cal Patient
Metabolic and Inflammatory Responses to
Trauma and Infection
Naji N. Aburnrad, !gal Breitman, Julia Wattacheril, William J. Hubbard, and Irshad H. Chaudry
INTRODUCTION
Surgery has its roots in providing care for
those patients coping with injury or infec-
tion. In the last decade, an enormous amount
of data has been published, which describes
the wide spectrum of illnesses that can re-
sult following trauma or infection-from a
minor, local reaction to surgery. to a sys-
temic stress response, to sepsis, to systemic
inflammatory response syndrome (SIRS),
and finally, to multi-organ failure (MOF).
This information has provided the basis for
many new concepts and techniques, which
are now used daily in modem surgery. Having
a thorough understanding of the mecha-
nisms leading to illness following trauma and
infection is crucial for any practicing surgeon.
This understanding is the very halbruuk of
transferring knowledge gained in research to
innovative surgical care at the bedside.
OVERVIEW
Following extensive tissue damage or sys-
temic insult, such as infection, hypoperfu-
sion, hypothermia, acid-base disturbance,
pain or severe emotional stress, various
physiologic and biochemical local and sys-
temic alternations can be present and are
referred to as "the stress response·. The sys-
temic alternations are mediated by a com-
plex signaling system, including afferent
and efferent nervous signals, immunologi-
cal and hormonal adaptations, and a sys-
temic washout of locally produced sub-
stances like cytokines and other mediators.
The first reference to the stress response re-
sulted from keen observations by Sir David
Cuthbertson in the 1930s who described a
biphasic immune, inflammatory, and meta-
bolic response to injury. This was further
modified by Francis Moore in the 1970s. The
first short ( <24 hours) hypometabolic phase
(termed "Ebb• by Cuthbertson) represents a
coordinated response directed toward im-
mediate survival. It starts with the activa-
tion oflocal coagulation and innate immune
system factors. While evidence of a systemic
response may be minimal in subjects with
mild injury, in an insult of sufficient magni-
tude, the local activation is followed by sys-
temic inflammatory and endocrine re-
sponses. These can present as surges in
2
plasma catecholamine, cortisol and aldos-
terone levels inflicting tachycardia, tachyp-
nea, vasoconstriction, lower cardiac output,
loWllr oxygen consumption, loWllr basal
metabolic rate, sodium and water retention,
translocation of blood from the peripheral
to the central vital organs, and acute-phase
protein (APP) production. If the organs sur-
vive, there is transition from the "ebb'' phase
to the "Flow" phase. The flow phase of the
stress response is characterized by explosive
metabolic activity. increasing immune ac-
tivity. enhanced enzymatic activity, and tis-
sue repair. This response is mediated by a
massive neuroendocrine flux involving the
production and secretion of catecholamines,
antidiuretic hormone (ADH), cortisol, insu-
lin, glucagon, and growth hormone (GH).
The increased adrenergic stimulation causes
an increase in the ratio of glucagon to insu-
lin and, combined with the increased corti-
sol and cytokines, induces the state of en-
hanced proteolysis and lipolysis.
The supply of amino acids comes from
catabolism of mostly skeletal muscle and
visceral organs. Some of these amino acids
are taken up by the liver as substrates for
gluconeogenesis and protein synthesis.
Others are reserved for enzyme synthesis
and collagen deposition at the site of injury.
The energy needs of most other tissues are
met by the availability of free fatty acids
(FFA) and ketone bodies. These are made
available via enhanced lipolysis with re-
leased glycerol acting as a glucose precur-
sor. The hepatic glucose production supplies
the glucose obligatory tissues.
Clearly, this process of catabolism re-
quires an enhancement ofblood flow to the
muscle, the liver, and the areas of injury.
Individuals present with tachycardia and
tachypnea, peripheral edema, fever, hyper-
glycemia, leukocytosis, increased o~ con-
sumption, increased C02 production, in-
creased minute ventilation, elevated resting
energy expenditure and negative nitrogen
balance. Consequently. the liver provides
substrates through gluconeogenesis and
synthesis of ketone bodies, detoxifies ni-
trogenous waste via the synthesis of urea
and elaborates a series of APPs that bind
metabolic by-products or limit the activity
of proteolytic enzymes secreted by acti-
vated leukocytes. Renal blood flow and
glomerular filtration increase and facilitate
excretion of the nitrogenous by-products.
Cytokines released from macrophages and
adipokines released from adipose tissue re-
sult in disruption of capillary tight junc-
tions, leading to vascular leak allowing fluid
and substrates to flow toward the avascular
area of injury, as well as to the interstitium
in other body parts.
Manifestations of this hypermetabolic
phase can be seen clinically in every postop-
erative patient. Patients retain fluid and so-
dium via concentrated urine, and redistrib-
ute blood flow to the vital organs, as well as
compensate for the intravascular depletion
secondary to capillary leak and possible ex-
ternal losses. If allOWlld to go unchecked,
this catabolic response would deplete en-
dogenous resources and become maladap-
tive. Systemic inflammatory response, se-
vere metabolic depletion, and possible
secondary infection can all cause damage
to vital organs that were not initially com-
promised by the injury. Adult respiratory
distress syndrome (ARDS), renal insuffi-
ciency, hepatic dysfunction, loss of gut epi-
thelial barrier function, immunoparalysis,
and sepsis may develop and the multi-organ
dysfunction can be fatal. Fortunately, with
appropriate support measures, the stress
response nearly always resolves itself with-
out complications.
The intensity and duration of the flow
phase roughly correlate to the extent and
type of injury. The catabolic process usually
peaks at about 48 to 72 hours post-injury. If
the insult is resolved, it can lead to an ana-
bolic state, dominated by insulin, GH. and
insulin-like growth factor I (IGF-1) within
5-10 days of injury. The change is associated
with a flux of protein, fluid, and electrolytes
returning to depleted intracellular space,
particularly the muscle. Interstitial edema
fluid is reabsorbed and the excess fluid is
eliminated with a brisk diuresis. As the cel-
lular space re-expands, the need for electro-
chemical equilibrium mandates the move-
ment of ions (K+, Mg2+ and POi-) from the
blood into the cells. Serum levels of these
ions decrease and require repletion. An-
orexia and fatigue gradually resolve, and
heart rate, respirations, and plasma glucose
normalize. Nitrogen balance becomes posi-
tive and homeostasis is restored.
llO'l..UIMll'OIIJWPONSI! 'llBo ... (I,. -~-loa.'"""'"
11aDCIIhmNIMDlt••"W•"._.,."" -
'Jb!nfWnm~~~oo>o_lo.....,.........
~ biDWl .....:J ,...,. (oD
Ma.lloiaJ!-
at•tiee,tn•ad«<:tttiiciJm4allzW! aalbll' 'II!o 'llll......pid!Mq - - - - 11!!-
tJ. rrwf!d!W ~.ad de,MtW) ...wID O<oqHia ID I~ 'OIII>Ibo loc>
'IUtmmt . . . . .U!7!te ' JUIIIIP - • lDIDlur +r tde•tt'*tD J!l'll.'lldlfm.
fll)q•"*"~ll'll uti u tlliiilt4iklcJ. llyct.ew<l~ ...........
...t.oltq>llft-" - - - . .
tonw etmhalldao«"• ntlel A1I:IZIUil.bli-
cac.1W • wul-t WIM""*"'J,..
-l>.~llol:al!y--­...
~-..lo - . . 4 f i ) -
- .!t-11-""""*
cUrw '"'•'

'll.llt.-llooa
•-oi.GIIIM<I>Ito_to_a.,..
hf Cll . ,. . . .. , . .m..to.
--lld>~llll4•f'l'"lli"-

cl6o 1!1001 ..., .... '"l<oc:ohlv

~'lta-J.tUG!!I6!IIdllf
J"WW"ao
bldm"' pxwt&:.~at oCwtUta 'l:l.lta tl .. l • • .......,R.tw ....
"""-tnqi!-'lolbotlg>""'f"""""' 'lbolo ro.-.ptoct 1d:ll:to 1 fteelrln •
......
cf.tf" IIi' "1'1 ... - · n.il<! l>ll.t malo
~do>~_,.,.
- -.. LI'S. Tl.&$, '1'1&-7, Gill
~ 1111 ~ .... - - IIIII.
UM-collola""'-'IDI!odo-
blll a&htalaeooe .,. :a
'l'LIIo - to> """ • """P8 colo """
-lbo-aoolllio " " " " " - ·
tjMml. 'l!oo7 ....... -.~ ... """""'' a. t'rrs.t
«yoi'_....,.... ....
..O.IIIOIT~...........-

..a<s~->-'lloo~'I'LioiD­
N,i!ll....h
'Jh& an!"llnjJI'f; 'JIIIbl!l ,....,..,.. o! mcw:
tblll80p:c••«. blakd•lllfllllt~
...J..0 --..... prolcill<l.llcii><J""" ol
ltytblr-'"' .....
ftl.aat tbt ~ tn:'I.Mn!l'!lttc'Jl1IIIJIGl*
M<ollo•, Up
......, ...... ibo 1lJio ... -!!lid ...
tb.t b:!.l:tM.tII&I&W• ,...... 1tll ~
_.,....c~ooo.-~pdor­
rd ......... &it &ttt-ttnn.: it. .. ~ tJdio.
tcnmraA 11lC4rpC- m1 - ..... edll - I l l • DOII.Ij>Odlll - - Ill - o(
.........., -llltos"' lbo _ ........ ..
- .... ~ c:lullo.-....
ll.!laa.._(NI')-tcB.NPod-"t'Sot• Gill~- poti!Mop. Ill
Wihoauc:llu ll'llmdlliklt..,..e N«•\r *"" .......~lilt dn.lallty ..
...e1)..,. ."7
t~~:m...ttblpxllda :t•·~·an·,Ra~ !ijJIOf lt!G~<""l"a '1111
~JIIta·cil.,.,....,

""""""lilt.-
''to~ cJaee- . . - a.

,.,. . ,. lOb--.. .
a);
ade.t. pwtl ktr.ll!ll. cod~enc.,.,.
~"1.""'"11' _ _ .... ~

-lito-
cllloodyby bUill" all wile 1•-
CJQ..,. .... m.......,,mth ".,...., ....
(hdoolal.....,.
IIllA Ill l'IJ)III ..... """"" - - &1111
11-biLJI<nri'l- &IIIITNkt---
tblr""""--
I!.I
..,.....,potb•
..
Wr-4 (l'Nit<t) ..a ~--1 {IL-l~ 'lb
~
'lloo .... ~(da pollntou> loloo-
~
tbltfboc.wc.ie1J '"111"14'by•rw "D
~ .,.~lbo"""""' -..-~JIIOCio<Cbpbollnr
1lul ncq• iii1lat e.e ~to-­ -
..,.,.,0" fAp:o 1).TLIII..., """lluolotil tblt oc ld:h'l.t.o c ~ diKftiD

lor--. ....
..... duoo P.llall . . oollol p - ta tb • ~ encScp ..... ~
from....,......, ....
't'ltOfP"dl:iM . . . . . t.t'll'l1:bliM t'U. t.r:rl.t>- 1lltd£tl1ft nil ... """" oll:l.e t.!III!IJiilll!crl
'fltb:)."""""" "' • """""'"t::l.&tdlll.:ll:ta
....... .&d>-
~'bo~lz<lo~-­ alii. or-"""'oclo;podol"'.......n. ID d<o ,._,- d""""' olo ll>ola¢ lol!oo
...t:.l.dl mtif!a ttrt.nWlvtiM! Glll ~
. , - c t . - - . 1111411pJoa . _ .
_..tt!dl _ _ ..,....,polb- '*"">l>jda-Jii.-.---
~ I 5 d• b&a balm unbe.J
-
IDclodo"'*
-.
dt•,•prtle
_ _ _ _ tllo!opo looct.a.,.,. . . , _ . . . . . ,_ _ !1&_10 P'MI!>qta!U Glllw.l W~a.t-..
~ed:hes ,..,. . . . . . .

- ad '""""J)JtItl
ad:l.eo. tty
'hcfltw:te bca.
iktAltft.

