demonstrated prolonged sur"i"al o!
neutrophils and diminished responsi"eness to +5JB stimuli. .lthough the mechanisms
are unclear, +5JB and /34R acti"ity may participate in organ injury during systemic
in!lammation.
+ell$Mediated In!lammatory Response
Platelets
+lot !ormation at the site o! injury releases in!lammatory mediators and ser"es as the
principal chemoattractant !or neutrophils and monocytes. /he migration o! platelets and
neutrophils through the "ascular endothelium occurs within & hours o! injury and is
mediated y serotonin release, platelet$acti"ating !actor, and prostaglandin '% . Platelets
can enhance or reduce neutrophil$mediated tissue injury y modulating neutrophil
adherence to the endothelium and suse8uent respiratory urst. Platelets are an important
source o! eicosanoids and "asoacti"e mediators. 3onsteroidal anti$in!lammatory drugs
irre"ersily inhiit thromo(ane production.
0ymphocytes and /$+ell Immunity
Injury, surgical or traumatic, is associated with acute impairment o! cell$mediated
immunity and macrophage !unction (4ig. #$#B).
4I*. #$#B.
Speci!ic immunity mediated y type I (/H#) and type % (/H%) /$helper lymphocytes
!ollowing injury. . /H# response is !a"ored in lesser injuries, with intact cell$mediated
and opsoni1ing antiody immunity against microial in!ections. /his cell$mediated
immunity includes acti"ation o! monocytes, > lymphocytes, and cytoto(ic /
lymphocytes. . shi!t toward the /H% response !rom naM"e /$helper cells is associated
with injuries o! greater magnitude and is not as e!!ecti"e against microial in!ections. .
/H% response includes the acti"ation o! eosinophils, mast cells, and >$lymphocyte Ig*<
and Ig' production. (Primary stimulants and principal cytokine products o! such
responses are in bold characters.) I0$< and I0$#: are known inhiitors o! the /H#
response. I43$ is a known inhiitor o! the /H% response. .lthough not cytokines,
glucocorticoids are potent stimulants o! a /H% response, which may partly contriute to
the immunosuppressi"e e!!ects o! cortisol. ($dapted %ith permission from Lin &'
(alvano )&' Lo%ry )F* !nflammatory cytokines and cell response in surgery0 )urgery
167*117' 68880)
/$helper lymphocytes are !unctionally di"ided into two sugroups, re!erred to as /H# and
/H%. ,hile oth /H# and /H% cells produce I0$&, /34$, and *M$+S4, /H# cell response
is !urther characteri1ed y the production o! I43$, I0$%, I0$#%, and /34$ (lymphoto(in),
and /H% cell response is primarily characteri1ed y I0$<, I0$B, I0$9, I0$J, I0$#:, and I0$
#& production. In se"ere in!ections and major injury, there appears to e a reduction in
/H# (cell$mediated immunity) cytokine production, with a lymphocyte population shi!t
toward the /H% response and its associated immunosuppressi"e e!!ects. In patients with
major urns, a shi!t to a /H% cytokine response has een a predictor o! in!ectious
complications. Howe"er, studies in patients undergoing major surgery ha"e demonstrated
a postoperati"e reduction in /H# cytokine production that is not necessarily associated
with increased /H% response. 3e"ertheless, depressed /H# response and systemic
immunosuppression !ollowing major insults to the host may e a use!ul paradigm in
predicting the suset o! patients who are prone to in!ectious complications and poor
outcome. It should e noted that an e(cessi"e /H# response can concei"aly lead to
o"erwhelming in!lammatory response and organ injury, ut this phenomenon has not
een well documented in surgical or trauma patients.
'osinophils
'osinophils are characteristically similar to neutrophils in that they migrate to in!lamed
endothelium and release cytoplasmic granules that are cytoto(ic. .s a result o! di!!erent
chemokine receptor e(pressions, eosinophils pre!erentially migrate to sites o! parasitic
in!ection and allergen challenge. Mature eosinophils reside in gastrointestinal, lung, and
genitourinary tissues, ut also can re$enter the circulation when needed. Major acti"ators
o! eosinophils include I0$&, *M$+S4, I0$B, platelet$acti"ating !actor, and complement
anaphylato(ins +&a and +Ba.
Mast +ells
Mast cells are important as !irst$responders at sites o! injury ecause they are pre$e(istent
in tissues. In response to trauma or in!ection, acti"ated mast cells produce histamine,
cytokines, eicosanoids, proteases, and chemokines. /he immediate results are
"asodilation, recruitment o! other immunocytes, and capillary leakage. /34$ is secreted
rapidly y mast cells ecause o! the aundant stores within granules. Mast cells also can
synthesi1e I0$&, I0$<, I0$B, I0$9, I0$#:, I0$#&, and I0$#<, as well as migration$inhiitory
!actor (MI4).
Monocytes
In humans, downregulation in monocyte and neutrophil /34R e(pression has een
demonstrated e(perimentally and clinically (4ig. #$#9). In clinical sepsis, nonsur"i"ing
patients with se"ere sepsis ha"e an immediate reduction in monocyte sur!ace /34R
e(pression with !ailure to reco"er, while sur"i"ing patients ha"e normal or near$normal
receptor le"els !rom the onset o! clinically$de!ined sepsis (4ig. #$#D). In patients with
congesti"e heart !ailure, there is also a signi!icant decrease in the amount o! monocyte
sur!ace /34R e(pression when compared with control patients (4ig. #$#=). /hus, /34R
e(pression potentially can e used as a prognostic indicator o! outcome in patients with
systemic in!lammation. /here is also decreased +5JB e(pression !ollowing e(perimental
endoto(emia in humans, which correlates with diminished +5JB$mediated apoptosis.
/aken together, the reduced receptor e(pression and delayed apoptosis may e a
mechanism !or prolonging the in!lammatory response during injury or in!ection.
4I*. #$#9.
Monocyte +5JB and /34R e(pression in healthy adult sujects !ollowing intra"enous
endoto(in administration at time 7 : hours. . reduction in receptor e(pression is
oser"ed at time 7 % hours, corresponding to the time o! ma(imal clinical response to
the endoto(in. In the asence o! !urther stimulus, receptor e(pression reco"ers to normal
le"els y <= hours. ($dapted %ith permission from Lin &' 9at: ,$' (alvano )&' et al*
The influence of human endoto;emia on (<25-induced apoptosis0 $rch )urg 133*1366'
122=0)
4I*. #$#D.
Monocyte /34R e(pression in healthy sujects, and in sur"i"ing and nonsur"i"ing
septic patients, on days : to <. /he gray o( indicates the range o! monocyte /34R
e(pression in sur"i"ing patients and healthy sujects. ($dapted %ith permission from
(alvano )&' van der Poll T' (oyle )M' et al* Monocyte tumor necrosis factor receptor
levels as a predictor of risk in human sepsis0 $rch )urg 131*>3>' 1224.)
4I*. #$#=.
$0 Patients without congesti"e heart !ailure (+H4) e(pressed higher /34R le"els than
patients with +H4 strati!ied y 3ew Nork Heart .ssociation (3NH.) classi!ication.
Monocyte memrane$associated /34R le"els are e(pressed as mean channel
!luorescence (M+4). B0 Patients with higher monocyte /34R e(pression also e(hiited
higher ejection !ractions. (0 Spontaneous apoptosis o! polymorphonuclear cells (PM3s)
was lower in patients with +H4, suggesting that the chronic in!lammatory milieu o!
+H4 patients contriutes to the delay in PM3 disposal. <0 Patients with higher ejection
!ractions also e(hiited higher spontaneous PM3 apoptosis.
3eutrophils
3eutrophils mediate important !unctions in e"ery !orm o! acute in!lammation, including
acute lung injury, ischemiaGreper!usion injury, and in!lammatory owel disease. ,ithin
the one marrow, *$+S4 is the primary stimulus !or neutrophil maturation. In!lammatory
mediators !rom a site o! injury induce neutrophil adherence to the "ascular endothelium
and promote e"entual cell migration into the injured tissue. 3eutrophil !unction is
mediated y a "ast array o! intracellular granules that are chemotactic or cytoto(ic to
local tissue and in"ading microorganisms.
'ndothelium$Mediated Injury
3eutrophil$'ndothelium Interaction
Increased "ascular permeaility during in!lammation is intended to !acilitate o(ygen
deli"ery and immunocyte migration to the sites o! injury. Howe"er, the accumulation and
in!iltration o! in!lammatory leukocytes, speci!ically neutrophils, at sites o! injury
contriute to the cytoto(icity o! "ital tissues and result in organ dys!unction.
IschemiaGreper!usion (IGR) injury potentiates this response y unleashing o(ygen
metaolites, lysosomal en1ymes that degrade tissue asal memranes, cause
micro"ascular thromosis, and acti"ate myelopero(idases. /he recruitment o! circulating
neutrophils to endothelial sur!aces is mediated y concerted actions o! adhesion
molecules re!erred to as selectins that are elaorated on cell sur!aces (/ale #$B).
3eutrophil rolling in the !irst #: to %: minutes !ollowing injury is mainly mediated y P$
selectin e(pression (4ig. #$#J). /his is consistent with the rapid e(pression o! P$selectins
!rom intracellular stores. >eyond %: minutes, the in!luence o! P$selectins diminishes
secondary to internal degradation, and 0$selectin ecomes the principal mediator o!
leukocyte rolling. In conjunction with 0$selectin, P$selectin glycoprotein ligand$#
(PS*0$#) is responsile !or o"er =BO o! monocyte$to$monocyte and monocyte$to$
endothelium adhesion acti"ity. .lthough there are distinguishale properties among
indi"idual selectins in leukocyte rolling, e!!ecti"e rolling most likely in"ol"es a
signi!icant degree o! !unctional o"erlap. Similarly, 0$selectin also initiates neutrophil$to$
neutrophil interaction, in part y inding to leukocyte sur!ace PS*0$#.
/ale #$B Molecules /hat Mediate 0eukocyte$'ndothelial .dhesion, +ategori1ed y
4amily
Adhesion
Molecule
Action *rigin Inducers of
%+pression
.arget Cells
)electins
0$selectin 4ast rolling 0eukocytes 3ati"e 'ndothelium,
platelets,
eosinophils
P$selectin Slow rolling Platelets and
endothelium
/hromin,
histamine
3eutrophils,
monocytes
Adhesion
Molecule
Action *rigin Inducers of
%+pression
.arget Cells
'$selectin -ery slow rolling 'ndothelium +ytokines 3eutrophils,
monocytes,
lymphocytes
!mmunoglobulins
I+.M$# 4irm
adhesionGtransmigration
'ndothelium,
leukocytes,
!irolasts,
epithelium
+ytokines 0eukocytes
I+.M$% 4irm adhesion 'ndothelium,
platelets
3ati"e 0eukocytes
-+.M$# 4irm
adhesionGtransmigration
'ndothelium +ytokines Monocytes,
lymphocytes
P'+.M$# .dhesionGtransmigration 'ndothelium,
platelets,
leukocytes
3ati"e 'ndothelium,
platelets,
leukocytes
6--(<1=.
!ntegrins

+5#=G##a 4irm
adhesionGtransmigration
0eukocytes 0eukocyte
acti"ation
'ndothelium
+5#=G##
(Mac$#)
4irm
adhesionGtransmigration
3eutrophils,
monocytes,
natural killer
cells
0eukocyte
acti"ation
'ndothelium
+5#=G##c .dhesion 3eutrophils,
monocytes,
natural killer
cells
0eukocyte
acti"ation
'ndothelium
1--(<62.
!ntegrins

-0.$< 4irm
.dhesionGtransmigration
0ymphocytes,
monocytes
0eukocyte
acti"ation
Monocytes,
endothelium,
epithelium
I+.M 7 intercellular adhesion molecule@ Mac 7 macrophage antigen@ P'+.M 7 platelet$
endothelial cell adhesion molecule@ -+.M 7 "ascular cell adhesion molecule@ -0. 7
"ery late antigen.
4I*. #$#J.
Simpli!ied se8uence o! selectin$mediated neutrophil$endothelium interaction !ollowing
an in!lammatory stimulus. ($PT/& (tethering), predominantly mediated y cell 0$
selectin with contriution !rom endothelial P$selectin, descries the initial recognition
etween leukocyte and endothelium, where circulating leukocytes marginate toward the
endothelial sur!ace. F$)T ?LL!@G (B: to #B: mGs) is a conse8uence o! rapid 0$
selectin shedding !rom cell sur!aces and !ormation o! new downstream 0$selectin to
endothelium onds, occurring in tandem. )L?A ?LL!@G (%: to B: mGs) is
predominantly mediated y P$selectins. /he slowest rolling (& to #: mGs) prior to arrest
is predominantly mediated y '$selectins, with contriution !rom P$selectins. $&)T
(!irm adhesion) leading to transmigration is mediated y $integrins and the
immunogloulin !amily o! adhesion molecules. In addition to interactions with the
endothelium, acti"ated leukocytes also recruit other leukocytes to the in!lammatory site
y direct interactions, which are mediated in part y selectins. ($dapted %ith permission
from Lin &' (alvano )&' Lo%ry )F* )electin neutrali:ation* <oes it make biological
senseB (rit (are Med 67*6858' 12220)
3itric 2(ide
3itric o(ide (32) is deri"ed !rom endothelial sur!aces in response to acetylcholine
stimulation, hypo(ia, endoto(in, cellular injury, or mechanical shear stress !rom
circulating lood. 3ormal "ascular smooth muscle rela(ation is maintained y a constant
output o! 32. 32 also can reduce microthromosis y reducing platelet adhesion and
aggregation (4ig. #$%:). 32 also mediates protein synthesis in hepatocytes and electron
transport in hepatocyte mitochondria. It is a readily di!!usile sustance with a hal!$li!e o!
a !ew seconds. 32 spontaneously decomposes into nitrate and nitrite.
4I*. #$%:.
'ndothelial interaction with smooth muscle cells and with intraluminal platelets.
Prostacyclin (P*I%) is deri"ed !rom arachidonic acid, and nitric o(ide (32) is deri"ed
!rom 0$arginine. /he increase in cyclic adenosine monophosphate (c.MP) and cyclic
guanosine monophosphate (c*MP) results in smooth muscle rela(ation and inhiition o!
platelet thromus !ormation. 'ndothelins ('/s) are deri"ed !rom Eig '/,E and they
counter the e!!ects o! prostacyclin and nitric o(ide.
32 is !ormed !rom o(idation o! 0$arginine, a process cataly1ed y nitric o(ide synthase
(32S). +o!actors o! 32S acti"ity include calmodulin, ioni1ed calcium, and reduced
nicotinamide adenine di$nucleotide phosphate (3.5PH). In addition to the endothelium,
32 !ormation also occurs in neutrophils, monocytes, renal cells, 6up!!er cells, and
cereellar neurons.
Prostacyclin
.lthough it is an arachidonate product, prostacyclin (P*I%) is another important
endothelium$deri"ed "asodilator synthesi1ed in response to "ascular shear stress and
hypo(ia. P*I% shares similar !unctions with 32, inducing "asorela(ation and platelet
deacti"ation y increasing c.MP. +linically, it has een used to reduce pulmonary
hypertension, particularly in the pediatric population.
'ndothelins
'ndothelins ('/s) are elaorated y "ascular endothelial cells in response to injury,
thromin, trans!orming growth !actor$ (/*4$), I0$#, angiotensin II, "asopressin,
catecholamines, and ano(ia. Structurally !ormed !rom a &=$amino$acid precursor
molecule, '/ is a %#$amino$acid peptide with potent "asoconstricting properties. 2! the
peptides in this !amily (e.g., '/$#, '/$%, and '/$&), endothelial cells appear to
e(clusi"ely produce '/$#. Moreo"er, '/$# appears to e the most iologically acti"e and
the most potent known "asoconstrictor. It is estimated to e #: times more potent than
angiotensin II. /hree endothelin receptors, re!erred to as '/., '/>, and '/+, ha"e een
identi!ied and !unction y the *$protein$coupled receptor mechanism. '/> receptors are
linked to the !ormation o! 32 and prostacyclin (P*I%), which ser"e as negati"e !eedack
mechanisms. /he maintenance o! physiologic tone in "ascular smooth muscle depends on
the alance etween 32 and '/ production. /he "asoconstrictor acti"ity o! '/ can e
re"ersed y the administration o! acetylcholine, which stimulates 32 production.
Increased serum le"els o! '/s correlate with the se"erity o! injury !ollowing major
trauma, major surgical procedures, and in cardiogenic or septic shock.
Platelet$.cti"ating 4actor
.nother endothelial$deri"ed product is platelet$acti"ating !actor (P.4), a natural
phospholipid constituent o! cell memranes, which under normal physiologic conditions
is minimally e(pressed. 5uring acute in!lammation, P.4 is released y neutrophils,
platelets, mast cells, and monocytes, and is e(pressed at the outer lea!let o! endothelial
cells. P.4 can !urther acti"ate neutrophils and platelets and increase "ascular
permeaility. .ntagonists to P.4 receptors ha"e een e(perimentally shown to mitigate
the e!!ects o! ischemiaGreper!usion injury. Human sepsis is associated with a reduction in
P.4$acetylhydrolase le"els, which is the endogenous inacti"ator o! P.4. Indeed, P.4$
acetylhydrolase administration in patients with se"ere sepsis has shown some reduction
in multiple organ dys!unction and mortality.
.trial 3atriuretic Peptides
.trial natriuretic peptides (.3Ps) are a !amily o! peptides released primarily y atrial
tissue, ut are also synthesi1ed y the gut, kidney, rain, adrenal glands, and
endothelium. /hey induce "asodilation as well as !luid and electrolyte e(cretion. .3Ps
are potent inhiitors o! aldosterone secretion and pre"ent reasorption o! sodium. /here
is some e(perimental e"idence to suggest that .3P can re"erse acute renal !ailure or
early acute tuular necrosis.
Surgical Metabolism
/he initial hours !ollowing surgical or traumatic injury 7reduced total ody energy
e(penditure and urinary nitrogen wasting. /his phase o! reco"ery also is characteri1ed y
!unctions that all participate in the restoration o! homeostasis, such as augmented
metaolic rates and o(ygen consumption, en1ymatic pre!erence !or readily o(idi1ale
sustrates such as glucose, and stimulation o! the immune system.
Metabolism /uring Fasting
$a normal healthy adult re8uires appro(imately %B kcalGkg per day drawn !rom
carohydrate, lipid, and protein sources.
$ short-term fasting -C5 days. D energy from muscle protein and body fat' %ith fat being
the most abundant source of energy -Table 1-4.0 The normal adult body contains 388 to
>88 g of carbohydrates in the form of glycogen' of %hich 75 to 188 g are stored in the
liver0 $ppro;imately 688 to 658 g of glycogen are stored %ithin skeletal' cardiac' and
smooth muscle cells0 The greater glycogen stores %ithin the muscle are not readily
available for systemic use due to a deficiency in glucose-4-phosphatase' but are
available for the energy needs of muscle cells0
-fasting stateDhepatic glycogen stores are rapidly and preferentially depleted' resulting
in a fall of serum glucose concentration %ithin hours -C14 hours.0
--glycogenolysis.DGlucagon' norepinephrine' vasopressin' and angiotensin !! during
fasting
-gluconeogenesis* glucagon' epinephrine' and cortisol
-epinephrine and cortisol also promote pyruvate shuttling to the liver for
gluconeogenesis
- Precursors gluconeogenesis *lactate' glycerol' and amino acids such as alanine and
glutamine0
-Lactate is released by glycolysis %ithin skeletal muscles' as %ell as by erythrocytes and
leukocytes0
-The recycling of lactate and pyruvate for gluconeogenesis is commonly referred to as the
(ori cycle' %hich can provide up to >8E of plasma glucose during starvation0
-Lactate production from skeletal muscle is insufficient to maintain systemic glucose
needs during short-term fasting -simple starvation.0 Therefore' significant amounts of
protein must be degraded daily -75 g/d for a 78-kg adult. for gluconeogenesis0
Proteolysis during starvation' %hich results primarily from decreased insulin and
increased cortisol release' is associated %ith elevated urinary nitrogen e;cretion from the
normal 7 to 18 g per day up to 38 g or more per day0
$In prolonged star"ation, systemic proteolysis is reduced to appro(imately %: g per day
and urinary nitrogen e(cretion staili1es at % to B g per day re!lecting the adaptation y
"ital organs (e.g., myocardium, rain, renal corte(, and skeletal muscle) to using ketone
odies as their principal !uel source. In e(tended !asting, ketone odies ecome an
important !uel source !or the rain a!ter % days, and gradually ecome the principal !uel
source y %< days.
0ong term !asting man
4uel utili1ation in e(tended star"ation. 0i"er glycogen stores are depleted and there is
adapti"e reduction in proteolysis as a source o! !uel. /he rain utili1es ketones !or !uel.
/he kidneys ecome important participants in gluconeogenesis
$Inc deamination o! amino acids !or gluconeogenesis during star"ation $Pinc renal
e(cretion o! ammonium ions.
$kidneys also participate in gluconeogenesis y the utili1ation o! glutamine and
glutamate, and can ecome the primary source o! gluconeogenesis during prolonged
star"ation, accounting !or up to one hal! o! systemic glucose production.
$0ipid stores within adipose tissue pro"ide up to <:O o! caloric e(penditure during
star"ation. 4ree !atty acid release is stimulated y dec in insulin the inc in circulating
glucagon and catecholamine. Such !ree !atty acids, as with ketone odies, are used as !uel
y tissues such as the heart, kidney (renal corte(), muscle, and li"er. /his decreases the
rate o! glycolysis, gluconeogenesis, and proteolysis, as well as the o"erall glucose
re8uirement to sustain the host. 6etone odies spare glucose utili1ation y inhiiting the
en1yme pyru"ate dehydrogenase.
Metaolism 4ollowing Injury
$ induce uni8ue neuroendocrine and immunologic responses that di!!erentiate injury
metaolism !rom that o! unstressed !asting
$inc in energy e(penditure is mediated y sympa.
$lipid metaolism !ollowing injury is the primary source o! energy during stressed states.
4ollowing trauma
.cute injury is associated with signi!icant alterations in sustrate utili1ation. /here is
enhanced nitrogen loss, indicati"e o! cataolism. 4at remains the primary !uel source
under these circumstances.