ct.h -...... _.. -

pcocum--dla-~
'lloo
- tU mermw morttort rldMI ea""rm.
~ lodiD ""4 ..tid> .........
...,... ""'Dl- &ld t.ulolo ,..,,, rl
-lz<>.
1&loz<ll{y poililorV -' ¥ dtt o! ciM':sl'l Cflkl"' ltkin~lil14.-d.airr.l.
. . ..., .... ¥-·-cba!ota- .........)!]~
tr.a•••m 111'111 ~~.,•••tbd• , . _ _ t d l - P"lr'"ll" ..,.
.......... ..,. •l&tfo-
~~""'~<: p'ln•"l"•'"" ID 'lUI& IDIJ tdot-
tlltll a P""'WO .....,...,. til ....... F« e
·-ct.a."""".,......,..
~~~~--~
o( .... ....,

-"'.
.,.., "'"""... ...t~ll>ol ... c~>or­
......W:feaf~N,M.O.atthl """""'•"""'
1LlU ouc:lo<lllclo
(IU\1-'I:IIIWG) ~"
11M- -!!lid bllllde 0 .....1•"•11 &d:h4idl67l of tbl ...
. . ~ CIIW'D " ' dell¢ • •.,
- """l''l<W diG blool to>_
..:a...u..a_,_,.,...., 1tododol
_
............. - --lo.dnplll""""""""

pe-- ~ !*""'...... ~t&.._fW'!IA« ......

t l l o - - - o! - - .... . . Fdlla:tt Wilb f.'f1B4 g11111 m I I h a_ . . 1ll:laD
lbo - .. "l"'"• (JUII) &lllllbo o- ~loiolt1as'ILR4.~Alo -tllc!.Cta.
__ ldi!o\.W ..
fl.tbo ···~-aadtocldKI:aat­
_111..-d... _ Q;o) ...
_ _,_ .,.._tlolocl
II!OI]IIOC~ "' -
elc!n•ol'-~11>
1bo
4 Part 1: Periopemtive care of the Swgical Patient

HMGBl was originally idelllitled as a

chromatin-binding protein that exists ubiq-
uitously in the nucleus of all eukaryotic
cells. HMGBI plays a critical role in stabiliz.-
ing nucleosome formation and in regulating
TNF UPS transcrlption; it also plays an important role
IL·1 uv in signaling following tissue damage. When
present in an extraA::ellular location. HMGBI
Unlmawn can activate the innate immune system and
UYSerwor promote inflammation. It is passively re-
leased by necrotic, but not apoptotic cells as
wen as actively secreted by immune cells,
macrophage&, and NK. cells upon activation
with TNF. HMBGI acts as a chemokine and
TRADD TRAFs is a chemoattractant for macrophages, neu-
RIP ,
II trophils, and dendritic cells and causes the
secretion of several proinflammatory cytok-
-1 ines (e.g., TNF, IL-Ia. IL-lb, IL-IRA. 11.-(;;
IL-8, MIP-la. and MIP2b) (Figure 2).
? 'Ihe role ofHMGBI in multi-organ dam-
age in sewre sepsis was demonstrated in an
animal modeL Inhibition of HMGBl by spe-
p cWc antibodies protected mice from mor-
NIK tality in both LPS-induced and cecalligation
and puncture-induced sepsis. Furthermore,
administration of recombinant HMGBI
protein recapitulated severe sepsis by in-
ducing lethal organ dyafunction. Several
techniques have been developed to inhibit
the biological activity ofHMGBI in sepsis. A
protein fragment A-box. which contains the
DNA-binding domain ofHMGBI. competes
with intact HMGBI for binding to its cell
surface receptor, and exhibited a therapeu-
tic effect in sepsis models even when ad-
ministered after the onset of the diseases.
Ethyl pyruvate, a stable and nontoxic deriv-
ative of pyruvic acid. has been shown to

..
C) Q . ; ;
suppressHMGBlreleasefrommacrophages
••••
·.•: in vttro, reduce serum HMGBllevels, and

TNF
L- -1
+······ •••.•
.... • ...
1/'oJii..a- ..... ......
improve survival in sepsis models in mice.

etc. - ... • •• Adaptive Immune System

A20 Jdlu • • ••• Adaptive immunity constitutes the second,
but more specific and efficient response to
Ffl.l. 'lhe proinflammatory signal transduction pathway. ACP, accessory membnme-spanning protein: invaders. It is subdivided into cellular and
~inhibitory protein It<B kinase a.; IKKJ3, IKB kinase pIL-L inteileukin-.I; IL-lR. IL-l receptor: IRAK. humoral immunity.
IL-lR-activated kinase: NIK. NF-t<B-lnducing kinase; RIP. reoeptor-interactlng protein: TNFR. twnor ne-
crosis factor reoeptor: TRADD, TNFR and associated death-domain protein; TRAF2, TNFR-associated. Cellular Immunity
factor 2. (Modified &om Baeuerle PA. Pro-inflammatory signaling last pieces in the NF-.kappaB puzzle? Surgical insult leads to the activation oflo-
Curr Bioll998;8:Rl9, with permission.)
cal host responses necessary for protection
against invading microorganisms and for
mortality following sepsis. Neutralization of leased either after a nonprogrammed cell the initiation of tissue repair. 'Ihe sequence
C5a. using a monoclonal antibody. resulted death or by cells of the immune system. of events begins immediately after injury.
in improved survival and decreased organ Within this family of endogenous triggers with the activation of the coagulation
damage in animal models. are high mobility group box! (HMGBI), heat cascade and the initiation of the lnOamma-
shock proteins (HSPs), defensins, cathelicl- tory phase. Local mediators of inflamma-
Alarmins din.. eosinophil-derived neurotoxin (EDN), tion. such as cytokines. histamine, kinins,
Activation of the immune system is trig- and others. 'Ihese structurally diverse pro- and arachidonic acid metabolites, cause
gered by injury or trauma without evidence teins serw as endogenous mediators of in- increased capillary permeability, allowing
of a bacterial focus. '1h1s is mediated by nate immunity as chemoattractants and ac- immune cell infiltration (primarily neutro-
alarmins or PAMPs. 'Ihe a.lannins are re- tivators of antigen-presenting cells. phils, followed by monocyte/macrophages

!Blood Vessel
Wall
Blood Flow
Fig.2. Schematic ofthe chemo.kinea-mediated process ofpolymorphonuclear leukocyte (PMN) recruit-
ment and infiltration. Chem.okines emanating from a source of injury and/or infection mediate the
positively regulated expression of adheaion molecules. In this example, selectins and integrins cause
tumbling and adherence, respectively, of PMNs to the endothelial lumen walL The adherent PMN then
moves through the wan by diapedesis and migretes along the chem.okines gradient, eventually inflltmt-
ing in and around the focus ofinjury. ROS, reactive oxygen species.
infiltration). Immune cell migration is a
complex process involving attachment to
the endothelial cells and extravasation reg-
ulated by many substances, the most im-
portant of which are the chemokines and
adhesion molecules. Most of these media-
tors act in a paracrine fashion and they are
short-lived because of rapid metabolism.
Therefore, serum measurements of these
mediators may not reflect their activity in
local tissues.
TLR activation causes secretion of c:y-
tokines (TNF-a and IL-l) and chemokines,
especially by local macrophages. Chemok-
ines are produced and secreted to the extra-
cellular matrix by activated leukocytes and
by various skin cells (epithelial cells. fi~
blasts, and endothelial cells), and mediate
cell motility. The local microcirculatory
inflammatory response is reflected by a
pronounced leukocyte accumulation and
adherence to the endothelial lining of post-
capillary and collecting venules. 'Ibis re-
sponse is associated with an increase in
microvascular permeability, indicating the
disruption of endothelial integrity.
Cytokines act on endothelial cells and
induce the adhesion molecules. Leukocytes
express carbohydrate ligands to bind to I!.
and P endotheUal select:l.ns (a fa:mUy of three
single-chain transmembrane glucoproteins,
named L. E. and P selectins), a process called
"tethering;" These are low-affinity interac-
tions and the leukocytes begin to roll along
to the endothelial surface due to the force of
the flowing blood. Chemokine signaling on
Chapter 1: Metabolic and Inflammatory Responses to Tnluma and Infection
Site of Injury
or Infection
rolling leukocytes results in the modifica-
tion of the structure of a family of ttans-
membrane proteins called •integrinS: al-
lowing for :firm adherence of leukocytes to
the endothelial surface. Chemokines can
then stimulate the extravasation and mi-
gration of the cells to the wound space.
Finally, at the time of injury, the produc-
tion ofpro-infJammarory cytokines and the
expression of 1!.-selectin. chemokines. and
integrin ligands on endothelial cells medi-
ate the selective recruitment of cutaneous
lymphocyte antigen (CLA)-poeltlve T-ceUs
into the wound. There, they recognize the
antigen for which their receptor is speclfic
and become activated. 'Ihe local mac-
rophages act as antigen-presenting cells
and also express the costimulatory mole-
cules that are essential forT~II activation.
.After antigen binding, T-cells dlJferentlate
preferentially into 'Ihl subsets. and secrete
interferon-gamma (IFN-'Y). the major
macrophage-activating cytokine. 'Ihe acti-
vated :mac::rophages remove debris from
dead cells to :facllitate repair after the infec-
tion is controlled. 'Ihe clearance of the de-
bris and the infectious organisms promotes
resolution of the inflammatory phase and
ensuing repair responses, which include
formation of granulation, reepitheliallza-
tion, and neovascularlzation. 'Ihe immune
response then produces the cardinal signs
ofswelling, pain.. erythema, and fever.
In the normal host response, these pro-
cesses are mostly limited to the site of
trauma~ howevet; every substantial trau-
5
matlc injury also leads to a degree of sys-
temic inflammation. Depending on the ....
magnitude of tissue damage. the local in- ~
flammarory process will cause washout of j:l.,
pro-inflammatory mediarors into the sys- }
temic circulation and inflicts a systemic in-
Oammatory process. The systemic leak of
cytokines leads to further activation of im-
i'aa
mune cells, mostly polymozphonuclear leu- ~
kocytes (PMN) priming. more cytokine se- u
cretlon, activation of complement and the !
coagulation cascade, and secretion of APPs S
and neuroendocrine mediators. '1h1s sys- .~
temic inflammationis followedby a compen- ,:r;
satory anti-inflammatmy response, creating
a balance. which will have significant im-
pact on the cliaical outcome. Hence, the
•rtght tuning" of systemic inflammation is
crucial for restoration of homeostasis. Se-
vere inflammation may lead to tissue de-
struction in organs not originally affected
by the initial trauma by a process com-
monly referred to as the multiple-organ
dysfunction syndrome (MODS).Aiesser in-
flammatory response (or too much anti-
inflammarory regulation) will induce a
state of immunosuppression during the
vulnerable time of recovery, which can re-
sult in deleterious sepsis for the hosL
Cytokines
Cytokines are small proteins. secreted by
systemicimmune cells, macrophages, mono-
cyte&, or lymphocytes {mostly T~) and by
diverse cell types at the site of injury. Cytok-
ines are crucial mediators in cell immunity
and inflammatnry response. In healthy hu-
mans, they are produced at low constitutive
lewis. reaching just picograms per milliliter
in plasma. and function in an endo-, para-,
or autocrine manner. Cytokine receptors are
expressed on the surface of the majority of
human cells. and some soluble cytokine re-
ceptors are detectable in plasma at low lev-
els. Cytoldnes activate intraceUular aignallng
pathways that regulate gene ttansc::rl.plion.
Examples include NF-KB. activating protein
1 (AP-I), signal transduction- and transcrip-
tion-activating factor 3 (STAT-3). and mem-
bers ofthe CCAAT/enhancer binding protein
(C/EBP) family of transcrlptlon factors, in
particular C/EBP-(l and 8.
'Ihe NF-tcB family oftranscription factors
is most often studied because of its central
role in the inflammatory process. Cytokines
influence Immune cell activity, differentia-
tion, proliferation, and survival. 'Ihese me-
diators also regulate the produ.clion and
activity of other cytokines in a watershed
manner. There is a significant overlap in bio-
activity among different cytokines.
Cytokines are not antigen-speclfic and
their effect can be stimulatory or inhibitory.
6 Part 1: Perioperative Care ofthe Surgical Patient
TNF, 11-lb, 11-6, IL-8, IL-12, and IFN--y are
the dominant stimulatory (or pro-inflam-
matory) cytokines and 11-4, IL-10, and IL-13
are considered inhibitory (or anti-inflam-
matory). Those compounds acting in be-
tween cells ofthe immune system are called
interleukins, and those inducing chemot-
axis ofleukocytes are referred to as chemok-
ines. Including about 50 chemokines and 30
interleukins, the number of characterized
cytokines is now well in excess of 100. The
number of cytokines recognized continues
to grow, and a list of cytokines and their
function(s), origin, target cells, and proper-
ties is provided in the Cytokine Online
Pathfinder Encyclopedia (COPE) web site,
created by Dr. Horst Ibelgaufts (www.cope-
withcytokines.de/cope.cgi).
During acute localized inflammation,
connective tissue, endothelial cells, and lo-
cal immune cells are first to secrete pro-
inflammatory cytokines, mostly IL-l and
TNF. Cytokines may leak to the circulation
and exceed the levels of soluble receptors,
which results in systemic inflammation and
possible development of SIRS and MODS.
The monocyte/macrophage also produces
the only natural and well-characterized
competitive cytokine antagonist. IL-l re-
ceptor antagonist (IL-lra), as well as liber-
ates soluble forms ofTNF and IL-l receptors
(IL-lRI) that are able to bind and neutralize
TNF and IL-l, respectively. The t~ of circu-
lating unbound cytokines can vary from < 5
minutes to a few hours.
Interleukins
One of the best-described pro-inflamma-
tory cytokines, TNF (previously known as
cachectin) is mainly produced by mac-
rophages and monocytes, and by T-cells,
endothelial cells, fibroblasts, and adipose
tissues. TNF is among the early cytokines
secreted after trauma with a t~ < 20 min-
utes. TNF acts through its receptors TNFRl
andTNFR2.
TNF, through TNF-Rl, activates the cas-
pase cascade and induces cell apoptosis, as
well as induction of transcription factors
(e.g., NF-KB) and activation of the mitogen-
activated protein kinase (MAPK) pathways
both involved in cell proliferation, transcrip-
tion of inflammatory genes, and anti-apop-
tosis. Binding ofTNF to TNFR2leads to acti-
vation and proliferation of immune cells.
TNF induces secretion of a variety of pro-
and anti-inflammatory cytokines (e.g., IL-6,
IL-8, IFN-'Y, andiL-lO),increases synthesis of
nitric oxide , activates the arachidonic acid
pathway and induces activation of cyclooxy-
genase andlipoxygenase enzymes. This leads
to the production of thromboxane A2 and
prostaglandins E2, which have multiple
physiological effects, including increased
permeability of endothelial cells. It also in-
duces the production of adhesion molecules,
such as selectins, platelet-activating factors,
andintracellular adhesion molecules (ICAM).
In addition, TNF increases the pro-coagu-
lated activity of endothelial cells.
The local effects of TNF can be physio-
logic, but the systemic effects often lead to
adverse outcomes. TNF has been identified
as a principal mediator in septic shock. In
the central nervous system (CNS), TNF
stimulates the release of corticotropin-
releasing hormone (CRH), induces fever,
and reduces appetite. In the liver, it stimu-
lates production and secretion ofAPPs, and
also causes insulin resistance. Inhibition of
TNF by either anti-TNF antibodies or solu-
ble receptors for TNF has become a strategy
in the treatment of patients with chronic
inflammatory diseases, but this strategy
does not work in septic patients.
IL-l was first described as endogenous
pyrogen over a half century ago, because it
caused fever when injected into rabbits. M-
ter being secreted by monocytes, mac-
rophages, or endothelial cells, it has at~ of
only 6 minutes. The two forms, IL-Ia and
IL-l~. are regulated by different antigens,
but both bind to the same 11-lRI. Binding
to this receptor activates a signaling cas-
cade that is shared also with IL-18 and
TLRs.The IL-l is a potent pyrogen. which
influences the hypothalamus to reset the
temperature of the body and induces fever.
It is associated with local hyperalgesia. IL-l
has similar effects to TNF on the immune
system following trauma. In fact, TNF and
IL-l are often described as synergistically
acting mediators.
Similar to other cytokines, IL-6 is pro-
duced by a variety of cell types. It is detect-
able within an hour oftrauma, and peaks at
4-48 hours following surgery. The secretion
of 11-6 is induced by TNF and IL-l. IL-6 in-
duces a proliferation and differentiation of
B- and T-lymphocytes, activates NK cells
and neutrophile, and inhibits its apoptosis.
IL-6 regulates the hepatic synthesis of APP.
such as C-reactive protein (CRP), fibrino-
gen. complement factors, a-2 macroglobu-
lin, al-antitrypsin, and others. 11-6 also in-
duces the release of soluble TNF-R and IL-l
receptor antagonist, and therefore plays a
dual role in the inflammatory response by
acting as both a pro-inflammatory and an
anti-inflammatory mediator. IL-6 has alon-
ger t~ than TNF or IL-l, which makes it
easier to monitor, and seem to correlate
with the magnitude of trauma. For example,
despite similar procedure times, there is a
greater degree of IL-6 elevation after ab-
dominal aortic and colorectal surgery than
after hip replacement; there are lower IL-6
levels after laparoscopic than after open
procedures, including cholecystectomy and
small-bowel and colonic resections. It has
been shown in murine models that IL-6 is
an important mediator of inflammation,
and blocking IL-6 increases survival. Fur-
thermore, IL-6 is regarded as a prognostic
marker of trauma patients with SIRS, sep-
sis, or MODS and as such has been used in
the intensive care unit (ICU) setting as an
indicator for the severity of the inflamma-
tory responses that is relatively indepen-
dent ofbacterial infections.
Chemokines
Overall, 18 chemokine receptors and 43
chemokines have been described. demon-
strating a sharing of receptors. Chemokines
acts as attractants to almost all blood cell
types of the innate and adaptive immune
response. In lower doses, chemokines act
mostly as chemoattractants, while in in-
creased concentrations they can lead to cell
activation, including cytotoxicity and even