"ipid Metabolism Folloing Injury
0ipids $minimi1e protein cataolism ; in!luences the structural integrity o! cell
memranes as well as the immune response during systemic in!lammation.
$response to catecholamine stimulus o! the hormone$sensiti"e triglyceride lipase. 2thers
include adrenocorticotropic hormone, catecholamines, thyroid hormone, cortisol,
glucagon, growth hormone release, reduction in insulin le"els, and increased sympathetic
stimulus.
0ipid .sorption
.lthough poorly understood, adipose tissue pro"ides !uel !or the host in the !orm o! !ree
!atty acids and glycerol during critical illness and injury. 2(idation o! # g o! !at yields
appro(imately J kcal o! energy. .lthough the li"er is capale o! synthesi1ing triglycerides
!rom carohydrates and amino acids, dietary and e(ogenous sources pro"ide the major
source o! triglycerides. 5ietary lipids are not readily asorale in the gut, ut re8uire
pancreatic lipase and phospholipase within the duodenum to hydroly1e the triglycerides
into !ree !atty acids and monoglycerides. /he !ree !atty acids and monoglycerides are
then readily asored y gut enterocytes, which resynthesi1e triglycerides y
esteri!ication o! the monoglycerides with !atty acyl coen1yme . (acyl$+o.) (4ig. #$%9).
0ong$chain triglycerides (0+/), de!ined as those with #% carons or more, generally
undergo this process o! esteri!ication and enter the circulation through the lymphatic
system as chylomicrons. Shorter !atty acid chains directly enter the portal circulation and
are transported to the li"er y alumin carriers. Hepatocytes utili1e !ree !atty acids as a
!uel source during stress states, ut can also synthesi1e phospholipids or triglycerides
(i.e., "ery$low$density lipoproteins) during !ed states. Systemic tissue (e.g., muscle and
the heart) can utili1e chylomicrons and triglycerides as !uel y hydrolysis with
lipoprotein lipase at the luminal sur!ace o! capillary endothelium. /rauma or sepsis
suppresses lipoprotein lipase acti"ity in oth adipose tissue and muscle, presumaly
mediated y /34$.
4I*. #$%9.
Pancreatic lipase within the small intestinal rush orders hydroly1es triglycerides into
monoglycerides and !atty acids. /hese components readily di!!use into the gut
enterocytes, where they are re$esteri!ied into triglycerides. /he resynthesi1ed
triglycerides ind carrier proteins to !orm chylomicrons, which are transported y the
lymphatic system. Shorter triglycerides (those with less than #: caron atoms) can
ypass this process and directly enter the portal circulation !or transport to the li"er.
0ipolysis and 4atty .cid 2(idation
Periods o! energy demand are accompanied y !ree !atty acid moili1ation !rom adipose
stores. /his is mediated y hormonal in!luences (e.g., catecholamines,
adrenocorticotropic hormone K.+/HL, thyroid hormones, growth hormone, and
glucagon) on triglyceride lipase through a c.MP pathway (4ig. #$%D). In adipose tissues,
triglyceride lipase hydroly1es triglycerides into !ree !atty acids and glycerol. 4ree !atty
acids enter the capillary circulation and are transported y alumin to tissues re8uiring
this !uel source (e.g., heart and skeletal muscle). Insulin inhiits lipolysis and !a"ors
triglyceride synthesis y augmenting lipoprotein lipase acti"ity as well as intracellular
le"els o! glycerol$&$phosphate. /he use o! glycerol !or !uel depends on the a"ailaility o!
tissue glycerokinase, which is aundant in the li"er and kidneys.
4I*. #$%D.
4at moili1ation in adipose tissue. /riglyceride lipase acti"ation y hormonal
stimulation o! adipose cells occurs through the c.MP pathway. /riglycerides are serially
hydroly1ed with resultant !ree !atty acid (44.) release at e"ery step. /he 44.s di!!use
readily into the capillary ed !or transport. /issues with glycerokinase can utili1e
glycerol !or !uel y !orming glycerol$&$phosphate. *lycerol$&$phosphate can esteri!y
with 44.s to !orm triglycerides, or can e used as a precursor !or renal and hepatic
gluconeogenesis. Skeletal muscle and adipose cells ha"e little glycerokinase, and thus
do not use glycerol !or !uel.
4ree !atty acids asored y cells conjugate with acyl$+o. within the cytoplasm. /he
transport o! !atty acyl$+o. !rom the outer mitochondrial memrane across the inner
mitochondrial memrane occurs "ia the carnitine shuttle (4ig. #$%=). Medium$chain
triglycerides (M+/), de!ined as those 9 to #% carons in length, ypass the carnitine
shuttle and readily cross the mitochondrial memranes. /his accounts in part !or why
M+/s are more e!!iciently o(idi1ed than 0+/s. Ideally, the rapid o(idation o! M+/s
makes them less prone to !at deposition, particularly within immune cells and the
reticuloendothelial systemQa common !inding with lipid in!usion in parenteral nutrition.
Howe"er, e(clusi"e use o! M+/s as !uel in animal studies has een associated with
higher metaolic demands and to(icity, as well as essential !atty acid de!iciency.
4I*. #$%=.
4ree !atty acids in the cells !orm !atty acyl$+o. with coen1yme .. 4atty acyl$+o.
cannot enter the inner mitochondrial memrane and re8uires carnitine as a carrier
protein (carnitine shuttle). 2nce inside the mitochondria, carnitine dissociates and !atty
acyl$+o. is re$!ormed. /he carnitine molecule is transported ack into the cytosol !or
reuse. /he !atty acyl$+o. undergoes $o(idation to !orm acetyl$+o. !or entry into the
tricaro(ylic acid cycle.
,ithin the mitochondria, !atty acyl$+o. undergoes $o(idation, which produces acetyl$
+o. with each pass through the cycle. 'ach acetyl$+o. molecule suse8uently enters the
tricaro(ylic acid (/+.) cycle !or !urther o(idation to yield #% adenosine triphosphate
(./P) molecules, caron dio(ide, and water. '(cess acetyl$+o. molecules ser"e as
precursors !or ketogenesis. ?nlike glucose metaolism, o(idation o! !atty acids re8uires
proportionally less o(ygen and produces less caron dio(ide. /his is !re8uently
8uanti!ied as the ratio o! caron dio(ide produced to o(ygen consumed !or the reaction,
and is known as the respiratory #uotient (RR). .n RR o! :.D would imply greater !atty
acid o(idation !or !uel, while an RR o! # indicates greater carohydrate o(idation
(overfeeding). .n RR o! :.=B suggests the o(idation o! e8ual amounts o! !atty acids and
glucose.
6etogenesis
+arohydrate depletion slows acetyl$+o. entry into the /+. cycle secondary to depleted
/+. intermediates and en1yme acti"ity. Increased lipolysis and reduced systemic
carohydrate a"ailaility during star"ation di"erts e(cess acetyl$+o. toward hepatic
ketogenesis. . numer o! e(trahepatic tissues, ut not the li"er itsel!, are capale o!
utili1ing ketones !or !uel. 6etosis represents a state in which hepatic ketone production
e(ceeds e(trahepatic ketone utili1ation.
/he rate o! ketogenesis appears to e in"ersely related to the se"erity o! injury. Major
trauma, se"ere shock, and sepsis attenuate ketogenesis y increasing insulin le"els and y
rapid tissue o(idation o! !ree !atty acids. Minor injuries and in!ections are associated with
modest ele"ations in plasma !ree !atty acid concentrations and ketogenesis. Howe"er,
ketogenesis in minor stress states does not e(ceed that o! nonstressed star"ation.
+arohydrate Metaolism
Ingested and enteral carohydrates are primarily digested in the small intestine, where
pancreatic and intestinal en1ymes reduce the comple( carohydrates to dimeric units.
5isaccharidases (e.g., sucrase, lactase, and maltase) within intestinal rush orders
dismantle the comple( carohydrates into simple he(ose units, which are transported into
the intestinal mucosa. *lucose and galactose are primarily asored y energy$dependent
acti"e transport coupled to the sodium pump. 4ructose asorption, howe"er, occurs y
concentration$dependent !acilitated di!!usion. >oth !ructose and galactose within the
circulation as well as e(ogenous mannitol (!or neurologic injury) do not e"oke an insulin
response. Intra"enous administration o! low$dose !ructose in !asting humans has een
associated with nitrogen conser"ation, ut the clinical utility o! !ructose administration in
human injury remains to e demonstrated.
5iscussion o! carohydrate metaolism primarily re!ers to the utili1ation o! glucose. /he
o(idation o! # g o! carohydrate yields < kcal, ut administered sugar solutions such as
that !ound in intra"enous !luids or parenteral nutrition pro"ides only &.< kcalGg o!
de(trose. In star"ation, glucose production occurs at the e(pense o! protein stores (i.e.,
skeletal muscle). Hence, the primary goal !or maintenance glucose administration in
surgical patients ser"es to minimi1e muscle wasting. /he e(ogenous administration o!
small amounts o! glucose (appro(imately B: gGd) !acilitates !at entry into the /+. cycle
and reduces ketosis. ?nlike star"ation in healthy sujects, studies pro"iding e(ogenous
glucose to septic and trauma patients ne"er ha"e een shown to !ully suppress amino acid
degradation !or gluconeogenesis. /his suggests that during periods o! stress, other
hormonal and proin!lammatory mediators ha"e pro!ound in!luence on the rate o! protein
degradation and that some degree o! muscle wasting is ine"itale. /he administration o!
insulin, howe"er, has een shown to re"erse protein cataolism during se"ere stress y
stimulating protein synthesis in skeletal muscles and y inhiiting hepatocyte protein
degradation. Insulin also stimulates the incorporation o! elemental precursors into nucleic
acids associated with R3. synthesis in muscle cells.
In cells, glucose is phosphorylated to !orm glucose$9$phosphate (*9P). *9P can e
polymeri1ed during glycogenesis or cataoli1ed in glycogenolysis. *lucose cataolism
occurs y clea"age to pyru"ate or lactate (pyru"ic acid pathway) or y decaro(ylation to
pentoses (pentose shunt) (4ig. #$%J).
4I*. #$%J.
Simpli!ied schema o! glucose cataolism through the pentose monophosphate pathway
or y reakdown into pyru"ate. *lucose$9$phosphate ecomes an important EcrossroadE
!or glucose metaolism.
'(cess glucose !rom o"er!eeding, as re!lected y RRs greater than #.:, can result in
conditions such as glucosuria, thermogenesis, and con"ersion to !at (lipogenesis).
'(cessi"e glucose administration results in ele"ated caron dio(ide production, which
may e deleterious in patients with suoptimal pulmonary !unction.
Injury and se"ere in!ections acutely induce a state o! peripheral glucose intolerance,
despite ample insulin production se"eral!old ao"e aseline. /his may occur in part due
to reduced skeletal muscle pyru"ate dehydrogenase acti"ity !ollowing injury, which
diminishes the con"ersion o! pyru"ate to acetyl$+o. and suse8uent entry into the /+.
cycle. /he conse8uent accumulation o! three$caron structures (e.g., pyru"ate and lactate)
are shunted to the li"er as sustrate !or gluconeogenesis. 4urthermore, regional tissue
catheteri1ation and isotope dilution studies ha"e shown an increase in net splanchnic
glucose production in septic patients y B: to 9:O, and a B: to #::O increase in urn
patients. /he increase in plasma glucose le"els is proportional to the se"erity o! injury,
and this net hepatic gluconeogenic response is elie"ed to e under the in!luence o!
glucagon. ?nlike the nonstressed suject, the hepatic gluconeogenic response to injury or
sepsis cannot e suppressed y e(ogenous or e(cess glucose administration, ut rather
persists in the hypermetaolic, critically ill patient. Hepatic gluconeogenesis, arising
primarily !rom alanine and glutamine cataolism, pro"ides a ready !uel source !or tissues
such as those o! the ner"ous system, wounds, and erythrocytes, which do not re8uire
insulin !or glucose transport. /he ele"ated glucose concentrations also pro"ide a
necessary energy source !or leukocytes in in!lamed tissues and in sites o! microial
in"asions.
/he shunting o! glucose away !rom nonessential organs such as skeletal muscle and
adipose tissues is mediated y catecholamines. '(periments with in!using catecholamines
and glucagon in animals ha"e demonstrated ele"ated plasma glucose le"els as a result o!
increased hepatic gluconeogenesis and peripheral insulin resistance. Interestingly, while
glucocorticoid in!usion alone does not increase glucose le"els, it does prolong and
augment the hyperglycemic e!!ects o! catecholamines and glucagon when in!used
concurrently.
*lycogen stores within skeletal muscles can e moili1ed y epinephrine acti"ation o!
$adrenergic receptors, a */P$inding protein (*$protein), which suse8uently acti"ates
the second messenger, c.MP. c.MP acti"ates phosphorylase kinase, which in turn leads
to con"ersion o! glycogen to glucose$#$phosphate. Phosphorylase kinase also can e
acti"ated y the second messenger, calcium, through the reakdown o!
phosphatidylinositol phosphate, which is the case in "asopressin$mediated hepatic
glycogenolysis.
*lucose /ransport and Signaling
Hydrophoic cell memranes are relati"ely impermeale to hydrophilic glucose
molecules. /here are two distinct classes o! memrane glucose transporters in human
systems. /hese are the !acilitated di!!usion glucose transporters (*0?/) that permit the
transport o! glucose down a concentration gradient (/ale #$D) and the 3a
S
Gglucose
transport system, which transports glucose molecules against concentration gradients y
acti"e transport. /he energy$dependent 3a
S
Gglucose transport system is relati"ely
pre"alent on rush orders o! small intestine enterocytes and the epithelium o! pro(imal
renal tuules.
/ale #$D Human 4acilitated 5i!!usion *lucose /ransporter 4amily
.ype Amino Acids Major %+pression Sites
*0?/ # <J% Placenta, rain, kidney, colon
*0?/ % B%< 0i"er, pancreatic cells, kidney, small intestine
*0?/ & <J9 >rain, testis
*0?/ < B:J Skeletal muscle, heart muscle, rown and white !at
*0?/ B B:# Small intestine, sperm
More than !i"e human !acilitated di!!usion glucose transporters ha"e een cloned since
#J=B. *0?/ # is the transporter in human erythrocytes. It is e(pressed on se"eral other
tissues, ut little is !ound in the li"er and skeletal muscle. Importantly, it is a constituti"e
part o! the endothelium in the lood$rain arrier. *0?/ % is predominantly e(pressed in
the sinusoidal memranes o! li"er, renal tuules, enterocytes, and insulin$secreting cells
o! the pancreas. *0?/ % is important !or rapid e(port o! glucose resulting !rom
gluconeogenesis. *0?/ & is highly e(pressed in neuronal tissue o! the rain, the kidney,
and placenta, ut *0?/ & mR3. has een detected in almost e"ery human tissue. *0?/
< is signi!icant to human metaolism ecause it is the primary glucose transporter o!
insulin$sensiti"e tissues, adipose tissue, and skeletal and cardiac muscle. /hese
transporters are usually packaged as intracellular "esicles, ut insulin induces rapid
translocation o! these "esicles to the cell sur!ace. *0?/ < !unction has important
implications in the physiology o! patients with insulin$resistant diaetes. *0?/ B has
een identi!ied in se"eral tissues, ut is primarily e(pressed in the jejunum. .lthough it
possesses some capacity !or glucose transport, it is predominantly a !ructose transporter.
3a
S
Gglucose transport systems are distinct glucose transport systems !ound in the
intestinal epithelium and in the pro(imal renal tuules. /his system transports oth
sodium and glucose intracellularly, and glucose a!!inity !or this transporter increases
when sodium ions are attached. In addition, the 3a
S
Gglucose transport system within the
intestinal lumen also enhances gut retention o! water through osmotic asorption.
Protein and .mino .cid Metaolism
/he a"erage protein intake in healthy, young adults ranges !rom =: to #%: gGd, and e"ery
9 g o! protein yields appro(imately # g o! nitrogen. /he degradation o! # g o! protein
yields appro(imately < kcal o! energy, almost the same as !or carohydrates.
4ollowing injury the initial systemic proteolysis, mediated primarily y glucocorticoids,
increases urinary nitrogen e(cretion to le"els in e(cess o! &: gGd, which roughly
corresponds to a loss in lean ody mass o! #.BO per day. .n injured indi"idual who does
not recei"e nutrition !or #: days can theoretically lose #BO lean ody mass. /here!ore
amino acids cannot e considered a long$term !uel reser"e, and indeed e(cessi"e protein
depletion (i.e., %B to &:O o! lean ody weight) is not compatile with sustaining li!e.
Protein cataolism !ollowing injury pro"ides sustrates !or gluconeogenesis and !or the
synthesis o! acute phase proteins. Radiolaeled amino acid incorporation studies and
protein analyses con!irm that skeletal muscles are pre!erentially depleted acutely
!ollowing injury, while "isceral tissues (e.g., the li"er and kidney) remain relati"ely
preser"ed. /he accelerated urea e(cretion !ollowing injury is also associated with the
e(cretion o! intracellular elements such as sul!ur, phosphorus, potassium, magnesium,
and creatinine. +on"ersely, the rapid utili1ation o! elements such as potassium and
magnesium during reco"ery !rom major injury may indicate a period o! tissue healing.
/he net changes in protein cataolism and synthesis correspond to the se"erity and
duration o! injury (4ig. #$&:). 'lecti"e operations and minor injuries result in lower
protein synthesis and moderate protein reakdown. Se"ere trauma, urns, and sepsis are
associated with increased protein cataolism. /he rise in urinary nitrogen and negati"e
nitrogen alance can e detected early !ollowing injury and peak y D days. /his state o!
protein cataolism may persist !or as long as & to D weeks. /he patientIs prior physical
status and age appear to in!luence the degree o! proteolysis !ollowing injury or sepsis.
4I*. #$&:.
/he e!!ect o! injury se"erity on nitrogen wasting. ($dapted %ith permission from Long
(L* Metabolic response to inFury and illness* &stimation of energy and protein needs
from indirect calorimetry and nitrogen balance0 , Parenter &nteral @utr 3*>56' 12720)
.cti"ation o! the ui8uitin$proteosome system in muscle cells is one o! the major
pathways !or protein degradation during acute injury. /his response is accentuated y
tissue hypo(ia, acidosis, insulin resistance, and ele"ated glucocorticoids.
3utrition in the Surgical Patient
/he goal o! nutritional support in the surgical patient is to pre"ent or re"erse the cataolic
e!!ects o! disease or injury. ,hile se"eral important iologic parameters ha"e een used
to measure the e!!icacy o! nutrition regimens, the ultimate "alidation !or nutritional
support in surgical patients should e impro"ement in clinical outcome and restoration o!
!unction.
'stimating 'nergy Re8uirements
2"erall nutritional assessment is undertaken to determine the se"erity o! nutrient
de!iciencies or e(cess and to aid in predicting nutritional re8uirements. Pertinent
in!ormation is otained y determining the presence o! weight loss, chronic illnesses, or
dietary haits that in!luence the 8uantity and 8uality o! !ood intake. Social haits
predisposing to malnutrition and the use o! medications that may in!luence !ood intake or
urination should also e in"estigated. Physical e(amination seeks to assess loss o! muscle
and adipose tissues, organ dys!unction, and sutle changes in skin, hair, or neuromuscular
!unction re!lecting !rank or impending nutritional de!iciency. .nthropometric data (i.e.,
weight change, skin!old thickness, and arm circum!erence muscle area) and iochemical
determinations (i.e., creatinine e(cretion, alumin, prealumin, total lymphocyte count,
and trans!errin) may e used to sustantiate the patientIs history and physical !indings. It
is imprecise to rely on any single or !i(ed comination o! the ao"e !indings to accurately
assess nutritional status or moridity. .ppreciation !or the stresses and natural history o!
the disease process, in comination with nutritional assessment, remains the asis !or
identi!ying patients in acute or anticipated need o! nutritional support.
. !undamental goal o! nutritional support is to meet the energy re8uirements !or
metaolic processes, core temperature maintenance, and tissue repair. 4ailure to pro"ide
ade8uate nonprotein energy sources will lead to dissolution o! lean tissue stores. /he
re8uirement !or energy may e measured y indirect calorimetry or estimated !rom
urinary nitrogen e(cretion, which is proportional to resting energy e(penditure. Howe"er,
the use o! indirect calorimetry, particularly in the critically ill patient, is laor intensi"e
and o!ten leads to o"erestimation o! caloric re8uirements.
>asal energy e(penditure (>'') may also e estimated using the Harris$>enedict
e8uations)
/hese e8uations, adjusted !or the type o! surgical stress, are suitale !or estimating energy
re8uirements in o"er =:O o! hospitali1ed patients. It has een demonstrated that the
pro"ision o! &: kcalGkg per day will ade8uately meet energy re8uirements in most
postsurgical patients, with low risk o! o"er!eeding. 4ollowing trauma or sepsis, energy
sustrate demands are increased, necessitating greater nonprotein calories eyond
calculated energy e(penditure (/ale #$=). /hese additional nonprotein calories pro"ided
a!ter injury are usually #.% to %.: times greater than calculated resting energy e(penditure
(R''), depending on the type o! injury. It is seldom appropriate to e(ceed this le"el o!
nonprotein energy intake during the height o! the cataolic phase.
/ale #$= +aloric .djustments .o"e >asal 'nergy '(penditure (>'') in
Hypermetaolic +onditions
Condition #cal,#g
per day
Adjustment
Abo)e 0%%
Grams of
Protein,#g per
day
'onprotein
Calories1'itrogen
3ormalGmoderate
malnutrition
%BC&: #.# #.: #B:)#
Mild stress %BC&: #.% #.% #B:)#
Moderate stress &: #.< #.B #%:)#
Se"ere stress &:C&B #.9 %.: J:C#%:)#
>urns &BC<: %.: %.B J:C#::)#
/he second ojecti"e o! nutritional support is to meet the sustrate re8uirements !or
protein synthesis. .n appropriate nonprotein calorie)nitrogen ratio o! #B:)# (e.g., # g 3 7
9.%B g protein) should e maintained, which is the asal calorie re8uirement pro"ided to
pre"ent use o! protein as an energy source. /here is now greater e"idence suggesting that
increased protein intake, and a lower calorie)nitrogen ratio o! =:)# to #::)#, may ene!it
healing in selected hypermetaolic or critically ill patients. In the asence o! se"ere renal
or hepatic dys!unction precluding the use o! standard nutritional regimens, appro(imately
:.%B to :.&B g o! nitrogen per kilogram o! ody weight should e pro"ided daily.