respiratory burst. Their receptors have also
been detected in endothelial cells, keratino-
cytes, and fibroblasts, suggesting that some
chemokines also contribute to the regula-
tion of epithelialization, angiogenesis, and
tissue remodeling. The chemokine recep-
tors belong to the family of G-protein-
coupled receptors, and binding to these re-
ceptors leads to effects, including both
chemotaxis and activation.
IL-8 is a typical chemotactic cytokine
and its secretion is induced by IL-l, TNF-a,
C5a. microbes and their products, hypoxia.
hyperoxia, and reperfusion. Interferons at-
tenuate the expression ofiL-8. It can be pro-
duced in an early state of inflammation fol-
lowing trauma and can persist over a long
period of time, even weeks. It has the ability
to act as potent angiogenic factor, as a po-
tent chemoattractant, and as an activator of
immune cells. IL-8 signaling also induces
the shedding of L-selectin from the neutro-
phil cell surface, and together with TNF-a
and IL-6 is responsible for the regulation of
adhesion molecules on endothelial cells. It is
not the concentration of IL-8, itself. but the
development of a concentration gradient
that directs the cellular recruitment to the
site of inflammation. There is also evidence
that IL-8 can protect neutrophils against
apoptosis, which could be one reason for
prolongation of the inflammatory response
at the site of injury or infection. It has also
been shown that IL-8 plays an important
role in the development of the ARDS.
Recently. a group of so-called silent
chemokine receptors has gained more atten-
tion. These receptors can bind chemokines,
 7

l l l l t c l o a a t - - e d l....
...,..apMeat.SM~«~
.. *""..., Qat,..
.,_. J:tiCtfliC'«& o!1til ~
"""!i'!' Ill\ 06 ...... -1»-
1\mrmdciJd.,...,...... -..ptJI..e. aa.tl!
--1:10 bo.,.._ll> .....lllo
'""""""""''J I~ tJ1 ~ cotm.e(
JZUiddl. flllcrwb:ll ~Wm rf ct..,..._
- Allolloor ....,._ ... w It lloo
DIIPJ Am¥ol lloarpt« ... ,_...,..
(tWIC). IWIC. &It~ • alilood
P"'P...,II.:Ioo"J · tts 1 &Jrollilood
-~~~~-pf!a!oo'II.);!*W ....
. . .dcMj!Mi. te.+.ihfaA. 'W'fd8D6
.,.,,, rt•1bet:rilllR"'M(K"'&aWtt! .......
-to •llfiw,tlet&
lloollABC ....... -Io"'-
t:b1& .......... ad d ......
···~-··'11.,
11'1""1 ..........,.
'Vidoi.Mta:n.tl-
.........._ll.t_of~
1DIDt (ail) ftwprmta P<i\. .....,""'"
c...... (l!odot .Ill).-~
-~(rm'.I!.I....t!W).­
I"'J""'"""lou l'qpllocllloll......)11111>-
....,. m 'l!l:lbld u 1:bt to'Dl""iH!tfm
1111); - -. . . -eoollfllllllllu!
<HI, "'!'odolly ~"JJ'-of-­
d.!atJW tnftc1km t: tiM bla ~ 1:tw1:t
~Cfl8-'""'"'"""'"rt ........
Wt""*'atb:l d. LPS « JL.l ~ tDo
CIDLICd.:!: 1h I cftclliWC~I'ti 4:1 . .
...__(ACm))-boblodddet-·
Ultld.by AMtqiY¥'Mt'O ~ 'ltdll
- - -""''be ocllftloii'IIJ' lloo-
- ol 1!.1 Ill [M'\I'I>m!- S]lodllt

--to . . . . . --..
U..l ~tilt.~ !JeGr14Cii#ea GD
-lb/trfiOIIII!!
- - ~'*'loP"' ...... ~~~ooo~
n.~~~::..a.tl1 - flt=u..O. ........ IOIIIo""""'...,....,
n.l-.,.11114a.llllut....,......,. .
kebaiiri..SWpnw:t~ao- -~mlllo~ot­

--.llo\IIC.......
- hll.o . , . _ - oa 1:11o ~-~~..., . . tttnlfl"*'ltfmol
111 ......... lo!t ............ ~~.l.
.,m..*"~---

---"'...-
~PMtlcc.m. . .,
_ _ """ _ _ _ 'lit"
taede Wlcmeet "'1 . ...,. Aa eu ceald.
IIIJ.IOCto 1llo ~
~-lt-IWIOI!oo_.
'"I,,...
pc&·
IIL:dl.-iiflll! It'' c. . . whsfft . . . .
--lla!u-ar101:btii'IOIIIJ lolortaod ...... - ........ ll.d
cilloo""'""'' "" \'ll1oolr..O ..........,
--c.-a.,-....uawo) *'ttLt"' ........ .,...."""'
cc-• d' ... c of
.......... Ill
«md!zf Cl'lll am::lo-
tlfla
poolJIOIIH>Ia:ytt-- 11:10211101- 'n!Jenzzzrw tmy ham • M L'lllr:PtDIG. WliiJe a::j-
~tD ......... ~ hJJJ"•+?«rd.IJ' dOf....,.,. .... ,., to41rnrlcte
.,._t!ltflll'""
(lCI!lo

6to1.--.......-po!l>.-
ora........tlodl1'!11clolapll.ol~
. . ._ . .
pmmttaftboham• ...
III"Mftll&•fihe~tWj .....
to·~-
trAma~lmmQil "'MMUJJS" ew:bl....t11111
-lbo-t11JMfl'-b>Ojlp!l-ll>-
...
_,_
'JU .,..U ad Ollllll k1aJ. tnflemmeay ,....., 'lbo b:ll:lllllafl QDIO to tl.flP*
.,,...........".a& NJ.lded hr t.ha
-·~"'-"*""
1'lll!niQU
'"...
"""'"""'.,-am. (I'IMiile!H• ,....,., -

~l'llnlt~ta-w-·'&tbe
~ &DII noc.pwtflc• tnnm• qlmf~
........ """..."'""""""~(!'111!.
Q,.ljl.IIA5, 1!.1.1,"""- &Ill!-.),
Drgtl!•+aftbopa I A m ef 4ji41111pcUII' CXU:f - tdlilt.... IDIGt i . . I tllllil:ta:-
~COa:dl:lmfof&..etal!m,enc.,,,.,., ....... ..a.. -.u_,...,..
tltlllfW.otbrniJKazr.t.fbetnfknw ... -l!ur&.llllt IMIIIJll!dtr,... wq 11> a
~ooy.,a,.eo.,..,..,o!._,_ ~ Cllf&ip:x w4 """'nsne 6sn~on.
ta111. tad aatll!lltr:a:t~ am. 'Jb p!'odDi tiQ fll. trmml ·~M tiJ

--~llqltU~~IIrda 7w w.
11114 - P"'- - ......_., ..
f:IJ d8k,red lJnw• Nltt.d:t) t6ta
tMtB& lldwU m~ ttw+·rtm,
lllotol _ _ ,.....fo!mlhb-
~ IIIII """'"'"'~ ...,... -
-----!IIOIItiJII:!'d-
,_..,.lib""' nodlll.o CNS ~­ - aod 'IIIIo
-"'<L " "-- - 1111-
' " -" ' ".... .. u.

.
~
,...,. .. . , . a,tW11f'lcmeW'e.,
- Wf!llll-. ............ l!lood-

--
'bomotrrftemmol'fmd ........ fJ'IIIlt - it " ..... Mit bJ mtt'" mocllt-
.... .... _al~ol· u•lljo.
'll!ro-~-
'XU aaznitllts4G p:ra111:1t. &AP:J.mo..
to a.etM&athe: CMk tl.e !0!1!t') akm .ttl.dt to•"""'l!lu.-'
"""""'"""' 01518.
mdlllo*""•*""-
J. ......... qtclldaild
8 Part 1: Periopemtive care of the Swgical Patient

Hypothalamus TNFa and IIr1(l and tn.mcate the iafla.:m-

matory response.
BRAIN~ Cell-Mediated Immune »,11function
Cellularimmuno-incompetence (also called
"immune paralysis•) is induced by elevated
PGEzo IIr10, and other anti-inflammatory
mediator&, mainly caused by the deactiva-
tion of monocytes. 'Ihe central role of n:..-10
and TGF(l in inducing monocyte '"immune
paralysis" is demonstrated by the up-
regulation ofHLA-DR expression on mono-
17P-estradiol/ cyte& following the application of an n:..-10
cytokine neutralizing antibody and the restoration
Anterior feedback of macrophage antigen presentation by us-
ing TGF-(l neutralizing antibodies.
Pituitary
Lymphocyte Dysfimctfon
Adrenal A n Major surgical interventions are associated
with a slgnificant decrease in total systemic
glands lJ V
lymphocyte counts. including both CD4+
~ and cos+ cells. 'Ihis lymphocyte depression
Glucocorticoids Immune correlates with the duration of the surgical
4 and
Cardiovascular
procedure and the volume of blood loss,
however, is not associated with the extent
System of the trauma, the age of the patient, or the
type of intensive care intervention. 'Ihese
events are accompanied (within 24 h) with
elevated ll.-10 and increased frequency of
Fig. 3. Relationship between the hypothaiamus-pituitary-gonad-adrenal {HPA) axis and the immune gy&- apoptosls of CD4+ and cos+ cells accom-
tem in phyl!iological Nsponses to injucy. The HPA is a neuroendocrine system that 81110 bas bidirectional panied by marked down-regulation of anti-
communication with the immune system in homeostasis and in times ofinjury. giving the bmin a major apoptotic factors such as Bcl-2. 'Ihe impact
role in regulating endocrine and immune fimctions. The hormonal Nsponsesare apparent at three levels: of this immune dysfunction was under-
the hypothalamus, tile pituitary; and tile adrenal&. It can be seen that organs are coupled with one another
scored by the fact that the rate of apoptotic
(functioning as a biologic osdllators1 with the coupling being mediated by neural. hormonal, aDd cytoldne
netwozks. Notably, cyto.kines and sex lwrmones are closely coupled in a countmegulatory fashion, which cos+ cells significantly correlated with the
sheds ligbl on the beneficial e1fects ofsex: lwrm.ones, espedaD:y jJ-estmdial, in responses to inJury. manifestation of infectious complications
dwing the postoperative coU1'8e.
A considerable number of studies have
shown that modulation of T-helper lym-
such as n:.-10. TGF-f:l. TNF-binding protein. activation of Jak-STAT pathways. Direct phocytes ('Ih cells) is also involved in the
and hormones such as corticosteroids. electrical stimulation of the peripheral va- development of immune suppression fol-
adrenaline. and a-melanocyte stimulating gus nerve in vivo during lethal endotoxemia lowing sUJ."gl.cal. trauma. 'Ihe cells can be
hormone (a-MSH).'.lbese act in concert with in rats inhibited TNF synthesis in liver. at- subdivided into two functionally distinct
local effector&, such as PG~. HSPs. and APPs. tenuated peak serum TNF amounts, and subsets: 1b1 and 1b2, according to individ-
'Ihese factors interact to inhibit macrophage prevented the development of shock. Sev- ual functional parameters. 'Ihl cells may
activation and down regulate the synthesis eral reports have confirmed that the activa- support an inflammatory response by pro-
ofpro-lnDammatory cytoldnes. tion of this pathway. either by electrical ducing Ilr2. lL-12. and IFN-'Y· while 1b2
stimulation of the vagus nerve or by admin- cells act as anti-inDammatory agents by se-
'Ihe Cholinergic istration of a7 selective drugs, is effective in creting Ilr4. Ilr5, ll.-6, lL-10. and 1Irl3.
Anti-inflammatory Pathway ameliorating inflammation and improving Major trauma is associated with a shift of
'Ihe activation of the cho.llnerglc pathway survival in a number of experimental mod- the 'Ihl/'.lb2 balance toward a 1b2 response.
leads to acetylcholine release in the reticu- els. such as sepsis. hemorrhagic shock. pan- ~hocyte dysfunction may present as a
loendothelial system that includes the creatitis. and postoperative ileus. complete lack of response to external stim-
spleen. liver. lymphoid tissue. and GI tract. uli, that is, anel'8Y.
Acetylcholine binds to an a7 subunit of the IL-6,As an lmm1111osuppressor
nicotinic acetylcholine receptor. expressed '.lbe massive and continuous ll.-6 release 'Ihe Second Bit Phenomenon
on tissue macrophage&, to inhibit the re- accounts for the up-regulation of major 'Ihe so-called two-hit model of in11amma-
lease ofpro-Inflammatory (TNF, IIrI(l, IIAi, anti-inflammatory mediators. such as glu- tory insult has become a commonly ac-
and IIr18), but not the anti-inDammatory cocorticoids. PGEzo IlrlO, and TGF(l. IIAi cepted pa.radigm. It takes place in many
cytokine lL-10. In macrophages. signaling stimulates the macrophage expression of common scenarios in which the patient has
through a7 attenuates TNF production anti-inflammatory mediators. such as B.rlRl to undergo a suzgical procedure following
through a mechanism dependent upon in- antagonist and soluble TNF receptors. 'lhese initial trauma or suffers further insults due
hibition ofNF-KB nuclear translocation and bind to the pro-in11ammatory cytokines to a complication. 'Ihe second hit may be
 '
llolfo.(opou-Aoo-.101"'""-
.._.,. ........... ""
w.w tzdltttoapot!t.....,.
___
..-
t:f:I&Jnfl..,,ee« "'Jcodd:119b1We~.,
_..,~.'11111-·
C1IS.. t.f J A*«NJbh o&aq
('1']18). ,..... mq;m.ws, +:a h:mnor!•
(Gollll). tiiO'ftl - . ........... bor-
..... (BH!al), &011 d'P'""'• Oadof
-lllo _...,.. - · llillllf
h.,....,.,,

lofooilooriooulloltaot•---
1101!>hll.o"""j_oil_wl__
olio-" ll.o ~ llwwF ll.o
......:li'IIIIIA(tmpol•. .- - -
ttnltrrmme~~~tbse ll.o ...... lo 1llo ~- ....
.. &0. to:ula fnrnl ...... q~....,..- ~
dooo "ibo t!wloe.t}....., " " - ·
iltledllllp1tre'rrmme~alliCifl Qalt ..,..:ICibciiarlblql>llkiiMH>onlolldlom-
lo 1-IP'IIpn.a. ~~a>'""""llr;lld, ~ .... ...c..,-~-.:J....a­
* -lbtbi]IOIIW~poctal
taftll'lt flnnmeikWefl &ttfiN&tm tfUII6
pawflltutt~po-Wipn ...tiiPJ6Cttf.

_ ... _oa-:Jd.-pl&ooCIIIIf _
•""""'"lloo
_ _
.....bto... _lbtoc¥t
IIJ!IIol....,.leod lolilll8dMOR 'lllopet- fb-~-'lhoq­ lotolllo~CIIjOir-

~a ...... ~ti.""""'"'IJ'wl_la.,.. . . . . .lllol... hoftomli>ollll&

d......,._.,.... __
... Ailaa>qit<i1:111411 _ _ _
wltlo
w.,s n•OJWd.t!" 1: j,Mq)
Y&o,y t:ffbemaJt«tou tWMtd ~!Do
ett:.r pmJnl•m'DMt!My tdhtty11'Wfll1b1A,

.....,__,..'"""""""""''-
1 W'R"toa ofpe(plmllttlmefll'll kDowD.
)lot~ I p!llloo,.s - - ... _,.IIJ_of.,.....ulpti-

_
tad tiftdm"' t:t ......... Glll Da'Oif)o JD&rf daa:t WCIW QllJI4 •"""""' b»f
~ .........tNua.
ratr1c:lra.&ka (!lc&oclu._poto"' ~""'­
~olne m l!!l!l'!illy!tM' M'II'IOTI* •
-u""""""-lf""""".,.,. __
tD&J:Jeda.,.,..!l•toa~wbltb.

., .
p&. . Da:!tlllll
0
floiWMI
- . . iloo-clidllpnic. .
.,lllll....
'""""'"...,.lh.M&. 'Jlto ctbn!wa.d ...
JIIIIDOI¥'ml ""'l""'olll- .....
-
-l"'' "'"il><"''l>lllo"-1
ct.llulll(llllll..m ID ~ A P"''IIDil
--p.,..,.._,,._~
---~

~loll-'-lmo11We...t ...
1Im» fllrr... "'!l

S,. ' I , 1 4p" 1 ,,

.,....,. ." t\' OlpD.
d ...... -
~~"' ~
-&ed,.ud.n"'....a
"'1llo ~
...
Cll)lold Jll(l1foUf. -
&Od ~ . . JilO'h-aod &ad ...
_....._
•

~.,.._ dXIrllll "Mi'"* kuOr

li:r irllD<l«M- OJ*>!<! pop!O!ee ... 11111d to In I ..... ll:oeliooi!IQ"- -Ia
opt&~.....,_ 'lloo moll.cuclool opolcl
, . . . . . _...}l. ..ao46.'1Juoe- __ .._.,.so.-,.,_
-..lftomfb-~ollbo

... put ct.ll.o ~ ........ n;-

---~~--llf.!loCI'II
-
"'l"""" Mtkl m 'P'th t•l k\ ~ _p!OOl.oool&ylbo~la- ....tardio
, .. ,., olfbe ~t as:. CGfti..
- 8lllllila IIIII . . -.poctocl -
_..., 'lloo """"" ............... :d W I - .....,._"""""" _.,.
-.!Ill llt.tlm!J>.'l)IIW""""-,.. oabolb....,..OOM. ~m)'lOlfta'..
11jjbml-~lllllllilll.oi­ lllollt- toe ll>lllo ~ Ol'lllo ....
...... Apl&lmlbsddlap:as. . . d'llte.W.!IJ»k ho.xdto .rt.:.ntn, &ed..,.
"""'.....of_..,
• • q,;aill¥- -... ""'-~-­
oplol<lr.
(1,-... ~--0oll'
the &e. "om"""' lew;a if ~
.............. .*'
1bll ,......., diidfuu of diJ'[ll ""Mk
--~
t.d:hiL&"<«. •tl! .... tmtdlertllld:l 'bJ
~tD&Dii&dM''•&A~~

---a
- . . Ia "'!' • lo lo)lty (t,otft&l ~,..__'lha~
fa·~~~- llapolue .............ct..booi~-­ ~Cil ooa::pa
ll»'iW t» ttu1 J:ll.ldcu
lloloot*Coalllilllot· -. , _ CI1JmriL 'Jha•"•r••*•patoft:b&Ciea)o "'-lll:ta:lo ... ''""""'"'"'to
ONA .,._
'lh8 CNI ~ ct. 4hd;. 'lle opo1ilJ•'••IQJO-e .....,......,..,.
~.,..,., •!!-Ill 1 - oil
IILo ,
- · -ta..Jcltl! ..._ ........
-l'l""ii - - - rmr.
IIPACidl_cod_w..tot
(A&tt.• ....,.,.. Cll'.,.,.,d"W). Nlaw-
--~lboloa 1: ~
_ _ _,_cr;wo_ct.ll.o
1
............. old_,...""'l"......,.-
ol ~-In ibo-..&--

........,..,..o!_.....,.llooli:Jl;o-
.... ..,.!l,_~~ alfttUrmtllltt!K
Ht.wtwM (otJdf! . .ut.,.
Iillo 'I.Ji8 of . . . . . Cl)o
...... (NIIIazJ)tDeltDir..WMtapfL........
-
-
fill> ·""
-...... ibo-·
llollnocllr liy - . . . 1:1>
·-•ilao.il&dloi!J
olo(Ur II!Dd.tvtraw,t;pttoafld«<,.al
llluocllo.,.US.Iil!" ......... _ dl:ilop!lllo ..._,,. _ _ claot ... ..liP-...
'lh8 Ill& l l l l l . o - "'lllo - - m
p:roN l'IIUIII'l t.rta1 Hood. p - • .mc:t
lllllllllo -.lllllio - - P'""' Uomd• -~mi!Xdlt­
ct. qlbo-,-<1.,....
ilooO) .,..,...,, ..,._""""'--- ....,.....
tbt Oltuf PIL*7'!ijfdwtlt ~ of 1bi lluDOt- ooq;ktolr-011.
...,.,...,.._.A:l-.tle
Ak4'CP' ..'(
pot&Mcnrqt ~tef. t:a f.,..... hf-
""""'"l.
-OJIIaldl---=-a•
. . _.... """'111lilorwCIJifo'd-
10 Part 1: Perioperative Care ofthe Surgical Patient
into the capillaries of the hypothalamo-
hypophysial portal system. CRH and AVP
act on CRH-1 and vasopressin-IP receptors
on the anterior pituitary to stimulate ACTH
secretion. Plasma ACTH levels rise directly
due to increased secretion and due to resis-
tance to or inhibition of the negative-feed-
back mechanism exerted by cortisol. Several
of the elevated cytokines have been shown
to modulate cortisol production, either by
directly affecting the hypothalamus/pitu-
itary (IL-Ia, IL-1j3, 11-6, and TNF-a) or by
direct stimulation of the adrenal cortex
(IL-Ia, IL-1j3, and 11-6). Cytokines can also
influence glucocorticoid receptor numbers
and affinity. During severe illness, corticos-
teroid-binding globulin levels are decreased,
resulting in proportionate increases in the
free hormone. The diurnal variation in corti-
sol secretion is lost in response to any type of
acute illness or trauma. An appropriate acti-
vation of the HPA axis and cortisol in re-
sponse to critical illness is essential for sur-
vival. The adrenal gland does not store
cortisol; therefore, increased secretion arises
due to increased synthesis of cortisol from
its principal precursor, cholesterol.
Cortisol Influence on
Post-trauma Physiology
The stress-induced hypercortisolism fosters
the acute provision of energy. Glucocorti-
coids increase blood glucose concentra-
tions by increasing the rate of hepatic glu-
coneogenesis and inhibiting adipose tissue
glucose uptake. Hepatic gluconeogenesis is
stimulated by increasing the activities of
phosphoenolpyruvate carboxykinase and
glucose-6-phosphatase as a result of bind-
ing of glucocorticoids to the glucocorticoid
response elements of the genes for these en-
zymes. Glucocorticoids also stimulate free
fatty acid release from adipose tissue and
amino acid release from body proteins. Major
roles of these processes are to supply energy
and substrate to the cell, which are required
for the response to stress and repair to injury.
The rise in glucocorticoids also protects
against excessive inflammation. The rise in
glucocorticoids during acute illness plays a
crucial role in preventing hazardous over-
stimulation of the immune system, including
lymphocytes, NK cells, monocytes, mac-
rophages, eosinophils, neutrophils, mast cells,
and basophils. Glucocorticoids decrease the
accumulation and function of most of these
cells at inflammatory sites. Most of the sup-
pressive effects ofglucocorticoids on immune
and inflammatory reactions appear to be a
consequence of the modulation of produc-
tion or activity of cytokines, chemokines,
eicosanoids, complement activation, and
other inflammatory mediators. Glucocorti-
coids control mediator production predomi-
nantly through inhibition of transcription
factors, such as NF-KB. Glucocorticoids also
produce anti-inflammatory effects by en-
hancingrelease offactors, such as IL-1m an-
tagonist, soluble TNF receptor, and IL-10.
Glucocorticoids also block the transcription
of messenger RNA for enzymes required for
the synthesis of some mediators (cyclooxyge-
nase-2 and iNOS).