-itamins and Minerals
/he re8uirements !or "itamins and essential trace minerals usually can e easily met in
the a"erage patient with an uncomplicated postoperati"e course. /here!ore "itamins are
usually not gi"en in the asence o! preoperati"e de!iciencies (/ale #$J). Patients
maintained on elemental diets or parenteral hyperalimentation re8uire complete "itamin
and mineral supplementation. +ommercial enteral diets contain "arying amounts o!
essential minerals and "itamins. It is necessary to ensure that ade8uate replacement is
a"ailale in the diet or y supplementation. 3umerous commercial "itamin preparations
are a"ailale !or intra"enous or intramuscular use, although most do not contain "itamin
6 and some do not contain "itamin >#% or !olic acid. Supplemental trace minerals may e
gi"en intra"enously y commercial preparations. 'ssential !atty acid supplementation
may also e necessary, especially in patients with depletion o! adipose stores.
/ale #$J +ommon Mani!estations o! -itamin and Mineral 5e!iciencies in .dults
Major Manifestations of /eficiencies
+itamins
-itamin . 3ight lindness, cornealGconjuncti"a drying
-itamin 5 Rickets, osteomalacia, one pain
-itamin ' +hronic cholestasis, spinocereellar ata(ia, hypore!le(ia
-itamin 6 Hemorrhagic disorders
/hiamin (>#)

5ry erieri (mental status changes, peripheral neuropathy), wet
erieri (heart !ailure)
Rio!la"in Seaceous gland in!lammation
3iacin 5ermatosis, pellagra
Pyrido(ine (>9)

Peripheral neuropathy
>iotin 5ry and scaling skin, glossitis
-itamin >#%

Pernicious anemia, neuropathy, myelopathy, glossitis
4olic acid Similar to >#% de!iciency

Pantothenic acid Headache, insomnia, paresthesias
-itamin + Scur"y (weakness, listlessness, musculoskeletal pain), peri!ollicular
hemorrhage
&ssential fatty
acids
Hair loss, dry skin, ec1ematoid dermatosis
Minerals
+alcium 5ementia, encephalopathy, tetany
Phosphorus Mental status changes, erythrocyte hemolysis, paresthesias
Potassium Respiratory !ailure, paralytic ileus, tetany, arrhythmias
Magnesium Hypocalcemia, hypokalemia, neuromuscular spasms, gut
malasorption
Iodine *oiter
Iron Microcytic anemia, !atigue, dyspnea
+opper Hypochromic anemia (unresponsi"e to iron), neutropenia,
osteoporosis
Tinc 5ermatosis, photophoia, night lindness, impaired wound healing,
alopecia, diarrhea
4luoride 3o acute clinical signs
Selenium +ardiomyopathy, myalgia, white nail eds
Major Manifestations of /eficiencies
+hromium *lucose intolerance
+oalt 3o acute clinical signs known
Molydenum Headache, night lindness, lethargy
Manganese Hair thinning, weight loss, dermatitis
2"er!eeding
2"er!eeding usually results !rom o"erestimation o! caloric needs, as occurs when actual
ody weight is used to calculate the >'' in such patient populations as the critically ill
with signi!icant !luid o"erload and the oese. Indirect calorimetry can e used to 8uanti!y
energy re8uirements, ut !re8uently o"erestimates >'' y #: to #BO in stressed patients,
particularly i! they are on a "entilator. In these instances, estimated dry weight should e
otained !rom preinjury records or !amily memers. .djusted lean ody weight also can
e calculated. +linically, increased o(ygen consumption, increased +2% production, !atty
li"er, suppression o! leukocyte !unction, and increased in!ectious risks ha"e all een
documented with o"er!eeding.
'nteral 3utrition
Rationale !or 'nteral 3utrition
'nteral nutrition generally is pre!erred o"er parenteral nutrition ased on reduced cost
and associated risks o! the intra"enous route. 0aoratory models ha"e long demonstrated
that luminal nutrient contact reduces intestinal mucosal atrophy when compared with
parenteral or no nutritional support. Studies comparing postoperati"e enteral and
parenteral nutrition in patients undergoing gastrointestinal surgery ha"e demonstrated
reduced in!ection complications and acute phase protein production when !ed y the
enteral route. Net, prospecti"ely randomi1ed studies !or patients with ade8uate nutritional
status (alumin < gGd0) undergoing gastrointestinal surgery demonstrate no di!!erences in
outcome and complications when administered enteral nutrition compared to
maintenance intra"enous !luids alone in the initial days !ollowing surgery. 4urthermore,
intestinal permeaility studies in well$nourished patients undergoing upper
gastrointestinal cancer surgery demonstrated normali1ation o! intestinal permeaility y
the !i!th postoperati"e day. .t the other e(treme, recent meta$analysis !or critically ill
patients demonstrates a <<O reduction in in!ectious complications in those recei"ing
enteral nutritional support o"er those recei"ing parenteral nutrition. Most prospecti"ely
randomi1ed studies !or se"ere adominal and thoracic trauma demonstrate signi!icant
reductions in in!ectious complications !or patients gi"en early enteral nutrition when
compared with those who are un!ed or recei"ing parenteral nutrition. /he e(ception has
een in studies !or patients with closed$head injury, ecause no signi!icant di!!erences in
outcome are demonstrated etween early jejunal !eeding compared with other nutritional
support modalities. Moreo"er, early gastric !eeding !ollowing closed$head injury was
!re8uently associated with under!eeding and calorie de!iciency due to di!!iculties
o"ercoming gastroparesis and the high risk o! aspiration.
/he early initiation o! enteral !eeding in urn patients, while sensile and supported y
retrospecti"e analysis, is an empiric practice supported y limited prospecti"e trials.
Recommendations !or instituting early enteral nutrition to surgical patients with moderate
malnutrition (alumin 7 %.J to &.B gGd0) can only e made y in!erences due to a lack o!
data directly pertaining to this population. 4or these patients, it is prudent to o!!er enteral
nutrition ased on measured energy e(penditure o! the reco"ering patient, or i!
complications arise that may alter the anticipated course o! reco"ery (e.g., anastomotic
leaks, return to surgery, sepsis, or !ailure to wean !rom the "entilator). 2ther clinical
scenarios with sustantiated ene!its !rom enteral nutritional support include permanent
neurologic impairment, oropharyngeal dys!unction, short owel syndrome, and one
marrow transplantation patients.
+ollecti"ely, the data support the use o! early enteral nutritional support !ollowing major
trauma and in patients who are anticipated to ha"e prolonged reco"ery a!ter surgery.
Healthy patients without malnutrition undergoing uncomplicated surgery can tolerate #:
days o! partial star"ation (i.e., maintenance intra"enous !luids only) e!ore any
signi!icant protein cataolism occurs. 'arlier inter"ention is likely indicated in patients
with poorer preoperati"e nutritional status.
Initiation o! enteral nutrition should occur immediately a!ter ade8uate resuscitation, most
readily determined y ade8uate urine output. Presence o! owel sounds and the passage
o! !latus or stool are not asolute re8uisites !or initiating enteral nutrition, ut !eedings in
the setting o! gastroparesis should e administered distal to the pylorus. *astric residuals
o! %:: m0 or more in a <$ to 9$hour period or adominal distention will re8uire cessation
o! !eeding and adjustment o! the in!usion rate. +oncomitant gastric decompression with
distal small owel !eedings may e appropriate in certain patients such as closed$head
injury patients with gastroparesis. /here is no e"idence to support withholding enteric
!eedings !or patients !ollowing owel resection, or in those with low$output
enterocutaneous !istulas o! less than B:: m0Gd, ut low$residue !ormulations may e
pre!erred. 'nteral !eeding should also e o!!ered to patients with short$owel syndrome
or clinical malasorption, ut caloric needs, essential minerals, and "itamins should e
supplemented with parenteral modalities.
'nteral 4ormulas
/he !unctional status o! the gastrointestinal tract determines the type o! enteral solutions
to e used. Patients with an intact gastrointestinal tract will tolerate comple( solutions,
ut patients who ha"e not een !ed "ia the gastrointestinal tract !or prolonged periods are
less likely to tolerate comple( carohydrates such as lactose. In patients with
malasorption such as in in!lammatory owel diseases, asorption may e impro"ed y
pro"ision o! dipeptides, tripeptides, and medium$chain triglycerides (M+/s). Howe"er,
M+/s are de!icient in essential !atty acids, which necessitates supplementation with some
long$chain triglycerides (0+/).
In general, !actors that in!luence the choice o! enteral !ormula include the e(tent o! organ
dys!unction (e.g., renal, pulmonary, hepatic, or gastrointestinal), the nutrient needs to
restore optimal !unction and healing, and the cost o! speci!ic products. /here are still no
conclusi"e data to recommend one category o! product o"er another, and nutritional
support committees typically de"elop the most cost$e!!icient set o! enteral !ormulary !or
the most commonly encountered disease categories within the institution.
"o!Residue Isotonic Formulas2 Most pro"ide a caloric density o! #.: kcalGm0, and
appro(imately #B:: to #=:: m0 are re8uired to meet daily re8uirements. /hese low$
osmolarity compositions pro"ide aseline carohydrates, protein, electrolytes, water, !at,
and !at$solule "itamins (some do not ha"e "itamin 6) and typically ha"e a nonprotein$
calorie)nitrogen ratio o! #B:)#. /hese contain no !ier ulk and there!ore lea"e minimum
residue. /hese solutions are usually considered to e the standard or !irst$line !ormulas
!or stale patients with an intact gastrointestinal tract.
Isotonic Formulas ith Fiber2 /hese !ormulas contain solule and insolule !ier which
are most o!ten soy ased. Physiologically, !ier$ased solutions delay intestinal transit
time and may reduce the incidence o! diarrhea compared with non!ier solutions. 4ier
stimulates pancreatic lipase acti"ity and are degraded y gut acteria into short$chain
!atty acids, an important !uel !or colonocytes. /here are no contraindications !or using
!ier$containing !ormulas in critically ill patients.
Immune!%nhancing Formulas2 /hese !ormulas are !orti!ied with special nutrients that
are purported to enhance "arious aspects o! immune or solid organ !unction. Such
additi"es include glutamine, arginine, ranched$chain amino acids, omega$& !atty acids,
nucleotides, and eta$carotene. ,hile se"eral trials ha"e proposed that one or more o!
these additi"es reduce surgical complications and impro"e outcome, these results ha"e
not een uni!ormly corroorated y other trials. /he addition o! amino acids to these
!ormulas generally doules the amount o! protein (nitrogen) !ound in standard !ormula@
howe"er, their use can e cost$prohiiti"e.
Calorie!/ense Formulas2 /he primary distinction o! these !ormulas is a greater caloric
"alue !or the same "olume. Most commercial products o! this "ariety pro"ide #.B to %
kcalGm0, and there!ore are suitale !or patients re8uiring !luid restriction or those unale
to tolerate large "olume in!usions. .s e(pected, these solutions ha"e higher osmolality
than standard !ormulas and are suitale !or intragastric !eedings.
High!Protein Formulas2 High$protein !ormulas are a"ailale in isotonic and nonisotonic
mi(tures and are proposed !or critically ill or trauma patients with high protein
re8uirements. /hese !ormulas comprise nonprotein calorie)nitrogen ratios etween =: and
#%:)#.
%lemental Formulas2 /hese !ormulas contain predigested nutrients and pro"ide proteins
in the !orm o! small peptides. +omple( carohydrates are limited, and !at content, in the
!orm o! M+/s and 0+/s, is minimal. /he primary ad"antage o! such a !ormula is ease o!
asorption, ut the inherent scarcity o! !at, associated "itamins, and trace elements limits
its long$term use as a primary source o! nutrients. 5ue to its high osmolarity, dilution or
slow in!usion rates are usually necessary, particularly in critically ill patients. /hese
!ormulas ha"e een used !re8uently in patients with malasorption, gut impairment, and
pancreatitis, ut their cost is signi!icantly higher than that o! standard !ormulas.
Renal!Failure Formulas2 /he primary ene!its o! the renal !ormula are the lower !luid
"olume and concentrations o! potassium, phosphorus, and magnesium needed to meet
daily calorie re8uirements. /his !ormulation almost e(clusi"ely contains essential amino
acids and has a high nonprotein)calorie ratio@ howe"er, it does not contain trace elements
or "itamins.
Pulmonary!Failure Formulas2 In these !ormulas, !at content is usually increased to B:O
o! the total calories, with a corresponding reduction in carohydrate content. /he goal is
to reduce +2% production and alle"iate "entilation urden !or !ailing lungs.
Hepatic!Failure Formulas2 +lose to B:O o! the proteins in this !ormula are ranched$
chain amino acids (e.g., leucine, isoleucine, and "aline). /he goal o! such a !ormula is to
reduce aromatic amino acid le"els and increase ranched$chain amino acids, which can
potentially re"erse encephalopathy in patients with hepatic !ailure. Howe"er, the use o!
this !ormula is contro"ersial ecause no clear ene!its ha"e een pro"en y clinical trials.
Protein restriction should e a"oided in patients with end$stage li"er disease, ecause
they ha"e signi!icant protein energy malnutrition, predisposing them to additional
moridity and mortality.
.ccess !or 'nteral 3utritional Support
/he a"ailale techni8ues and repertoire !or enteral access ha"e pro"ided multiple options
!or !eeding the gut. Presently utili1ed methods and pre!erred indications are summari1ed
in /ale #$#:.
/ale #$#: 2ptions !or 'nteral 4eeding .ccess
Access *ption Comments
3asogastric tue Short$term use only@ aspiration risks@ nasopharyngeal
trauma@ !re8uent dislodgment
3asoduodenalGnasojejunal Short$term use@ lower aspiration risks in jejunum@
placement challenges (radiographic assistance o!ten
necessary)
Percutaneous endoscopic
gastrostomy (P'*)
'ndoscopy skills re8uired@ may e used !or gastric
decompression or olus !eeds@ aspiration risks@ can last
Access *ption Comments
#%C%< months@ slightly higher complication rates with
placement and site leaks
Surgical gastrostomy Re8uires general anesthesia and small laparotomy@ may
allow placement o! e(tended duodenalGjejunal !eeding
ports@ laparoscopic placement possile
4luoroscopic gastrostomy >lind placement using needle and /$prongs to anchor to
stomach@ can thread smaller catheter through
gastrostomy into duodenumGjejunum under !luoroscopy
P'*$jejunal tue Hejunal placement with regular endoscope is operator
dependent@ jejunal tue o!ten dislodges retrograde@ two$
stage procedure with P'* placement, !ollowed y
!luoroscopic con"ersion with jejunal !eeding tue
through P'*
5irect percutaneous
endoscopic jejunostomy
(5P'H)
5irect endoscopic placement with enteroscope@
placement challenges@ greater injury risks
Surgical jejunostomy +ommonly applied during laparotomy@ general
anesthesia@ laparoscopic placement usually re8uires
assistant to thread catheter@ laparoscopy o!!ers direct
"isuali1ation o! catheter placement
4luoroscopic jejunostomy 5i!!icult approach with injury risks@ not commonly
done
'asoenteric .ubes2 3asogastric !eeding should e reser"ed !or those with intact mental
status and protecti"e laryngeal re!le(es to minimi1e risks o! aspiration. '"en in intuated
patients, nasogastric !eedings can o!ten e reco"ered !rom tracheal suction. 3asojejunal
!eedings are associated with !ewer pulmonary complications, ut access past the pylorus
re8uires greater e!!ort to accomplish. >lind insertion o! nasogastric !eeding tues is
!raught with misplacement, and air instillation with auscultation is inaccurate !or
ascertaining proper positioning. Radiographic con!irmation is usually re8uired to "eri!y
the position o! the nasogastric !eeding tue.
Se"eral methods ha"e een recommended !or the passage o! nasoenteric !eeding tues
into the small owel, including prokinetic agents, right lateral decuitus positioning,
gastric insu!!lation, tue angulation, and clockwise tor8ue. Howe"er, the success!ul
placement o! !eeding tues y these methods is highly "ariale and operator dependent.
4urthermore, it is time$consuming, and success rates !or intuation past the duodenum
into the jejunum y these methods are less than %:O. 4luoroscopy$guided intuation past
the pylorus has a greater than J:O success rate, and more than hal! o! these intuations
result in jejunal placement. Similarly, endoscopy$guided placement past the pylorus has
high success rates, ut ad"ancing the tue eyond the second portion o! the duodenum
using a standard gastroduodenoscope is unlikely to e success!ul.
Small owel !eeding is more reliale !or deli"ering nutrition than nasogastric !eeding.
4urthermore, the risks o! aspiration pneumonia can e reduced y %BO with small owel
!eeding when compared with nasogastric !eeding. /he disad"antages o! nasoenteric
!eeding tues are clogging, kinking, inad"ertent displacement or remo"al, and
nasopharyngeal complications. I! nasoenteric !eeding will e re8uired !or longer than &:
days, access should e con"erted to a percutaneous one.
Percutaneous %ndoscopic Gastrostomy2 /he most common indications !or
percutaneous endoscopic gastrostomy (P'*) placement include impaired swallowing
mechanisms, oropharyngeal or esophageal ostruction, and major !acial trauma. It is
!re8uently utili1ed !or deilitated patients re8uiring caloric supplementation, hydration,
or !re8uent medication dosing. It is also appropriate !or patients re8uiring passi"e gastric
decompression. Relati"e contraindications !or P'* placement include ascites,
coagulopathy, gastric "arices, gastric neoplasm, and lack o! a suitale adominal site.
Most tues are #=4 to %=4 in si1e and may e used !or #% to %< months.
Identi!ication o! the P'* site re8uires endoscopic transillumination o! the anterior
stomach against the adominal wall. . #<$gauge angiocatheter is passed through the
adominal wall into the !ully insu!!lated stomach. . guidewire is threaded through the
angiocatheter, grasped y snares or !orceps, and pulled out through the mouth. /he
tapered end o! the P'* tue is secured to the guidewire and is pulled into position out o!
the adominal wall. 2nce the P'* tue is secured without tension against the adominal
wall, many ha"e reported using the tue within hours o! placement. It has een the
practice o! some to connect the P'* tue to a drainage ag !or passi"e decompression !or
%< hours prior to use, allowing more time !or the stomach to seal against the peritoneum.
I! endoscopy is not a"ailale or technical ostacles preclude P'* placement, the
inter"entional radiologist can attempt the procedure percutaneously under !luoroscopic
guidance y !irst insu!!lating the stomach against the adominal wall with a nasogastric
tue. I! this is also unsuccess!ul, surgical gastrostomy tue placement can e considered,
particularly with minimally in"asi"e methods. ,hen surgery is consulted, it may e wise
to consider directly accessing the small owel !or nutrition deli"ery.
,hile P'* tues enhance nutritional deli"ery, !acilitate nursing care, and are superior to
nasogastric tues, serious complications can occur in appro(imately &O o! patients.
/hese complications include wound in!ection, necroti1ing !asciitis, peritonitis, aspiration,
leaks, dislodgment, owel per!oration, enteric !istulas, leeding, and aspiration
pneumonia. 4or patients with signi!icant gastroparesis or gastric outlet ostruction,
!eedings through P'* tues are ha1ardous. In this instance, the P'* tue can e used !or
decompression and to allow access !or con"erting the P'* tue to a transpyloric !eeding
tue.
Percutaneous %ndoscopic Gastrostomy!3ejunostomy and /irect Percutaneous
%ndoscopic 3ejunostomy2 ,hile gastric olus !eedings are more physiologic, patients
who cannot tolerate gastric !eedings or ha"e signi!icant aspiration risks should e !ed
directly past the pylorus. /he percutaneous endoscopic gastrostomy$jejunostomy (P'*$H)
method passes a J4 to #%4 tue through an e(isting P'* tue, past the pylorus, and into
the duodenum. /his can e achie"ed y endoscopic or !luoroscopic guidance. ,ith
weighted catheter tips and guidewires, the tue can e !urther ad"anced past the ligament
o! /reit1. Howe"er, long$term P'*$H mal!unction has een reported to e greater than
B:O as a result o! retrograde tue migration into the stomach, kinking, or clogging.
5irect percutaneous endoscopic jejunostomy (5P'H) placement uses the same techni8ues
as P'* tue placement, ut re8uires an enteroscope or colonoscope to reach the jejunum.
5P'H mal!unctions are proaly less !re8uent than with P'*$H, and kinking or clogging
is usually a"erted y placement o! larger calier catheters. /he success rate o! 5P'H
placement is "ariale ecause o! the comple(ity o! endoscopic skills re8uired to locate a
suitale jejunal site. In such cases, surgical jejunostomy tue placement is more
appropriate, especially when minimally in"asi"e techni8ues are a"ailale.
Surgical Gastrostomy and 3ejunostomy2 In a patient undergoing comple( adominal or
trauma surgery, thought should e gi"en during surgery to the possile routes !or
suse8uent nutritional support, ecause laparotomy a!!ords direct access to the stomach
or small owel. /he only asolute contraindication to !eeding jejunostomy is distal
intestinal ostruction. Relati"e contraindications include se"ere edema o! the intestinal
wall, radiation enteritis, in!lammatory owel disease, ascites, se"ere immunode!iciency,
and owel ischemia. 3eedle$catheter jejunostomies can also e done with a minimal
learning cur"e. /he iggest drawack is usually related to clogging and knotting o! the 94
catheter.
.dominal distention and cramps are common ad"erse e!!ects o! early enteral nutrition.
Some ha"e also reported impaired respiratory mechanics as a result o! intolerance to
enteral !eedings. /hese are mostly correctale y temporarily discontinuing !eeds and
resuming at a lower in!usion rate.