A rise in glucocorticoid concentrations
plays an important role in improving hemo-
dynamic levels, by inducing fluid and sodium
kidney retention. Glucocorticoids are also
required for the needed increased sensitivity
of the cardiovascular system to vasocon-
strictors. The reactivity to angiotensin II, epi-
nephrine (Epi), and norepinephrine (Norepi)
contributes to the maintenance of cardiac
contractility, vascular tone, and blood pres-
sure. These effects are mediated partly by the
increased transcription and expression of
the receptors for these hormones. Glucocor-
ticoids are required for the synthesis ofNa+,
K+-ATPase, and catecholamines. The ef-
fects of glucocorticoids on synthesis of cate-
cholamines and catecholamine receptors
are partially responsible for the positive ino-
tropic effects ofthese hormones. Glucocorti-
coids also decrease the production of nitric
oxide, a major vasorelaxant and modulator
ofvascular permeability.
During surgical procedures, such as lap-
arotomy, serum corticotropin and cortisol
rise rapidly. peaking in the immediate post-
operative period The magnitude of the
postoperative increase in serum cortisol
concentration is correlated with the extent
of the surgery. From a normal secretion rate
of 10 mg/day. cortisol production rate in-
creases to 75 to I 50 mg/day following major
surgery and can reach to 250 to 300 mg/day
in severe stress. Unless there is a repeated
insult, such as sepsis, the glucocorticoid
concentrations decline to baseline levels
over the next 72 hours. This decline can of-
ten be noticed clinically as increased diure-
sis, improved glucose control, and, occa-
sionally, increased pain. In critical illness,
the kinetics of the response differ from
those mentioned above: pain, fever, hypov-
olemia, hypotension, and tissue damage all
result in a sustained increase in corticotro-
pin and cortisol secretion and a loss of the
normal diurnal variation in these hor-
mones. During severe illness, serum corti-
sol concentrations tend to be higher than
even in patients undergoing major surgery
( ~30 J.tg/dL vs. 4G-50 J.tg/dL).
Adrenal Insufficiency
Critical illness is associated with activation
of the HPA axis; hoWllver, many factors can
impair the integrity of the HPA axis, such as
blunt normal response leading to either
transient or, rarely, permanent adrenal in-
sufficiency. This scenario can lead to a po-
tentially lethal condition. Refractory hy-
potension is the most common aspect of
acute adrenal insufficiency. Adrenal insuf-
ficiency should be suspected in any criti-
cally ill patient who has persistent hyp oten-
sion and hemodynamic instability that
persists despite adequate fluid resuscita-
tion and/or requires vasopressor support.
Other nonspecific signs can include multi-
ple organ dysfunction, otherwise unex-
plained hypoglycemia, hyponatremia, hy-
perkalemiametabolicacidosis,eosinophilia,
hyperdynamic circulation, and other pitu-
itary deficiencies (gonadotropin. thyroid,
and diabetes insipidus). Recently, much at-
tention had been focused on the so-called
relative or functional adrenal insufficiency
of critical illness, a condition defined as
subnormal adrenal corticosteroid produc-
tion in the absence of any structural defects
of the HPA axis. The explanation for the de-
velopment of this condition is hypothetical
exhaustion of the secretory adrenocortical
reserve as a result of ongoing near-maximal
stimulation. Other contributing factors
may include the suppression of cortisol and
ACTH production by circulating cytokines
and other inflammatory mediators, as well
as the development of target tissue resis-
tance to glucocorticoids and/ or adrenal
cortex resistance to ACTH action. Currently.
the clinical significance of this condition is
not clear and was only demonstrated in a
setup of septic shock. Although corticoster-
oid replacement therapy might also be ben-
eficial to patients who have other critical
illnesses in which there is evidence of rela-
tive hypoadrenalism, no high-quality data
from large randomized studies is available.
As mentioned earlier, there is no clear
or current threshold definition for physio-
logical "normal" and low cortisol plasma
concentration during critical illness. Since
about 90% to 95% of plasma cortisol is
bound to protein, the routine decrease in
cortisol-binding protein and albumin fol-
lowing critical illness makes it difficult to
calculate and interpret the meaning of total
cortisol concentration. While the plasma
proteins are low and there is a peripheral
increased resistance to cortisol, as often
happens in critical illness, the free cortisol
levels are not a reliable reflection of either
total cortisol secretion or action. Many
thresholds, below which adrenal insuffi-
ciency is likely to be present, have been sug-
gested, ranging widely from IO to 34 J.l8/dL.
Many textbooks and published articles
state that the normal circulating cortisol
 1t~by6' m ... a.OoiJI- (OO'Cj]lo
1 liD-) - ta 1:llo ~ ll.o
h ...llllllllldo. TIEIIIIII.Tt- 111
·
am-_, ll!tdJ
tat .., ..... aod ""-J·""" . .
~ ""rroab DJII.OQ> IICI'nWI
!llo-. Tt tn.it- k - . . J ,'IQ low
n"""' pm~a boi)'OOd TSB -
-·---a.u"'Ulaov19
~·'Jheti!TI!ttyt61nwf.&tpAJ caJ
llllllo. . .o!tile U . l l l -'I'S clildll«
tb - 2t""""' oflorlb llldl, llotbr-
lflm't. CD tzn1:rM 6l:mf.dm 'haftla '18

-
lllllllu--.. .
!mit - ~ lou .,_, .,.....,_
,_.&I Od!.orr.-t..o~ooc~hd!.OJo...'D
,.,. • .,l!dltnftJ.tf:tJMJ.~
~ &t'114 tnbfN:t:lon of •M'!7ICIII• 'btr:IJl.
lag.~ ..arnel1lldto-"' •.•,.,
l.e'l'fiU fl. &thf':f'W••• c*il l'ay
l.'lll.j tad 6GDl.l
~

cmrmodytaiOII md.,.tSme (lmW~

!odloo -}It-,_,_
'llltuitlrt dn 1 r.. or tt.e llftn:xlm.
CloQ!o) ....... ~ ................
k.U&pceudfta~n~to

- tllo--··•lllto:ze)...
•""""'c·ho~ll.:das-
lDPI'*"WW<!CIIIIolllllilnl.&_o!...
~lid: .,.a.-It .....0,"'"""""Ill
-ll.opalud•1'&11-ll-
..a
tcol.r ...b:od -te..~o o! t.:;l 'M
coo~n ... ~ow.-Illll..,._
-loll.o~lu-­

........
ID~II~wloclod.-l:o
!DIIDo-llltpnWn!n...,~a!lllt>
of tile- ·-~~ ..... - t b
.,.lf"•Mt• -of~
.cdii:Oilldllabll•llm'P't"lfiD:II
cdlloolylll"'"'"'llmuH-...0
...-1b&tmqdolqwJ--

- ... ..--..-
!IIoooo ..., llwbo. .....u """"" --
~1'o-.bG•••H4t.rtUtlu~
hen oa.t tbci:IQif t. DOt. bola ~
~-
laii111P"'-- - p:o:oll:at111!"
""fcli'CUon,~ :JoiJ!fm-.ti'J'P.:dCIIJ
. . . . . . . . . ~I !Ilk, braitttllll!ib..l!ldJII-

_,_. """""d"'-lllllllll!lm:
"'->. ~ t.••llo• lliboald llo .,_.
-11114-I'Aa~ll,.­

bot--
w!llt 'wo(llj<..... ~ lojpAij Jll-
!ml al.oalol
12 Part 1: Perioperative Care ofthe Surgical Patient
large randomized trials in 1999 noted in-
creased mortality associated with infection
and organ dysfunction. Currently. the pos-
sible use, correct dosage, and method of
administration of GH/ILG-1 in critically ill
patients are under investigation.
The Gonadal Axis
GnRH, secreted in a pulsatile pattern by the
hypothalamus, stimulates the release of
luteinizing hormone (LH) and follicle-stimu-
lating hormone (FSH) from the gonadotro-
pes in the pituitary. In men, LH stimulates
the production of androgens (testosterone
and androstenedione) by the Leydig cells in
the testes, whereas the combined action of
FSH and testosterone on Sertoli cells sup-
ports spermatogenesis. In women, LH also
mediates androgen production by the ovary.
whereas FSH drives the aromatization of an-
drogens to estrogens in the ovary. Sex ste-
roids exert a negative feedback on GnRH and
gonadotropin secretion.
Acute stress brings along an immediate
fall in the serum levels of testosterone, even
though LH levels are elevated. The en-
hanced release of CRH and ~endorphin
suppresses GnRH release directly and indi-
rectly through the release of glucocorti-
coids, which in turn also produce gonado-
tropin resistance at the gonads. Clinical
data on the changes within the gonadal axis
are scarce in critically ill women, as most
patients are older and thus in the meno-
pausal state. It seems that in the days di-
rectly following surgery, the FSH, LH, and
estradiol levels decline, while the proges-
terone and prolactin levels do not change
significantly. The state of relative hypogo-
nadism is often expressed in premeno-
pausal women by an unexpected metror-
rhagia shortly after trauma.
With prolongation of the disease, a more
substantial hypogonadotropism in both men
and women ensues. The circulating levels of
testosterone become extremely low and are
often even undetectable; yet the mean LH
concentrations and pulsatile LH release are
suppressed Total estradiol levels in women
are relatively low. Since exogenous GnRH is
only partially and transiently effective in cor-
recting these abnormalities, the profound
hypoandrogenism must result from com-
bined central and peripheral defects.
Prolactin
Prolactin is synthesized and secreted by
lactotrophs in the anterior pituitary gland.
Prolactin levels are higher in females than
in males, and the role of prolactin in male
physiology is not completely understood. It
is physiologically secreted in a pulsatile and
diurnal pattern. Plasma concentrations of
prolactin are highest during sleep and loWllst
during the waking hours. Prolactin release is
predominantly under tonic inhibition by dop-
amine derived from hypothalamic dopamin-
ergic neurons. Prolactin release is affected by
a large variety of stimuli, the most important
being suckling. increased levels of estrogen,
and stress. Several neuropeptides have been
identified as prolactin-releasing factors.
These include TRH, oxytocin, vasoactive in-
testinal peptide (VIP), andneurotensin.
Prolactin is a Wllll-known stress hor-
mone and is presumed to have immune-en-
hancing properties. It increases the synthe-
sis of IFN-'Y and IL-2 by 1h1lymphocytes,
and induces pro-inflammatory responses
and antibody production. While the main
physiological functions of prolactin are re-
lated to the mammary glands and the ova-
ries, it has been shown to also have an im-
portant role in the innate and adaptive
immune response. Prolactin receptors can
be found throughout immune system cells.
Binding ofprolactin to its receptor activates
several signaling pathways, which include
the janus kinase-signal transducer and acti-
vator of transcription (Jak-Stat), the MAPK.
and the phosphoinositide 3 kinase (PI3K).
Activation of these cascades results in end-
points such as differentiation, proliferation,
survival, and secretion.
Sympathetic Stress Response
Physiology of Sympathetic Activation
The sympathetic reaction is activated by a
vast range of stressful stimuli, including
both psychological and physical stressors.
Afferent neurons of the sympathetic system
are multiple in quantity and quality
(chemoreceptors, baroreceptors, and vis-
ceral receptors). The activity of autonomic
nerves is dependent on descending excit-
atory and inhibitory inputs from several
brain regions, including the cortex and the
hypothalamus. A major source of excitatory
drive to sympathetic preganglionic neurons
comes from the rostral ventrolateral me-
dulla in the medulla oblongata. This region
of the brain stem contains the cardiac, re-
spiratory. and vasomotor autonomic cen-
ters, and connects the upper brain area to
the spinal cord. Medullary neurons project
to the spinal cord to inhibit or excite sym-
pathetic activity. In addition, many brain
stem nuclei that feed directly into these
pathways can modulate these activities. In
contrast to the parasympathetic nervous
system with its predominantly selective in-
nervation of single effector organs, the sym-
pathetic system often reacts with a ·mas-
sive none organ specific discharge~ Increased
traffic down the spinal cord via the lateral
funiculi causes an increased activity in the
sympathetic preganglionic nerve fibers,
which results in burst-pattern release of
norepinephrine from the sympathetic post-
ganglionic nerve terminals, as well as
epinephrine (about 80% of the secretion),
norepinephrine, and dopamine from the
adrenal gland. The secretion of norepineph-
rine from nerve terminals is immediate fol-
lowing the trigger (some of it originating
from a spinal reflex arc). After secretion into
the synaptic gap, norepinephrine is cleared
by reuptake into the nerve endings, degra-
dation by the catechol-o-methyltransferase
or diffusion into the extra-synaptic space
and blood. During stress, the latter mecha-
nism is the main source of circulating nor-
epinephrine. In view of its richness in sym-
pathetic nerve endings, the intestinal tract
is the main producer of norepinephrine
(40% of total body norepinephrine) and do-
pamine (>50% of total body dopamine).
Circulating epinephrine and norepineph-
rine are degraded 5 to 10 times more slowly
than when secreted into the synaptic gap
(20 to 30 s). Mechanisms of degradation of
circulating catecholamine are nonenzy-
matic (extra-neural uptake in the lung. kid-
ney, and intestines, and neural uptake into
postsynaptic sympathetic nerve endings),
and enzymatic (cytoplasmic monoamine-
oxidase in sympathetic nerve endings, the
liver, kidney. stomach. and jejunum).
Adrenal catecholamine secretion is also
very rapid and it takes place within seconds
of stimulation. Norepinephrine and epi-
nephrine are stored in granules within the
adrenal medulla and their exocytosis is ini-
tiated by acetylcholine stimulation from by
the preganglionic sympathetic fibers that
innervate the medulla. The normal resting
rate of secretion by the adrenal medulla is
about 0.2 jAg/kg/min of epinephrine and
~o.o5 JAg/kg/min Norepinephrine. These
quantities give rise to circulating levels of
catecholarnines that in basal conditions are
enough to maintain the blood pressure near
normal, even if all direct sympathetic path-
ways to the cardiovascular system are re-
moved. During severe physical stress or
sepsis, both plasma epinephrine and nor-
epinephrine rise significantly.
Medullary epinephrine secretion is de-
pendent not just on neural acetylcholine
stimulation, but also on the hormonal HPA
axis. The activity of phenylethanolamine N-
methyltransferase (the rate-limiting en-
zyme in the conversion of norepinephrine
to epinephrine) is enhanced by high doses
of glucocorticoids. The medulla is exposed
to uniquely high doses of glucocorticoster-
oid directly through a cortical-medullary.
intra-adrenal portal vascular system.
 Ill

....t&lim _ , . bloool-:ool """"'

d•mljteAu ~ (&f"'fM'""*" rae-
-IO~~Olii!P'*'*Od>
C!:m'b), ll 14 ut "'"' - lbt
plt~CIDIM(I) if &1l ~ pift ft lidJS

"' """""*' lo ....._ ....... ted ...

Wor)t"'~~- a.dm.to
..,,, ,.,..a. t:Soa- 11. a"'~ UICI4""
ICil ML:JI. 'llu ......... l:o ~
~-1'rl!a!llllyllcma ofllto..,llllll&
p>o::!tcloro ot4oollo a. C3llfao'lr ID poll-
M! IN _ _ of....,"'lfoaca.
1.11 """',...,...... '**tbe . . . . . . J!l&eoo
-II!CIIIIdlllo_lllo_<llllllj•
bli:Ps'1lfll~ lis " 0 kl4 t:aCIUlc:w,l~
a••..,..,..... 1nffM'IM Qf 1:b .,.....

m-
CD
tldle- fjOtllm-""'"... J:o:oo;oj, M!allcHc~
OIJIL'IhUht"""'-•tnfh,.. .. SdCII!bdrli
ID 1llo ll!ltllp oflllo ICU l>r!IO'
t:ta:ts~WJd···~· tpd"Ptk:apo
polt.---mqb!t-lacl
1 ,...,...Ia ...-_.._~p~, ...
fl:tay m4 tDcc~a b:ube M• "'"'
x--
mr~M••••t11!1611; spata:ad.1115u1. 'lbl
'll:o "--tobo- ...pl!io co !hot lodl!lltlb"""......""""*'. . ."'
a m.,w
au 41! wlrttcra· dlta • •li!l!l!t4l
.,ll(W" Mfe tl'~.,., ~

_,_ ............. ,_.

. . . SDcale bqdrecl dltl ""'" tm " " •
~-..
·-lj:olj:Uio-llutllld.-
...... .lolllt.o . _ _ . , - " " '
cl141!_..... - - aod - 1 : 4 , . tbt-I!IOIIol.lldlol_,.fii!D. ....
- coloclda..... - .... :tl:lo"'""" ll:oko!J~Wonllolilow'"'~
~) ,..,..,.,. 1:bt ~ ....
abM:nlll
tb ....tD{pcd.lf
... _OIF\
_ _ _alM
ftmd1-.
p.........,.
abldll!tfi 51 ..,... .... .......,
""'*1411tofooulo!IIU-

~"'W'""tlf CDd liD 1rlD foal».

~ e~ !hn ..,.,...,.., IIIII "'"lii#o> o1
.I. P"""'W4). ~(d.,... .... )Do
I -

---~~"-"'ll:r- .
'IQ .... IIIcolod~ ..

- -
S.. ..... 8114o1ol ~~
~_
--.uptm """"'_
"' _
.
I¥' *'-' -~o.,...a....J
(tmm••'*"'' (jll-bl)
0!11M

:
-·
,.,~ad tl:b:ltJJ&.
tfoa. ot ......., ... ~ ~••ttsn ~
0De11!1J sqMJ'IIIbrM,
w:)fjt:w:'<o:·~·~....._..=
·~~or--
l~
~,..,..,...._
- Clll

------I"
~"""11").'-'w• (p,..l).
'lhooo-·-lbolOI.Ojot- co:I'*-I...U.(-wll"**:l"""
nmttoa. a4 IJltPOIU}. ~tiee·tn­

-......
.._- . A.llolofrom-Jibloilo,
_,1111-.- ta dlo IIIIIIIIJ II!!...,.
.,. ......, ... · - 0, "'""""'l"'...
PI :WI~"""'JUG.Ib 16-
cl&f.oa. e:pta""'"t.lJ"'dmed •Ofll)j· In•*·
- - -......,. ollllo 111110- t:koi tl ~)let f ~,.

"""'*'
1 ,...

- - " " " " " ..,. do: 'lldo tbzoqjb Ml/l:·.a:fiUI .. m:irlm ~
eo ••• on \1 tD u "' oau •
'O:olb:7 'lldo .. - mq:jJ;y Ill !CO ""' \Aftolp , .. ,_Ci',.tr«p,r.,.oftb
--...-Yl~Oot(lollt.- _....II:!Paii&.Aj)at--..-
__..,lbo...........,..
Qn------..-.
*"""" . -.. --.E'JCJ••t
111111&Dil biadD ta) m., u'WIOu Eq1Deta- botk> lllbcsb. edidrirmtw - -of
baw:D. to
~ ~xdi¥XD& ot d>J'O" ct.JW b:JfudUo.
...
':+~l:t-·~
'""-"" "'ll:o olllf"'P'ool:-'• -·-~~~~(moolllto!lt.,.U
.... ~- I>WI.OJb'dlo Glll cd J:lallltal 4fJ& feMon ctbl:pdlc til).

.. - ............___
J:llOI& ~ l:tWeN fl. Akf'Ol'lic . . -.1-!lo::l po~ooo~ ... charm~!), ""
fiM••ike Awtrawk drtfirettkm f.&cmei1J' ~ll!.elodot,jl:l cod jl.3 .......,.-.

"'*' , _ < : 1 - N!!/1:-.II'IU!

.,.Lo:oi.......
-"----
" ' - 4 .. ted boct Jl:tO 't'lld&blJ:.
wc11&4 otl.o&lt 1110 dl ID--~~~~~--M...O
...,CM~ttt--.l!::f

... ..-...
(511> liD IIIII)
~one .,.um.. ~a .,.... ta
...... ad,,....,., .. ~
-"""'_
- ...... - " ' " " " " :tl:lobt:tnb
fll:a:dNl.:c:ol.,..,.........,~
_ _ ..........,
MnZ!D. pc!Uuhn
...,. 1lul Gl8caliit111 dilt!LdlilwDt tba
- y f b n.kof- aal)iltodo&010
14 Part 1: Perioperative CaJe of the Surgical Patient

SEPSIS the more extensive injuries and/or infec-

\. MACROPHAGE$ tions, one can see a urinary loss of up to 30
ADRENAL ~ . g nitrogen/ day, which represents a degra-