Pneumatosis intestinalis and small owel necrosis are in!re8uent ut signi!icant prolems
associated with patients recei"ing jejunal tue !eedings. Se"eral contriuting !actors ha"e
een proposed, including the hyperosmolar consistency o! enteral solutions, acterial
o"ergrowth, !ermentation, and metaolic reakdown products. /he common
pathophysiology is elie"ed to e owel distention and conse8uent reduction in owel
wall per!usion. Risk !actors !or these complications include cardiogenic and circulatory
shock, "asopressor use, diaetes mellitus, and chronic ostructi"e pulmonary disease.
/here!ore, enteral !eedings in the critically ill patient should e delayed until ade8uate
resuscitation has een achie"ed. .lternati"ely, dilution o! standard enteral !ormula,
delaying the progression to goal in!usion rates, or using monomeric solutions with low
osmolality re8uiring less digestion y the gastrointestinal tract ha"e all een success!ully
employed.
Parenteral 3utrition
Parenteral nutrition in"ol"es the continuous in!usion o! a hyperosmolar solution
containing carohydrates, proteins, !at, and other necessary nutrients through an
indwelling catheter inserted into the superior "ena ca"a. In order to otain the ma(imum
ene!it, the ratio o! calories to nitrogen must e ade8uate (at least #:: to #B: kcalGg
nitrogen), and oth carohydrates and proteins must e in!used simultaneously. ,hen the
sources o! calories and nitrogen are gi"en at di!!erent times, there is a signi!icant decrease
in nitrogen utili1ation. /hese nutrients can e gi"en in 8uantities consideraly greater
than the asic caloric and nitrogen re8uirements, and this method has pro"ed to e highly
success!ul in achie"ing growth and de"elopment, positi"e nitrogen alance, and weight
gain in a "ariety o! clinical situations. +linical trials and meta$analysis o! parenteral
!eeding in the perioperati"e period ha"e suggested that preoperati"e nutritional support
may ene!it some surgical patients, particularly those with e(tensi"e malnutrition. Short$
term use o! parenteral nutrition in critically ill patients (i.e., duration AD days) when
enteral nutrition may ha"e een instituted is associated with higher rates o! in!ectious
complications. 4ollowing se"ere injury, parenteral nutrition is associated with higher
rates o! in!ectious risks when compared with enteral !eeding (/ale #$##). +linical
studies ha"e demonstrated that parenteral !eeding with complete owel rest results in
augmented stress hormone and in!lammatory mediator response to an antigenic challenge
(4ig. #$&#). Howe"er, parenteral !eeding still has !ewer in!ectious complications
compared with no !eeding at all. In cancer patients, parenteral nutrition has not een
shown to ene!it clinical response, sur"i"al, or to(ic e!!ects o! chemotherapy, while
in!ectious complications increased.
/ale #$## Incidence o! Septic Moridity in Parenterally and 'nterally 4ed /rauma
Patients
0lunt .rauma Penetrating
.rauma
.otal
.%' .P' .%' .P' .%' .P'
Complication n 4 56 n 4 55 n 4 76 n 4 56 n 4 55 n 4 65
.dominal .scess % # % 9 < D
Pneumonia < #: # % B #%
,ound In!ection : % & # & &
>acteremia # < : # # B
?rinary /ract # # : # # %
2ther B < # # 9 B
.otal Complications 87 99 : 89 9; 75
< Complications per patient
group
9:< =;< 86< 7;< 97< 7><
S2?R+') .dapted with permission !rom 6at1 H., 0owry S4) Sustrate utili1ation and
hypermetaolism, in >one R+ (ed)) )epsis and Multiorgan Failure0 Philadelphia)
,illiams ; ,ilkins, #JJD, p &#B.
4I*. #$&#.
/he appearance o! circulating epinephrine, glucagons, and tumor necrosis !actor (/34)
a!ter a olus injection o! endoto(in in sujects who recei"ed D days o! parenteral
nutrition and complete owel rest (closed circles), as compared to sujects who recei"ed
enteral !eedings (open circles). Sujects recei"ing intra"enous !eedings and owel rest
had signi!icantly e(aggerated response to injury. ($dapted %ith permission from Fong G'
Marano M$' Barber $' et al* Total parenteral nutrition and bo%el rest modify the
metabolic response to endoto;in in humans0 $nn )urg 618*>>2' 12=20)
Rationale !or Parenteral 3utrition
/he principal indications !or parenteral nutrition are !ound in seriously ill patients
su!!ering !rom malnutrition, sepsis, or surgical or accidental trauma, when use o! the
gastrointestinal tract !or !eedings is not possile. In some instances, intra"enous nutrition
may e used to supplement inade8uate oral intake. /he sa!e and success!ul use o!
parenteral nutrition re8uires proper selection o! patients with speci!ic nutritional needs,
e(perience with the techni8ue, and an awareness o! the associated complications. .s with
enteral nutrition, the !undamental goals are to pro"ide su!!icient calories and nitrogen
sustrate to promote tissue repair and to maintain the integrity or growth o! lean tissue
mass. 0isted elow are situations in which parenteral nutrition has een used in an e!!ort
to achie"e these goals)
#.
3eworn in!ants with catastrophic gastrointestinal anomalies, such as
tracheoesophageal !istula, gastroschisis, omphalocele, or massi"e intestinal atresia.
%.
In!ants who !ail to thri"e due to gastrointestinal insu!!iciency associated with short
owel syndrome, malasorption, en1yme de!iciency, meconium ileus, or idiopathic
diarrhea.
&.
.dult patients with short owel syndrome secondary to massi"e small owel
resection (A#:: cm without colon or ileocecal "al"e, or AB: cm with intact ileocecal
"al"e and colon).
<.
'nteroenteric, enterocolic, entero"esical, or high$output enterocutaneous !istulas
(PB:: m0Gd).
B.
Surgical patients with prolonged paralytic ileus !ollowing major operations (PD to #:
days), multiple injuries, lunt or open adominal trauma, or patients with re!le(
ileus complicating "arious medical diseases.
9.
Patients with normal owel length ut with malasorption secondary to sprue,
hypoproteinemia, en1yme or pancreatic insu!!iciency, regional enteritis, or ulcerati"e
colitis.
D.
.dult patients with !unctional gastrointestinal disorders such as esophageal
dyskinesia !ollowing cerero"ascular accident, idiopathic diarrhea, psychogenic
"omiting, or anore(ia ner"osa.
=.
Patients with granulomatous colitis, ulcerati"e colitis, and tuerculous enteritis, in
which major portions o! the asorpti"e mucosa are diseased.
J.
Patients with malignancy, with or without cache(ia, in whom malnutrition might
jeopardi1e success!ul deli"ery o! a therapeutic option.
#:.
4ailed attempts to pro"ide ade8uate calories y enteral tue !eedings or high
residuals.
##.
+ritically ill patients who are hypermetaolic !or more than B days or when enteral
nutrition is not !easile.
+onditions contraindicating hyperalimentation include the !ollowing)
#.
0ack o! a speci!ic goal !or patient management, or in cases in which instead o!
e(tending a meaning!ul li!e, ine"itale dying is delayed.
%.
Periods o! hemodynamic instaility or se"ere metaolic derangement (e.g., se"ere
hyperglycemia, a1otemia, encephalopathy, hyperosmolality, and !luid$electrolyte
disturances) re8uiring control or correction e!ore attempting hypertonic
intra"enous !eeding.
&.
4easile gastrointestinal tract !eeding@ in the "ast majority o! instances, this is the
est route y which to pro"ide nutrition.
<.
Patients with good nutritional status.
B.
In!ants with less than = cm o! small owel, since "irtually all ha"e een unale to
adapt su!!iciently despite prolonged periods o! parenteral nutrition.
9.
Patients who are irre"ersily decererate or otherwise dehumani1ed.
/otal Parenteral 3utrition
/otal parenteral nutrition (/P3), also re!erred to as central parenteral nutrition, re8uires
access to a large$diameter "ein to deli"er the entire nutritional re8uirements o! the
indi"idual. 5e(trose content is high (#B to %BO) and all other macro$ and micronutrients
are deli"erale y this route.
Peripheral Parenteral 3utrition
/he lower osmolarity o! the solution used !or peripheral parenteral nutrition (PP3),
secondary to reduced de(trose (B to #:O) and protein (&O) le"els, allows !or its
administration "ia peripheral "eins. Some nutrients cannot e supplemented due to
inaility to concentrate them into small "olumes. /here!ore PP3 is not appropriate !or
repleting patients with se"ere malnutrition. It can e considered i! central routes are not
a"ailale or i! supplemental nutritional support is re8uired. /ypically, PP3 is used !or
short periods (A% weeks). >eyond this time, /P3 should e instituted.
Initiating Parenteral 3utrition
/he asic solution contains a !inal concentration o! #B to %BO de(trose and & to BO
crystalline amino acids. /he solutions are usually prepared in sterile conditions in the
pharmacy !rom commercially a"ailale kits containing the component solutions and
trans!er apparatus. Preparation in the pharmacy under laminar !low hoods reduces the
incidence o! acterial contamination o! the solution. Proper preparation with suitale
8uality control is asolutely essential to a"oid septic complications.
/he proper pro"ision o! electrolytes and amino acids is dependent on routes o! !luid and
electrolyte loss, renal !unction, metaolic rate, cardiac !unction, and the underlying
disease state.
Intra"enous "itamin preparations should also e added to parenteral !ormulas. -itamin
de!iciencies are rare occurrences i! such preparations are utili1ed. In addition, ecause
"itamin 6 is not part o! any commercially prepared "itamin solution, it should e
supplemented on a weekly asis. 5uring prolonged !at$!ree parenteral nutrition, essential
!atty acid de!iciency may ecome clinically apparent and mani!ests as dry, scaly
dermatitis and loss o! hair. /he syndrome may e pre"ented y periodic in!usion o! a !at
emulsion at a rate e8ui"alent to #: to #BO o! total calories. 'ssential trace minerals may
e re8uired a!ter prolonged total parenteral nutrition, and may e supplied y direct
addition o! commercial preparations. /he most !re8uent presentation o! trace mineral
de!iciencies is the ec1ematoid rash de"eloping oth di!!usely and at intertriginous areas
in 1inc$de!icient patients. 2ther rare trace mineral de!iciencies include a microcytic
anemia associated with copper de!iciency, and glucose intolerance presumaly related to
chromium de!iciency. /he latter complications are seldom seen e(cept in patients
recei"ing parenteral nutrition !or e(tended periods o! time. /he daily administration o!
commercially a"ailale trace mineral supplements will o"iate most such prolems.
5epending on !luid and nitrogen tolerance, parenteral nutrition solutions can generally e
increased o"er % to & days to achie"e the desired in!usion rate. Insulin may e
supplemented as necessary to ensure glucose tolerance. .dditional intra"enous !luids and
electrolytes may occasionally e necessary with persistently high !luid losses. /he patient
should e care!ully monitored !or de"elopment o! electrolyte, "olume, acid$ase, and
septic complications. -ital signs and urinary output are regularly oser"ed, and the
patient should e weighed regularly. 4re8uent adjustments o! the "olume and
composition o! the solutions are necessary during the course o! therapy. 'lectrolytes are
drawn daily until stale and e"ery % or & days therea!ter. >lood counts, lood urea
nitrogen, li"er !unctions, and phosphate and magnesium le"els are determined at least
weekly.