~~~ ~
/ dation rate of about 180 g protein or 900 g
muscle a day. Utilization of body protein
may prolong convalescence and even con-
"'· tribute to mortality.

cgi.ggg~u-1
In contrast to fat. less than one-halfofthe
body's protein can be mobilized before death
occurs, which means that only about 4 to
5 kg of protein (or 500 to 800 g of nitrogen)
can be degraded. 'lhis suggests that only
~? 1,500 to 2,400 g of glucose could be synth~
sized without an external source of glucose
{ andlor proteins (1 g of nitrogen can be
PROTEOLYSIS equated to hepatic synthesis of about 3 g of
Fig. 4, Interactions among (1) glucocorticoids, {2) tumor necrosis factor (TNF), and {3) interleu.kin-1 glucose). If the brain continued to oxidize
(IIr1) in the regulation of sepsis-induced mUBcle proteolysis. The e:lfect ofTNF on muscle proteolysia Ia 100 to 145 g of IJI.ucose each day during star-
mediated primarily by glucocorticoida, whereas n.-1 regulates muscle proteolysis by glucocorticoid- vation, survival would be limited to 10 to 20
independent pathway{a). (From Hasselgren PO. Protein Memboliam in Sepaia. Austin. TX: RG Landes; days. During •simple" fastin& the patient's
1993, with permission.) body gnu:lually adapts to use FFAs and ~
tone bodies as the main energy source,
wbich decreases the daily glucose consump-
tion to about 30 to 40 g. 'lhis enables the
the kidney) mostly by using the glycogen protein tumowr. mostly ofskeletal and car- gradual decrease of the protein degradation
storage. 'Ihe quantity of glucose stored as diac muscles. In healthy humans under rate to about 10 glday of nitrogen after a
liver IJI.ycogen is about65 g.lk8 ofHver mass, pbysiologl.c conditions, approximately 250- week and about 5 glday of nitrogen loss after
which is about 100 g glycogen for a normal 350 g of proteins are degraded each day. 3 weeks of starvation. allowing a much lon-
1.500 g adult liver. 'Ihis amount of liver Most of the amino acids produced are ~ ger survival period. ('lhere are reports of up
glycogen is limited to approximately 1 to L5 used to synthesize new proteins, but some to 2 months of starvation with drlnldng.)
days of systemic glucose supply. So, about are lost (enezget:ic purposes, semted in Unlib in starvation. the posU:rauma pa-
24 hours p081:-injury, the hepatic glucose urine or feces). The depleted protein is~ tients are exposed to the persistentinfiuence
production has to challge from hepatic gly- placed by dietary protein. ofcatecholamines, glucocortlcoids, and glu-
cogenolysis to gluconeogenesis. An average In the post-injury period, the balance cqon. 'Ihese cataboJi.c hormones preclude a
human of 75 kg has roughly 15 kg of fat between muscle degradation and synthesis similar substantial reduction in protein deg-
stored in 16 kg of adipose tissue (the rest is is changed due to increasing infiuence of radation and the hypercatabolism of muscle
water) and 10 to 12 kg of protein suspended catabolic hormones and cytokines, and the and organ protein continues as part of the
in 60 kg of lean body ma&8, mostly muscle. limitations imposed by bed rest and lack of systemic infiammatory process.
Nearly all of the body fat is expendable dietary inpu.L 'lhe muscle is not merely an
without serious adverse effects. Unfortu- organ restricted to movtnnent or contrac- Mitochondria: 'Ihe Center
nately, glucose synthesis by the liver to sup- tion; it also plays an important role in main-
ply the glucos~dependent metabolism is taining the general metabolism of the hu- of Metabolism
primarily from protein, not from fat. Unlike man body. Muscle mass is -4596 of the dry Altho1141b metabolic dysfunction post-
lipids or IJI.ucose, there is no bodily •protein weight of a healthy person, and m081: recep- trauma or as a resuh: of infection affects
storage;' per ae. 'Ihe body protein compo- tors for l.nsulln, cortisol, and glucagon are critical organs in a variety of ways. ita gen~
nent consists of muscle protein, visceral located in the muscle. sis is generally linked to a single organelle,
organs, protein, and enzymes. Under nor- With mild to moderate injury. this cata- the mitochondrion (Figure 5). Mitochondria
mal circumstances. there is a continuous bolic response causes minimal debility. In are commonly referred to as the •power-

VI
Uncoupler Protein
Complex

NADH NAD Succinate Fumarate 02 Hp ADP+Pi ATP

FJt. 5. OJidative phosphorylation in mitochondria. The diagnun depicts the enzymes and cofactors involved in oxidative
phospbmylation employed within the mitochondrion to produce ATP from a variety of BUbstrates. Electrons are transfened
via a sequence of redox acceptors, ultimately being accepted by oxygen. The molecules that shuttle electrons are coenzyme Q
and cytochrome c. Gray shading denotes the points at which reactive oxygen apeciea (ROS) may be Uberated. ROS are promi-
nent in injury. and h~m the potential to do damage to biologic molecules, compromising cells and organa.
 Chapter 1: Metabolic and Inflammatory Responses to Tnluma and Infection 15

of vital (renaL hepatic, lung. and cardiac)

and nonvltal {skeletal muscle) organ func-
tions. 'Ihese failures are exacerbated by per-
sistent hypotension. even in the face of
J
p.,
more than adequate volume resuscitation. ~
~ ·. ~ In most cases, these tissues exhibit a loss of ·t
. 13LOOD,-~ mitochondrial function. Cellular tissue ATP (i)