/he urine or capillary lood sugar le"el is checked e"ery 9 hours and serum sugar
concentration checked at least once daily during the !irst !ew days o! the in!usion and at
!re8uent inter"als therea!ter. Relati"e glucose intolerance that o!ten mani!ests as
glycosuria may occur !ollowing initiation o! parenteral nutrition. I! lood sugar le"els
remain ele"ated or glycosuria persists, the de(trose concentration may e decreased, the
in!usion rate slowed, or regular insulin added to each ottle. /he rise in lood glucose
concentration oser"ed a!ter initiating parenteral nutrition may e temporary, as the
normal pancreas increases its output o! insulin in response to the continuous carohydrate
in!usion. In patients with diaetes mellitus, additional insulin may e re8uired.
Potassium is essential to achie"e positi"e nitrogen alance and replace depleted
intracellular stores. In addition, a signi!icant shi!t o! potassium ion !rom the e(tracellular
to the intracellular space may take place ecause o! the large glucose in!usion, with
resultant hypokalemia, metaolic alkalosis, and poor glucose utili1ation. In some cases as
much as %<: m'8 o! potassium ion daily may e re8uired. Hypokalemia may cause
glycosuria, which would e treated with potassium, not insulin. /hus, e!ore gi"ing
insulin, the serum potassium le"el must e checked to a"oid e(acerating the
hypokalemia.
Patients with insulin$dependent diaetes mellitus may e(hiit wide !luctuations in lood
glucose during parenteral nutrition. Partial replacement with lipid emulsions !or de(trose
calories may alle"iate these prolems in selected patients.
0ipid emulsions deri"ed !rom soyean or sa!!lower oils are widely used as an adjuncti"e
nutrient to pre"ent the de"elopment o! essential !atty acid de!iciency. /here is no
e"idence o! enhanced metaolic ene!it when greater than #: to #BO o! calories are
pro"ided as lipid emulsions. ,hile the administration o! B:: m0 o! %:O !at emulsion one
to three times a week is su!!icient to pre"ent essential !atty acid de!iciency, it is common
to pro"ide !at emulsions on a daily asis to pro"ide additional calories. /he triple mi( o!
carohydrate, !at, and amino acids is in!used at a constant rate during a %<$hour period.
/he theoretical ad"antages o! a constant !at in!usion rate include increased e!!iciency o!
lipid utili1ation and reduced impairment o! reticuloendothelial !unction normally
identi!ied with olus lipid in!usions. /he addition o! lipids to an in!usion ag may alter
the staility o! some micronutrients in a de(trose$amino acid preparation.
Intra"enous .ccess Methods
/emporary or short$term access can e achie"ed with a #9$gauge, percutaneous catheter
inserted into a sucla"ian or internal jugular "ein and threaded into the superior "ena
ca"a. More permanent access, with the intention o! pro"iding long$term or home
parenteral nutrition, can e achie"ed y placement o! a catheter with a sucutaneous port
!or access, y tunneling a catheter with a sustantial sucutaneous length, or threading a
long catheter through the asilic or cephalic "ein into the superior "ena ca"a.
+omplications o! Parenteral 3utrition
/echnical +omplications
2ne o! the more common and serious complications associated with long$term parenteral
!eeding is sepsis secondary to contamination o! the central "enous catheter.
+ontamination o! solutions should e considered, ut is rare when proper pharmacy
protocols ha"e een !ollowed. /his prolem occurs more !re8uently in patients with
systemic sepsis, and in many cases is due to hematogenous seeding o! the catheter with
acteria. 2ne o! the earliest signs o! systemic sepsis may e the sudden de"elopment o!
glucose intolerance (with or without temperature increase) in a patient who pre"iously
has een maintained on parenteral alimentation without di!!iculty. ,hen this occurs or i!
high !e"er (P&=.BU+) de"elops without o"ious cause, a diligent search !or a potential
septic !ocus is indicated. 2ther causes o! !e"er should also e in"estigated. I! !e"er
persists, the in!usion catheter should e remo"ed and cultured. I! the catheter is the cause
o! !e"er, remo"al o! the in!ectious source is usually !ollowed y rapid de!er"escence.
Some centers are now replacing catheters considered at low risk !or in!ection o"er a
guidewire. Should e"idence o! in!ection persist o"er %< to <= hours without a de!inale
source, the catheter should e replaced in the opposite sucla"ian "ein or into one o! the
internal jugular "eins and the in!usion restarted. It is prudent to delay reinserting the
catheter y #% to %< hours, especially i! acteremia is present.
2ther complications related to catheter placement include the de"elopment o!
pneumothora(, hemothora(, hydrothora(, sucla"ian artery injury, thoracic duct injury,
cardiac arrhythmia, air emolism, catheter emolism, and cardiac per!oration with
tamponade. .ll o! these complications may e a"oided y strict adherence to proper
techni8ues.
/he use o! multilumen catheters may e associated with a slightly increased risk o!
in!ection. /his is most likely associated with greater catheter manipulation and intensi"e
use. +atheter in!ections are highest when placed in the !emoral "ein, lower with jugular
"ein, and lowest !or the sucla"ian "ein. ,hen catheters are indwelling !or less than &
days, in!ection risks are negligile. I! indwelling time is & to D days, the in!ection risk is &
to BO. *reater than D days indwelling time is associated with a catheter in!ection risk o!
B to #:O.
Metaolic +omplications
Hyperglycemia may de"elop with normal rates o! in!usion in patients with impaired
glucose tolerance or in any patient i! the hypertonic solutions are administered too
rapidly. /his is a particularly common complication in latent diaetics and in patients
sujected to se"ere surgical stress or trauma. /reatment o! the condition consists o!
"olume replacement with correction o! electrolyte anormalities and the administration o!
insulin. /his complication can e a"oided with care!ul attention to daily !luid alance and
!re8uent monitoring o! lood sugar le"els and serum electrolytes.
Increasing e(perience has emphasi1ed the importance o! not o"er!eeding the parenterally
nourished patient. /his is particularly true o! the depleted patient in whom e(cess calorie
in!usion may result in caron dio(ide retention and respiratory insu!!iciency. In addition,
e(cess !eeding also has een related to the de"elopment o! hepatic steatosis or marked
glycogen deposition in selected patients. +holestasis and !ormation o! gallstones are
common in patients recei"ing long$term parenteral nutrition. Mild ut transient
anormalities o! serum transaminase, alkaline phosphatase, and iliruin may occur in
many parenterally nourished patients. 4ailure o! the li"er en1ymes to plateau or return to
normal o"er D to #< days should suggest another etiology.
Intestinal .trophy
0ack o! intestinal stimulation is associated with intestinal mucosal atrophy, diminished
"illous height, acterial o"ergrowth, reduced lymphoid tissue si1e, reduced Ig.
production, and impaired gut immunity. /he !ull clinical implications o! these changes
are not well reali1ed, although acterial translocation has een demonstrated in animal
models. /he most e!!icacious method to pre"ent these changes is to pro"ide nutrients
enterally. In patients re8uiring total parenteral nutrition, it may e !easile to in!use small
amounts o! trophic !eedings "ia the gastrointestinal tract.
Special 4ormulations
*lutamine and .rginine
*lutamine is the most aundant amino acid in the human ody, comprising nearly two
thirds o! the !ree intracellular amino acid pool. 2! this, DBO is !ound within the skeletal
muscles. In healthy indi"iduals, glutamine is considered a nonessential amino acid
ecause it is synthesi1ed within the skeletal muscles and the lungs. *lutamine is a
necessary sustrate !or nucleotide synthesis in most di"iding cells, and hence pro"ides a
major !uel source !or enterocytes. It also ser"es as an important !uel source !or
immunocytes such as lymphocytes and macrophages, as well as a precursor !or
glutathione, a major intracellular antio(idant. 5uring stress states such as sepsis, or in
tumor$earing hosts, peripheral glutamine stores are rapidly depleted and the amino acid
is pre!erentially shunted as a !uel source toward the "isceral organs and tumors,
respecti"ely. /hese situations create, at least e(perimentally, a glutamine$depleted
en"ironment, with conse8uences including enterocyte and immunocyte star"ation.
/he ene!icial e!!ects o! glutamine supplementation demonstrated e(perimentally are
multi!aceted (/ale #$#%). Howe"er, glutamine metaolism during stress in humans may
e more comple( than in pre"iously reported animal data. More ad"anced methods o!
detecting glutamine tra!!ic in patients with gastrointestinal cancer ha"e not demonstrated
more tumor se8uestration o! glutamine than normal intestine. /here are data
demonstrating decreased dependency on /P3 in se"ere cases o! short owel syndrome
when glutamine therapy with modi!ied diets and growth hormones are used. Howe"er, in
patients with milder !orms o! short owel syndrome and etter nutritional status,
glutamine supplementation did not demonstrate appreciale enhancement in intestinal
asorption. In healthy sujects, glutamine$supplemented /P3 did not attenuate
endoto(in$induced symptoms or proin!lammatory cytokine release compared to standard
/P3. .lthough it is hypothesi1ed that pro"ision o! glutamine may preser"e immune cell
and enterocyte !unction and enhance nitrogen alance during injury or sepsis, the clinical
e"idence in support o! these phenomena in human sujects remains inconclusi"e.
/ale #$#% '(perimental >ene!its o! *lutamine and .rginine Supplementation
Glutamine
'nhances owel asorpti"e capacity a!ter intestinal resection
5ecreases intestinal permeaility
'arly resolution o! e(perimental pancreatitis
Maintains nitrogen alance
Promotes li"er regeneration a!ter hepatectomy
Restores mucosal immunogloulin . !unction
'nhances acterial clearance in peritonitis
Protects postradiation enterocyte "iaility
Restores intracellular glutathione le"els
4acilitates tumor sensiti"ity to chemotherapy and radiation therapy
'nhances natural killer and lymphokine$acti"ated killer cell !unction
Arginine
Minimi1es hepatic ischemiaGreper!usion injury
Reduces intestinal acterial translocation
'nhances natural killer and lymphokine$acti"ated killer cell !unction
Increases nitrogen retention and protein synthesis
.rginine, also a nonessential amino acid in healthy sujects, !irst attracted attention !or
its immunoenhancing properties, wound$healing ene!its, and impro"ed sur"i"al in
animal models o! sepsis and injury. .s with glutamine, the ene!its o! e(perimental
arginine supplementation during stress states are di"erse. +linical studies in which
arginine was administered enterally ha"e demonstrated net nitrogen retention and protein
synthesis compared to isonitrogenous diets in critically ill and injured patients and
!ollowing surgery !or certain malignancies. Some o! these studies also are associated with
in "itro e"idence o! enhanced immunocyte !unction. /he clinical utility o! arginine in
impro"ing o"erall patient outcome remains an area o! in"estigation.
2mega$& 4atty .cids
/he pro"ision o! omega$& polyunsaturated !atty acids (canola oil or !ish oil) displaces
omega$9 !atty acids in cell memranes, which theoretically reduce the proin!lammatory
response !rom prostaglandin production.
3ucleotides
R3. supplementation in solutions is purported, at least e(perimentally, to increase cell
proli!eration, pro"ide uilding locks !or 53. synthesis, and impro"e /$helper cell
!unction.