Haart - · . . ~ . Vasculature levels will also fall. matched by a rise in £

'a
· 1 Su'bttrate f .u&Js ADP and adenosine monophosphate ~
. ' 1ISugars, Uplcb, ete.) {AMP). u
Although injuries vary greatly, serious ~
Ffl. 6. Consequences of mirochondrlal dysfunction in iDjury. Mitochondrial dysfunction has sevml
fonns, the most important ofwhich are the generation of reactive Q~tygen species (ROS) and the opening
injuries have common characteristics that S
can unfavorably affect mitochondrial me- .~
of permeability tnmsition pores. 'lhe tnmsition pores release mitochondrial contents, which can cause
severe damage to the cell, such as induction ofapoptosis as mediated by mitochondrial cytochrome c. tabolism. Hemorzhage effectively produces ,:t
'lhe combination oflung. heart. and vascular pathophysiology in injury can lead to mitochondrial dys- hypoxia. which initiates a cascade of re-
function by virtue ofinadequate respiration. poor blood ftow and vascular b'ansport and delivery. which sponses that are directed toward adapta-
in turn adversely affects these same organs. tion to lowered oxygen, which, at the same
time. can be damaging to an already injured
body. Hypoxia and ischemia-reperfusion.
with their lowered oxygen a'Yailability to the
house of the celL" 'Ihe power is distributed and/or blood flow. lung oxygenation. glu- tissues. will drive the cells to depend on an-
via the high-enellJY phosphate bonds ofATI!. cose transport, etc.), there is a rapid onset of aerobic glycolysis for their hlgh-enellJY
'Ibis enellJY resides in the terminal phos- metabollc dysfunction. At the level of the phosphate production. 'Ibis can initiate a
phate of.ATP. When this bond {Le.. between mitochondrion, this dysfunction has many feedback situation, wherein lactic acid in-
the second and the thizd phosphates) is forms. One failure of the mitochondrion creases. effectively shutting down anaero-
cleawd. it releases a substantial amount of with immediate biochemical consequences bic glycolysis as an energy source. In this
eneigy ( -7 kcal/mol .ATP)• .ATP is thus a is the production of reactive oxygen species setting. FFA can also increase systemically..
safe and stable fuel. which contains a large (ROS). 'Ihese products take numerous forms, probably from peripheral adrenergic stimu-
amount of energy that may be used to faclli- such as superoxide. peroxide8, n.itrlc oxide, lation oflipolysis. Limited oxygen also com-
tate a wide variety of biologic processes. 'Ihe and peroxynitrite. Since ROS are constitu- promises 13-oxldatlon. the principal means
conversion of substrates {glucose. ketones. tively produced by mitochondria. neutraliz- of converting fats to energy. 'Ibis. in turn.
fatty acids. lad:ate. etc.) to ATP is accom- ing compounds (antioxidants) such as glu- causes a similar '"stack:ing up" of FFA. acyl
plished via a hi8Jlly efficient process that tathione can buff'er against the damage of coenzyme A (acyl CoA), acylcarnltlnes. and
uses oxygen. AlthotJ8h it is e:xJJ:emely em- ROS {Figure 6)•.An additional consequence so on, which compromises the heart. Under
dent. the process is not absolutely perfect of mitochondrial dysfunction is spillage of these conditions, the heart and other tis-
as it has the capacity to "leak" electrons. As the contents of the mitochondrion into the sues are already at a disadvantage because.
a consequence. these free electrons can gen- cell's cytoplasm. 'Ibis is initiated at times by despite the high energy stored in fat. ~
erate oxygen-free radicals. Mitochondria ·permeabllity transition pores: which are oxidation cannot match the efficiency of
can increase the output of.ATP in response transient sttuctmes that open in a fission carbohydrate metabolism. 'Ihus, reoxygen-
to a variety of trlggeriDg events. 'Ihese in- response to stress, enabling molecules atlon.lf it occurs, may take place in a setting
clude accumulation of ADP or the greater <1.500 Da to move betwl!en inner mem- in which aerobic metabolism is not possi-
a'Yailability of"fuel" and oxygen. Cell-stimu- branes. Mitochondrial transition pore open- ble. because of large-scale diversion of me-
latocy signals. such as the presence of in- ing can lead to swelling and rupture of the tabolism into the less efficient "backup•
creased Ca2+ in the cytoplasm. also stimu- mitochondria. 'Ibis ultimately will allow modes of ~-oxidation and anaerobic glyco-
late the mitochondria togeneratemoreATR larger molecules, such as cytochrome C, to lysis. 'Ihere is one additional consequence
'Ihese stimuli are tied to an increased de- enter the cytosol and trigger programmed of elevated lactic acid worth noting. As
mand for work from the body. be it muscu- cell death {apoptosis). 'Ihus. besides failing mentioned previously.. an intracellular flux
lar (heart or skeletal muscle contraction). to produce w:gentlyneeded ATP in times of of calcium will cause a demand for in-
biosynthesis (production of proteins by the crisis. the mitochondrion generates sub- creased ATP synthesis. 'Ihe presence of
liver), cell dlvision (immune responses or stances that do considerable, often irrepa- increased lactic acid in the cell will cause
tissue repair). or the generation of heat (re- rable, damage and. in the extreme, can cause calcium to enter the cytoplasm from the
sponse to hypothermia). Clearly. all of these death to itself and its host cell 'Ibis is the exterior, providing a spurious signal for in-
functions can be tied to the demands of stage in which insults ofinjury and infection creased workload at a time when the meta-
dealing with infection and injury. can wreak havoc on metabolism. bolic machinecy is incapable of reacting
Under conditions of severe injucy and appropriately. 'Ibis has the untoward effect
.Miwehondr:lal Dysfunetlon especially shock. there will vecy likely be se- of further depleting already low supplies of
'Ihe failure of mitochondrial energy produc- vere morphologic damage to the mitochon- ATR Finally, regarding theloweredATP sup-
tion lies not with the organelle itself. but dria. ATP levels will decline. ROS will in- plies. an obvious solution for treatment
with its various '"supplies~ Unlike sugars or crease. exhausting the reserve of would be to administer agents/drugs that
fats, which are stored as glycogen or adipose antioxidants and damaging not only the increase ATP production under low-flow
tissue, respectively, there are no depot stores mitochondrion itsel£ but also other organ- conditions. However, such agents will not
of.ATP. 'Ihus, with a failure to dell.ver any of elles and molecules within the cell. includ- be effective if the microcirculation is mark-
the essential components {cardiac output ing DNA. 'Ihere may be serious impairment edly impaired prior to its administration.
16 Part 1: Perioperative Care ofthe Surgical Patient
Carbohydrate Metabolism
Glucose plasma concentration in healthy
subjects is strictly controlled. During the
fed state, digested carbohydrates are deliv-
ered to the liver, with galactose and fructose
rapidly converted into glucose. The glucose
is either secreted to the circulation or used
for storage in the form of glycogen or fat. An
increased post-prandial glucose level is fol-
lowed by pancreatic ~cell insulin secretion,
which enhances peripheral glucose utiliza-
tion, as well as glycogen and fat synthesis. In
the fasted state, the plasma glucose origi-
nates mostly from hepatic output. Liver
glucose production arises from glycogen
breakdown, synthesis from recycled carbons
(lactate and glycerol), and (to a much lesser
extent) de noYo synthesis from amino acids
such as alanine. Under normal conditions,
the rates ofliver glucose production and pe-
ripheral incorpomtion ofglucose is matched
exactly, keeping the plasma concentmtion
of glucose set within a very strict limit.
After being absomed by peripheral cell
tissue, the glucose is processed through gly-
colysis. The glycolysis yields three types of
products: energy as ATP, pyruvate, and inter-
mediates for amino acid production. The
pyruvate can be further processed to water
and co~ through the citric acid cycle for
more ATP production, or be secreted to the
blood stream as lactate. Most glucose uptake
is completely metabolized to C02 and water.
Pathophysiology of Hyperglycemia
in Criticallllness
Early in the course of the stress response,
serum glucose levels rise. Glucose availabil-
ity is needed to supply the immediate en-
ergy demand during the posttmuma hyper-
metabolism, especially for the explosive
immune activity. Glucose utilization is in-
creased in multiple tissues, including liver,
spleen, small intestine, skin, and some
muscles. A common feature of some of
these tissues is a high content of mac-
rophages. Studies have shown that in the
liver, the high glucose uptake reflects in-
creased utilization of glucose by Kupffer
cells. However, because the overall rate of
glucose secretion into the plasma exceeds
the mte of glucose disposal, serum glucose
levels are elevated.
Hyperglycemia as a sequela of critical ill-
ness commonly appears even in patients
who do not have diabetes mellitus. There
are many preexisting conditions (diabetes
mellitus, pancreatitis, cirrhosis, advancing
age, and obesity} or possible iatrogenic
causes (administmtion of corticosteroids,
sympathomimetics, total parenteral nutri-
tion, or dextrose in excess) to hyperglyce-
mia in the posttmumatic patient, but usu-
ally the hyperglycemia is due to alterations
in glucose metabolism, secondary to the
adaptive metabolic response. The synergis-
tic activities oftheHPA axis (catecholamines
and glucocorticoids), pancreatic endocrine
hormones (glucagon and insulin), and pro-
inflammatory cytokines are at the heart of
that change to glucose metabolism.
Increased Sympathetic Tone
and Hyperglycemia
Elevated catecholamine levels post-injury
have a well established effect on glucose me-
tabolism by a number of mechanisms. Epi-
nephrine directly promotes hepatic and
skeletal muscle glycogenolysis, and hepatic
gluconeogenesis independent of insulin or
glucagon concentmtions. Dufour et al. dem-
onstmted that under constant insulin con-
centmtion, an increase ofepinephrine plasma
concentration from 100 to 2,000 pmol/L
(which is equivalent to the levels observed
during exercise at 60% to 80% ofV~} was
followed by a 3-fold increase in glucose
plasma concentmtion and a 2.5-fold increase
in liver glucose production. During the first
hour of epinephrine infusion, glycogenolysis
was the source of 60% of glucose production
and later gluconeogenesis accounted for
about80%.
Gluconeogenesis is further increased by
catecholamines through the peripheral in-
duction of lipolysis, which supplies the liver
with glycerol. In addition, epinephrine stim-
ulates pancreatic release of glucagon and
inhibits release ofinsulin, further contribut-
ing to hyperglycemia. The catecholamines
also affect glucose disposal through in-
creased peripheral insulin resistance.
Hypereortisolism
Diabetes mellitus is very common (>50%}
in patients with Cushing's syndrome. The
typical elevated cortisol concentmtion
found posttrauma promotes hyperglycemia
through a number of mechanisms. In the
liver, cortisol stimulates phosphoenolpyru-
vate carboxykinase, the enzyme that cata-
lyzes the rate-controlling step of gluconeo-
genesis. Cortisol also stimulates the activity
of the enzyme glucose-6-phosphatase,
which catalyzes the completion of the final
step in gluconeogenesis and glycogenolysis.
Hepatic glucose production is further en-
hanced by the excessive flow of substmtes
to the liver, secondary to peripheral lipoly-
sis and proteolysis. As with catecholamines,
glucocorticosteroid not only increases the
amount of glucose secreted to the blood
stream, but also induces increased insulin
resistance. In this manner, it contributes
even more to hyperglycemia.
Insulin
Insulin levels vary depending on the phase
of injury. During the ebb phase, insulin lev-
els are reduced despite hyperglycemia. The
combined effects of catecholamines, soma-
tostatin, glucocorticoids, and reduced pan-
creatic blood flow may reduce pancreatic
~-cell sensitivity to glucose. During the flow
phase, ~-cells regain their sensitivity, and
insulinconcentrationsrise.Despite increased
insulin concentmtions, however. hypergly-
cemia may persist due to peripheral insulin
resistance.
Insulin resistance: Insulin resistance is
the inability of insulin to adequately stimu-
late glucose uptake, mainly into skeletal
muscle, or to inhibit gluconeogenesis in the
liver. Unlike in the case of chronic insulin
resistance, such as in type 2 diabetes, which
takes years and even decades to develop, in-
sulin resistance post-injury develops within
hours or minutes of insult. This form of in-
sulin resistance is called "acute insulin resis-
tance" and sometimes "stress diabetes" or
"critical illness diabetes:· There are numer-
ous studies on the development of chronic
insulin resistance, but little is known regard-
ing the pathophysiology of acute insulin re-
sistance. Studies suggest that acute insulin
resistance is complex and might differ in a
tissue-specific manner. involving multiple
causative factors and intracellular signaling
pathways.
Insulin signaling is initiated by binding
of insulin to its receptor, followed by activa-
tion oftwo main intracellular insulin signal-
ing pathways: the metabolic pathway (the
IRS/PI3K/Akt pathway) and the anabolic
pathway (MEK/ERK} pathway. The meta-
bolic pathway involves the activation of glu-
cose transporter-4 (GLUT-4), which charac-
teristicallyisinvolvedintheinsulin-mediated
glucose transport into the skeletal muscle,
cardiac muscle, and adipose tissue.
Several tissue-specific mechanisms are
involved in the development of insulin re-
sistance including alterations related to in-
sulin receptors, including impairment of
receptor expression, or binding or inhibition
of intermediaries involved in the insulin-
signaling pathway for glucose uptake. Srud-
ies investigating potential mechanisms of
skeletal muscle insulin resistance in experi-
mental animal models demonstrated de-
creased insulin signaling via the metabolic
pathway following burn injury and reduced
GLUT4 mRNA and protein levels in rat adi-
pose tissue during sepsis. Epinephrine has
been reported to enhance insulin resistance
through inhibition of insulin binding.
GLUT-4 translocation, and IRS-I(metabolic
pathway). Moreover, different tissues have
been shown to develop various degrees of
 ll.tplllo-11>--~­
m,.,.,.,.,..,_
ii-._I_...,...,_III.W, . ., ar p>....,_,
.
-
~- -111141»11o-llfllll'
J1at ,..,_.., bt. eetll,. ...., .. TKP .... bohlododll)' .. -
poLCra:mll.• • *lid fll.lw!W!IJ ..,_ 11111 ~
"""" ..... *"""-'ofllll'l'lil'-
ll!:fA JW'Drw Ia ~
. . . rD! . . . . . . . .lbolhotlf_...,.tot<.......e..ol-
- 11114CIIIIfn>lnlrnel-lllcll> _ltl_tl>tllo-Oiltil_.
tfJII« _.,.,¢
l'i",......, .........II1J4tlll,
'lllo~ ... ,.,.iiwrrJ ·~ 1m OXf r:..& &
_ ...... 1110 Ia
- -.. -rP--111
llocttna . a f:l:trlhtt W1tana tr1 tile ......, • . . , _ -~~~ '"IO<)lo IIIII
--...~~~-~~~~~~~-­ llill,po<JUI-

--.-·-of
..00 TIIPoQ- ltolll
~4tnlct J.1119''4Mtar!«s.AID.x:edt-
ltl,y!lul doom ...- - - " - " , . . .
lj>l.,..,.otlt'kd!Df-- .......d!.o-oflboliiA!A1W>IJIIOl cod
--....-·~ar
-
- pm!_...., .,-.
............m..b .... _ !lulliiA!A
...,...., """'-"""" po'bllllr'by-
.....,.....,Jih>sm
~T!il\ .,.._
!J>. nlla,lm!nNN!ory-~
o!............t.
J>Gbwlf 4olmt".......' ' - ~& Stlml&r t& TNJ.. n..l . . 0&0. m& •...,.. 1ftlltlllltllltJI!I!D
t:f»~
TIIP-u -.:&ttlll8
Uillt.o!l.&adt..· ••blfabt.~~
n....,. "'"""' """""tbU ...
1:bt a.:ata matno 1 zentata tD tlllfu,
- - . . ll -
uloiltm .._..., to
..... ibo n,..ljl
lljJidt,. I CU. o(Mnl'l!le! 11101"' tlol.""
tf:to ma& eftt49N; &t m"""'ft: a.efiJ db:lfo.
!OIID-!tta!M••li!~ll.l' .,._'lha-yUiol-l&afltlljtadll!t

*'-----""
-~lll<iollocal .........
"'. . .d!.o """"""'- """~~~- Ollllr
-9 ...... """""""' • .,..._.(o!-
'Jhl..t 6t'JM'1l tiL¥111 S)lfdfte ll'llll£b. allopq&ftlltta ~~~~·-of ~lloow-~ .... lt.!dt'o-
--to"" ltucillocl
ma:lolWirlital!led#......
Ia dto -op-
-
1DIIIt&'tdhm4Ddalfl+"'QI -~ ~
<l.od!o,I-CIIIolo.oodp-.,....... db:l!i9cll:o ...... '::sl;; ....... MllirM ., ... eat;
!'lloiU
~ .... - - . ... I!J-
a's:..,. eaoc-~ ..IW ..~'lido*''""'
.,_,...,._R>r_"JJk
-~~oow­
.A:r1oCtulr ~~ • ...,. t:t 1act~Jo»-
""~~~~~-of !lui <tltloollr 11.11 --~~~--­
-.. ~-boo~~!~&
,.. _ _,,.,_ _ _ "1»
-
~'*'¥"" thr.,..._
Jib~ .. ,.
"" ...... tx irKI'•d P1010 pJ»'b"'1on
... -~co
tr.:wm '""-«='•"4, cod lltt_........,
.. ___
-13llooll/(f-- 'IIIU-ibo:l
illl_tllo

boll>"""'-""'""""- ---~.~.----
10~~ ........ ocllllllll.ll"~ - ~~~-JIOI' Wfllt/";~ lbo th-
llotoc¥t
~'lha-<ll _ _ _!tDOt 1w ...... t:lt.t ~II. ~Wit -&--~mll.tbmcii>W/0>-
matnWneil GRr U.met: hz ::u;a b lod;:folt. -(l'OJ). ... ibo- _ o f .....
..,,_..,,.,11.....-laaaoddl- flo- """'"""""'
COM-.! ibo-""
Ia ibo !CU cop.
Ia lbt Sodr..tlldl ....,.UJIIIot""'plof"'~--m
llnllllllllll'_lllo_of'!)IIIIIJ)It- t&mllied 1.648 P"'""". milt alwb:mlblcl a::u:r Olta' «<:U:r hw •• •• ad. • t7D:"
- Cll!tiJtol.. 02UI GILt......... "!'".,.. ........ """""*"ff'l'JO'Ioel-~
......!Ill _ _ __
thl*o!d .,.....,_,., eedptoch'*'m~
mow/1'"--"'--..
th<,... ""'*'
~-

'lllo .....-~M ar loj< lm..IIIIIP-IoJolo-•ml>C::-

l"''l...,.. ...... ~ m.a., ""J''I<.
-
811-ll.O ""':IL(.:t.4 106.1 'DirAii/L}.. ...,_
_ ...._Ait!J'_...
S:tral.t 'hor!Mr!M, ,.,..,........,. ~1tiJIII.
-•prcCJill""""" ~llor­
aetiP llltD.ted m411P • •nw atllll 'Wtl1* pam! 'db. 00Ufl!!' 11 111111 t..Lb. tUrw - - tllilt ar iiJillhtl""' II> dto-
_do-

lbohoa>l--lllodlldbJ"" ..... "'... - .... ~~orp&lit:odtP-tlooolofl.IO &omcoo~lli--,Jpl<"""""'

m-IDOI]III<-aoltbt- ll>lllii...,:IL(IG.O!»W -~ 'IIIUt~>­ • - ildd!t-
-
-lmU.
otP<-potlx~ ... ....,...,._, 1» prw.clt,.,.......,...toc.d m ...... &om
'IG .... ""'-..
8!1ltr:1.1bl M)l:rofll U> 4ft tr:l.tbl.,..tuc.
tll_'llto_of _ _ _
~ If putltrLa!,- _ ..., Ia -
""""""~
...Cilled·ll1f·•tw·•"" ---dl:ot
*""
'lloooo"'""'.,.oloo-
til....,·-
-""'to rom'Jhe,.........
_PIIA>_'IIIIl..
....
llod, llpllil ro Ill! Jlll'*lplltlli>!Ito--
~

-~--- ...... llllll

6..,..._,,,,..ibo.W,wuod~~'OI!k- lilo""f...,.,....,IMP_('.U)L)cod
-o!-~ibo:l........t -liM lo!!» !Itt--~ ....
m•atttulpe'" 1 '
-
(A ....••It,tll . .
... lll!roled, """ d!.o ......:llf Ia
---~-ll>tlltlll
til ~-ll>tcllpocj1ooll>--­
---«.d>•l!&!la.oord!fl.o:lool
'OIIlotlll:tlllut-.I>!Nitl:l-«
otbra;ob:;...,._A~
t~Uqll.l'!lttam.t _ _ ......... l,210 _ltJ<IJ..,..
lltor.'lloo...,.,.,ll...,... w-.,_
.irn!lolta:t!'l'6oo bdll>flllll'
&ll......:llfcod_ r.tlo:l
....tc.IICU pollolnt> to cotlxo
_ .... __ _..• -""-..uan,a.tr .,.,.,..,..IIIIo ibo ....
cfJMW'IIpiMl dlla.M.
. . .- ..-~-(1&7!1~ ~ 'lOto- ~ ltuo
llmhor ""'-~~-.. m"'""ctil lilA d fl1mrA II ""'-
'llll!dlll-mdb)' _M ~
_ __
Non~ID-C...IIill»-
__. ......Oib&ta-Aip _,,,,m;.....
•'"loit ~·~ ._,~

- (NICS«J&AAI) 11111 ibo:tMolo! ~ D01'i!{iltu(tll

~illP"'i"olllllC-IIoloolto<loia>­
dtllt, IIIII p..uily -
",..,...*boodttn.......,dW& cod<lllola.do,l-- clllloi8 -
'lbtohoa>l .....
18 Part 1: Perioperative Care ofthe Surgical Patient
bind to cell-surface receptors that are cou-
pled to the activation of adenylate cyclase
upon ligand binding. The result is activation
of cAMP-dependent protein kinase, which,
in turn, activates the intracellular version
of lipoprotein lipase, known as hormone-
sensitive lipase (HSL). The net result of the
action of these enzymes is FFA and glycerol.
The FFAs diffuse from adipose cells, com-
bine with albumin in the blood, and are
thereby transported to other tissues where
they are transported into cells. Fatty acids
are the most efficient source of energy for
most cell types. For example, catabolism of
1 mol of a six-carbon fatty acid through the
citric acid cycle to C02 and H~O generates
44 mol of ATP, compared with the 38 mol
generated by catabolism of 1 mol of the six-
carbon carbohydrate glucose.
In the normal state, glucose is the domi-
nant contributor of energy production. Ac-
tive glucose metabolism down regulates FFA
oxidation, thereby channeling those fatty ac-
ids into TG stores in the muscle, liver, and
adipose tissue. However, in the fasted state,
FFA is the dominant contributor of energy
production. The main breakdown of fatty ac-
ids for energy happens within the mitochon-
dria in a process called 13-oxidation, as it oc-
curs by recurrent oxidation of the fatty acid
chain, at the !3-carbon position. The rate of
FFAs oxidation is determined by the rate of
transfer into the mitochondria. Medium-
and short-chain fatty acids can enter the mi-
tochondria without difficulty, but the major-
ity, which make up the long-chain fatty acids,
must be transferred actively through the mi-
tochondrial outer membrane. This process
starts with the fatty acid reacting in the cy-
tosol withATP and coenzyme A to become a
fatty acyl-Co.A. The fatty acyl-CoA is trans-
ferred to the mitochondria via the carnitine
palmitoyltransferase enzyme system (CPT-I,
CPT-II). This is the crucial point in the regu-
lation of the FFA oxidation rate. Glucose
availability and metabolism control the oxi-
dation of fatty acyl-CoA by regulating CPT-I
activity via changes in malonyl CoA concen-
tration (malonyl CoA is a regulator of CPT-I
and its activity is dependent on the activity
of acetyl CoA carboxylase [ACC]). ACC, in
turn, is regulated by changes in the concen-
tration of citrate, which is activator and pre-
cursor. Citrate is the intermediate product
of glucose metabolism through the Krebs
cycle. Once inside mitochondria, the fatty
acyl-CoA undergoes (3-oxidation until the
entire chain is cleaved into acetyl CoA units,
which, in turn, enter the citric acid cycle.
Upid Metabolism During Critical lllness
During a critical illness, under the increased
influence of hormones such as epinephrine
and glucagon, and under substantial influ-
ence by pro-inflammatory cytokines, exces-
sive peripheral lipolysis and mobilization of
FFAs is observed. Likewise, a concomitant
increase in the de novo synthesis of FFAs
takes place in the liver. The FFAs are used as
an alternative, available energy source for
the peripheral tissue in a time of need,
which spares much needed glucose reserves
for use by the nervous system and erythro-
cytes. TNF was found to play a major role in
enhancing peripheral lipolysis and hepatic
synthesis ofFFAs. TNF also has an inhibit-
ing effect on peripheral lipoprotein lipase,
which causes a peripheral resistance to TG
resulting in increased lipemia. Other cytok-
ines, including IL-l, IFN-a, (3, and -y, may
also influence lipid metabolism.
At the same time, while the organism re-
cruits its energy sources, there is a para-
doxical increase in liver esterification of
FFAs to TG. A number of contributing fac-
tors play a part in this paradox:
1. FFA flux is elevated to higher level than
the oxidation rate of the body, which ex-
poses the liver to an excess ofFFAs.
2. Both glucose and FFA levels simultane-
ously increase in blood plasma. This hy-
perglycemia leads to increased hepatic
glucose uptake and metabolism, which
leads to inhibition of CPT-I and fatty
acid oxidation, leading to more accumu-
lation of hepatic pool FFAs.
3. The increased !3-adrenergic stimulation
causes increased peripheral glycolysis
with concomitant production of pyru-
vate, which exceeds its utilization by
the mitochondria. The pyruvate-lactate
equilibrium results in excessive secre-
tion oflactate to the blood even without
any hypoxia or hypoperfusion. This lac-
tate is metabolized by the hepatocytes,
increasing either gluconeogenesis or the
citrate production through the Krebs
cycle, and possibly the de novo fatty acid
synthesis, thereby also contributing to
the inhibition of FFA oxidation or TG
synthesis in the liver.
The result of this process is an enhanced
liver TG synthesis causing hypertriglyceri-
demia and often accumulation of hepatic
TG that leads to a fatty liver. The reduced
activity of the enzyme lipoprotein lipase in
the muscle and the adipose tissue decreases
the clearance of lipoproteins, leading to
worsened hypertriglyceridemia. The clini-
cal significance of this hyper lipidemia, hy-
pertrigliceridemia. and the tendency for
fatty liver during critical illness is not com-
pletely clear. However, these findings have
important implications to the management
of nutrition support in these patients. It has
been observed with regularity that over-
feeding. especially by parenteral access,
causes enhanced steatohepatitis and a de-
teriorating prognosis for ICU patients.
Protein Metabolism
Proteins contribute to both structure (skel-
etal muscle) and the function (enzymes) of
the body. The absolute amount of protein
depends on the age, weight, disease state,
and nutritional status ofthe patient. Skeletal
muscle mass represents 30% to 50% of total
body protein, is greater in men than women,
and declines with age. Between the ages
20 and 80, total muscle cross-sectional area
declines about40%. Following injury. the in-
creased urinary excretion of nitrogen from
the body is roughly related to the extent of
the injury. Nitrogen is primarily lost in the
form of urea. which represents about 85% of
the urinary nitrogen loss, although this pro-
portion varies widely. Creatinine, ammonia,
uric acid, and amino acids are also found in
the urine in larger quantities than normal
following injury. The nitrogen molecule is
used as a surrogate marker of protein be-
cause of the fixed relation between the two
substances (6.25 gprotein to 1 g of nitrogen).
Thus, the net loss or gain of body protein is
determined by nitrogen balance, and this is
a general measure of the catabolic state.
Maintenance of protein within an indi-
vidual tissue is a balance between rates of
protein synthesis and breakdown. Synthe-
sis and breakdown are often mismatched
during catabolic states, resulting in organ
protein loss or gain. The catabolic response
occurs by a relative increase of breakdown
over synthesis. Protein turnover responds
to injury and infection in a manner that re-
distributes body protein to satisfy its needs.
The synthesis rate is decreased in "nones-
sential" tissues (e.g., limb skeletal muscle or
gut) and is maintained or enhanced in tis-
sues where work is increased (respiratory
and cardiac muscle, lung. liver, and spleen).
These events result in translocation of pro-
tein from skeletal muscle to the visceral or-
gans (primarily liver, spleen, and heart),
which are vital for survival.
Two amino acids, alanine and glutamine,
account for approximately 50% to 75% of the
amino acid nitrogen released from skeletal
muscle. Alanine is used as a building block
for various proteins and it is an important
glucose precursor. Glutamine plays a very
important role during the stress response.
Similar to alanine, glutamine is also a gluco-
neogenesis substrate, but it mainly serves as
a primary substrate for immune cells and
enterocytes as both rely on glutamine for
optimal function and energy production.
 l'
Ololom'•• allo .1001;1c'P•• lo 0<1!1-""" w!llt~··~.a\ll .... •lmo-

.....--...
't.cn! ......... '\ tad_,. M
,....,.,~ctmpocta.tt=.,,...,_.
*ptMmiO!I' far
- n.. '""'-I!IOd!ll'llio-
- j)illllwiq tl. 1111)111 , _ lo ~
twf..Wt fa~ 1D Jr''... ,., tf» fJ:aoa.
mrPI'In i •• 1 f1m rl -~ J:lllll --~
ijidtNI1tfli.f!MI!lmt8lc:eaal.r~
Iiiii by....... 811111olo- ~ t:lllolo ...... Al'Pit.llllllllll~-
dt:op 11 all> .-1111 oo:toonl-
1""'
taodu IIIII ,.........aa...........
pdf Go so • """"""" ta ""
.......
•tllo_ _ _ _, _. . .. 'Jlto 1m""'*" tl.e ~ .... ef a&!>
""'". . (Ji""" edll) Ill til """" IIICllt
XIW..l.'fade:t
_<tf&_ 'ft:l!eiJ'
_ of tf«M*'•• tba
~·-""""'lbo'"""'""...., ...
_ _ lllbo
~ boCb. u .. aB'Cit of tnfllri'IP'I'CO!J
....Ill~ loubi II> cJo.p~o~~ ... Ill ....,.,_. ...t ... Cqttl ..... for lbo !1!-
....--"""'J'&tSI•-••·~ &d:a ~ tl.e "'"'"S!Nt!~ mdd!W. 1he

IIIII-
llltt.ltlu_ltjp_.... tltlt t l l o - fiG!IIdilla bilt!Rm t.ptoqta mel

-·--""'····--...
""'l'l'- for .,._... ..., -.!p JG.¢e< ....plojol•ior... l!ollio ......
1111bocl,r'll ~ Jll'llll.!t odd. -d.lbo ~- Jnqdlr
edJI ""'Jlb*IID doe lopolio . _.. CO
ad:lrtle4 't!r aM t1 ttrtcda • , ....,.,., • 11]11111. - adliCOcl, llliiJ)IItr - ...
-·-lila&...,_-.,""' JMI·a
1ltal!l. ",..,,,.. ., me'*""sd
lU1Ib.
•ajla-11.--al·
.u., terbfrc poo"'"""tl'ld!)ty ~
tc:C'Idt:fcale '«fil C'llltu d . ct.rmMtw. J1l:tlk ~ ~ QZJWil\
- ...... .,_._Ill
~""'"_a_,-~
jitiWJ1tiJ:« til

·-"!jed!
a.,., . .
i!Sezzrrt:oef:(m of'blgt«d• ad. tmd.......,.
- tboJIO'Uid1<A ..... Iolbo,_
c.frcll !lrttcm fD I:D alml) J:IUifild.. 5 m., e I M
Q!llol...,._
Wed til .,.......a 11:\ tl.e 1lqdtr
..0.. ~ rJJJ/1 ... """" • ......lot
""'*'J:dk: tete. ltd aJ.6o da tAJMw!A d.e,
Ji&t$111111. . citit*t :QIIHIJtOct fx JUit Ill

.. . .
til ....... ~~~~ ...... """"""'

- """-llllatllo
., ""'"·~"""' ....,.,.,.,..,.~
Slo\lloo 1tl
rw "'""'
. .dbcrwecltheta-tnw. wtfb
Nldtecl m r,.,.,..
ciloNio,--ll:qtmlrCidl-...
el tftrw\ec;ID$ ee.do-
tl:lltrlwtt.• ,,••••, ~tatD.lt......
!I,......__,""'IIOICIOiodm lito c.-

- ..- "'_.,_-...
&mt,jort!ta&t
'llltlhlrllaloto ,.,..,.-a! of llJI.c 7, ,......
blctGzta A1li:a 1bo IJMado ctm;elef:lm Dlldllltil-- t i l - -
Ail<rd 'lOIII "~II. tlllli cod !16'111
tllt-wt'mmtl-lollto-1~
.,"'JtM.~h tlon, .. -·~""'"""-""*'"'-
Ml • .,..,_ fodor~
Blpd:lt a M d d ct1ll cata ~ WI, ...1\U-d,!IIOI,&ttll.t-.ctlloo.
- Jiljllb - acl.llll)llt ..,......,_,_ _ . , . ...... tl. p:aaiD. c - - -
- 'ldli-. 'llltw.....,o! oollt.r- ttt, ....,., m. lJu Jr.:w oil O!P J11Mm.
...., Ill lito ,..,........, - "" -·~tlul'l!l'!Wmof­

~..:;.,"':=~
fodor. lito bolllll-ol t b o -

_,__j!dl.., 'lh&--
ltlllio.,...... ... <J.dto""'""'• cods.- -.pl<lr. 1'1:\l'!- of_..,.... .,..
d.oa:lDg.,._, t, ,.,..., e1w ca&la.t

p&t!IJI!ylbo-lt.....Wiio_tl_
Uwt
'l o 1101111.-... -.,..so -CIIjlll- llljayiiiClpoll!bll _ _ , . . . "

...,.,....,..,.. ,..._"""""""""""R....
""""Pllr>•aopido .......... Ill la!M, ... ~odd!!,~ - ...,..._ .._ltulltll.... ,.,.,..
- cotll:
tl.crd>ra, 1:btllm "'')iiaJ llowii- lllal>r- & t a l - cod-.
-
a•• "rwttna
llll*D 11.1111- - · It II .IIIDclb)'HOdro.~ ... ~ ~_.._..

11*1--
tbo amm~ ~ GIIIJIUl

111olllptioeol1!1*tat
... tDtd:tod lolbor , ... O!Wio
hJ tbo: "*'«'PWiW ft..-fW!mn.
m ... ~pz-~llfu­
poo!todt,lo;lboittuu-..., _
"""*'
...""
.,.., •
Cltttlo&I-
-~~-.s

*'m......taz.d*'ham....
SII!S-Iloj)lltr..... ~aod
+wMel !!wfn(trfillldll. 'm-e eeJtJpot
O)IIMINAkW bt, f.~~-
....-.'llo--of~-
&I - - ~
11111 ~
lljorJ. Of II>
<-,u o(),
'Ibeun ....
COt)'""""'_.a""""'-~­
boillld!- "-'·---......,""
20 Part 1: Perioperative Care ofthe Surgical Patient
compromised due to stress (shock and sep-
sis), a situation that may lead to liver dysfunc-
tion. Liver dysfunction can be divided into
two: primary and secondary. In normal phys-
iologic conditions, post-prandial splanchnic
blood flow accounts for up to 30% of total
cardiac outpuL During the stress response
period after a severe tissue trauma or sepsis,
the portal flow, which arises from the
splanchno-mesenteric vascular bed, is sub-
ject to disproportionate vasoconstriction
(under the influences of a-adrenergic and
renin-angiotensin stimulus). A physiologic
compensatory process (referred to as hepatic
arterial buffer response) of inverse changes in
hepatic blood flow in response to changes in
portal flow takes place, but this response of
the hepatic artery is often altered during se-
vere sepsis or shock. compromising hepatic
blood flow. Hepatic dysfunction that occurs
in the hours after the insult or onset of sepsis
can be viewed as a primary dysfunction and
is most likely linked to hypoperfusion. The
outcome of such acute liver dysfunction can
be catastrophic with disseminated intravas-
cular coagulation, reduced hepatic lactate
and amino acid clearance with metabolic
acidosis, decreased gluconeogenesis, and
glycogenolysis with subsequent hypoglyce-
mia. These effects are potentially fatal.
Secondary hepatic dysfunction is be-
lieved to be caused by spillover of bacteria
or endotoxin and the subsequent activation
of inflammatory cytokines and mediators
in the absence of circulatory changes. Mild
cholestasis is a common sign of secondary
liver dysfunction during critical illness. It is
often an isolated finding secondary to intra-
hepatic cholestasis caused by rapid down-
regulation of transporter proteins, such as
NTCP (a basolateral sodium-dependent bile
salt transporter) and multidrug-resistant
protein 2 (MRP2), which is a canalicular an-
ionic conjugate transporter. and a bile salt
pump.
Heat Shock Proteins
One of the hepatic mechanisms to deal with
the stress and avoid a secondary liver dys-
function is dramatic up-regulation of liver
synthesis of HSPs. The HSPs are a group of
proteins discovered during the 1960s in
drosophila cells that were exposed to sub-
lethal temperature. Although named heat
shock proteins after their discovery, HSPs
actually serve as general survival proteins
by increasing cellular resistance against a
vast range of stressors and not just elevated
temperatures. In normal physiological con-
ditions, HSPs act as regulatory intra-cellu-
lar proteins, stabilizing other proteins in
proper formation by chaperoning proteins
across cell membranes. HSPs have the
capacity to repair denatured/injured pro-
teins and serve as part of the cells' own re-
pair system. HSPs serve as one of the most
highly conserved mechanisms of cellular
protection, are found in virtually all living
organisms, and are a key part of cellular re-
sponse to stress. Enhanced HSP expression.
using transgenic mice or by a mild stress
before the insult, has been shown to be cy-
toprotective in experimental models of sep-
sis and other types of stress. Increased ex-
pression of HSPs has been detected in a
variety of clinical settings. In patients with
severe trauma, a correlation was shown be-
tween survival and the ability to mount a
higherHSP.
Glutathione
Cellular glutathiones play an important
role in the cells' ability to reduce cellular
damage, which is initiated by the typically
high oxidative stress present during severe
illness. In an animal model of sepsis, a six-
fold increase in de novo synthesis of gluta-
thione by hepatocytes was demonstrated in
the first 2 days of sepsis. In contrast to acute
phases proteins, persistence of stress re-
sponse throughout the course of sepsis in
rats (4 days after infection) led to depletion
of liver glutathione. The mechanism of late
glutathione depletion is not clear: one hy-
pothesis is that it is secondary to selenium
depletion. Selenium is an essential cofactor
for glutathione peroxidase activity and it
has been shown that depletion of that mi-
cronutrient in sepsis is associated with in-
creased morbidity and mortality. The sele-
nium requirement in sepsis increases in
parallel with increased glutathione peroxi-
dase activity and glutathione turnover. Re-
cent randomized and placebo-controlled
trials indicated that high-dose selenium
supplementation can improve outcome in
sepsis and septic shock.
Steatohepatitis
Another important factor related to liver
dysfunction in critically ill patients is ste-
atohepatitis. The liver in critically ill pa-
tients faces an increased flux of FFA, amino
acids, and carbon-3 compounds, such as
lactate and glycerol, together with condi-
lions of hyperglycemia and hyperinsuline-
mia. The hepatic capacity of FFA oxidation
and secretion seems to be inhibited, and
TGs accumulate in hepatocytes leading to
steatosis. Steatohepatitis in critically ill pa-
tients has been reported mostly in relation
to artificial nutrition, especially total par-
enteral nutrition. Torgersen et al. have re-
cently reported in a retrospective study the
pathological findings of a postmortem ex-
ploration performed on 235 patients who
died in ICU due to sepsis. They found ste-
atosis in 33.2% patients, signs of hypoxic
liver damage and cholestasis in 13.2% and
14% respectively. Koskinas et al. reported
on end-stage pathologic changes in the liver
of 15 septic patients dying in the ICU. His-
tology of liver biopsy specimens showed
portal inflammation in 73.3%, centrilobular
necrosis in 80%, lobular inflammation in
66.7%, and hepatocellular apoptosis in
66.6%. Various degree of steatosis was ob-
served in 11/15 (73.3%) ofpatients.
Intestine
Our understanding of intestinal barrier
function biology, its potential clinical im-
portance, as well as the pathophysiology
and consequences of gut barrier failure has
changed considerably over the course of
time. Now, it is clear that the intestinal mu-
cosa functions physiologically as a local de-
fense barrier to prevent bacteria and endo-
toxin, which normally are present within
the intestinal lumen. from escaping and
reaching extra-intestinal tissues and organs.
More recently. it has become apparent that
the gut can become a pro-inflammatory or-
gan and that gut-derived factors, liberated
after periods of splanchnic hypoperfusion,
can lead to acute distant organ dysfunction,
playing a role in the development of multi-
ple organ failure.
Initial interest in gut barrier failure and
bacterial translocation was based on clini-
cal observations that trauma, burn. and
critically ill patients, especially those
developing MODs, frequently had life-
threatening bacteremias with enteric or-
ganisms in the absence of an identifiable
focus of infection. These clinical observa-
tions resulted in a large body of work inves-
tigating the relationships among gut barrier
function, intestinal bacterial flora, systemic
host defenses, and injury in an attempt to
delineate the mechanisms by which bacte-
ria contained within the GI tract can trans-
locate to cause systemic infections. From
these and subsequent studies, the current
role of the gut and gut barrier function in
the prevention and potentiation of systemic
infections and MODS have evolved
Gut Barrier and
Bacterial Translocation
Intestinal barrier function can be seen to be
of major importance when one considers
that the distal small bowel and colon con-
tain enormous concentrations of bacteria
and endotoxin. Under certain clinical cir-
cumstances, intestinal barrier function be-
comes impaired, resulting in the movement
of 'bo.doda PIN.,. ~"''" 1o lloo .,._ -b)' wb:l> poll- ... lldb w...,
_ _ 'IIU_<Il_&Dd
tbctt ,aldDatt ~ l:tul ......... CDI.t- __ lo...,..-...-
e:11»:1hl tmnm ..t•dlamdciJ tad~

CDMl t.Mit cod q-11!1 "'• ~-M,....,. d.Joca ef te&dk-s 0>'9keth:w cod J
lu-.- -•
_.n.o.r...,.... -"''llloa
...bod_ _ .. ll.onlly i
---ol'-lllmald-
'llo~_,
... _ _ _ ... tlooF badedal
""'"'"'""",._,
- · . .- &
. """"
-~ t'G'Ie4e'ftl 11:\ aprr!,..,ul

_.--""""-"""""""'
- ·p:t--·-
loa-rll--~-­
ak &:ledtoWlec:tetJ• ortJCda:tedot:atba
p!Kial-ot-.:tyllljlo:od,_I!IICI. I
t
bolb1Dizll>¢e)dolal'--1Dcl•- ~~fa hsmPtltlJlleert::l1'\ Qae
mdflll I'W'tl..,...flnll I 11 411f*!l\CIIqlol•
pcw<tM
, .., . .. ._
.-- "'ll.oO; - dl!f.
-~d!.c
"' ...,._""
tn
blltedll
.....mrm..tlb
"""*'x--
.. - -....
""•
rwJooetton O'PieG
10;
., to - ~c..-
tr.ll!ll (1rit(bgtl . . tD .,......
IIIII.- IIIIIIIY I!! !1ilddQg111o , _
,oft..,,.,..,.,
ledt:aft'rrptb'eei Cil(l.med!cteol..,.,,.,.
wIt:*) ...,...,.,, 'b1ooll ~ iMd:tll« t& d:r!uldlae, * d1.e mW'Made l.r'~'
-tllopoltal- ~ o:u
,...,. liM- -lo
.. , ......_.....,..,.ocJ!IIIod pill>-
-
~,.....,.._ofll.o
lie • . . . , _ ta P-l/mlliiii:!P't!:td'l>t:Wtbo--
tbo liM f!Lm'Yft') bmSaf bCkl: &ld
mal.,..,.-.
batWW ~......,..., to m.edQiM ~ tbef.. -
....·
llod-""""" ""Ill lint
co lie "'l'"""
6loclr. ...,_ lOJI!entwrfe ~·-• tLttD:ra (mwnt«rk
~ lo
lllljor -

_ ... lillltooo......,..., ... _.IDJ..,. IJ..p ....... , _ clo:d- 1ia

~ ....,.,.Uf CD & liS ~ tU thradt ~ wt:.ldl ~ 1.at6 tl.e
DJ"'''*"bl).lrJ'tll'tM\IIIIIIldktotta,Pat. --11114-dloplllr><•l
hf"'Ch'··~ .........,... ~'lhaou-dlxil<ol..a
• • ,bel mdaiK:e ~ tblt ....
..l:!tlttu•.tOII..,.. ....... ~~id•a,p-Jhoct.~fll~Gl''b.:.Jm.
d:bdaef. ad eqwwheefl.ltlteA$ut ~ ...t-
llloputtwo- l!ol!ct.tll~
'*"'- ......
'lle- fl.~ J::t1C14teel '•oaetoa tDjlq l:lt pl dS' 75l JD-tn:'WDlri4taiJ
~ ld co
&a!lolocort./D1
tfoo <iibo• oo•op;o!p:t'blalor_ ....
-~~----lllllll.tmajor
~""""'co t1>o .,~- ol--'1
- ~<Ipdf- !l.o<llr- ...
~ 'lbo IJ!IbW ,.,•••• e) a4ttnxtl&ll
....~<lfll.oGI....,.dopo"''"'-..
«ootll.o pill &II~--­
lll,y _.w ..-... .--:1 "'1¥tt
_.,111
'by ,.tnttlntn&tm"- f:XIIII\ ~
«ii pn'i""""'w\ mdof!1ntog'fl-
..,~wll>'•••...,.,.ll.o,......., .. <i

ofll.o _....,1!!
'tnibbaldar iiiiijiD& ,_.,,e) tal• • ,
lf<W"Iollb)'-
-...---..-.ll.o-
JDeO aftlt(bt .trmttee e1 ~lMIMIIl

- -lo
..,... -..
tbe:t.:cqstted~ CG~ll,«tmrlcbt ~

""' ...... of •

major
'bomhooll\
1llo pt. llllllll.o pooiD It!'I!

...t-...,
oqillc
...-.
""''Cf " ...,..._
-.,.........
l l"""*-
ll'o ...... a1l o - ...

- -... """""' ,..,.,. -

tfwlm:t i1fallt.~IPidPM''Iil O'PtikiDoo a-
lolllll.ol•- WOp!tolio•DIII"lll....
p-..tm- -~PI""

- pomW4I - . lll1lml!r Ad a:m-

miloM¥1to!laii!IJIII......- -
at"""& fed a . ..,.,. diet l"'P"~
1MI 11111''........ tbw:tidi6Ji .... bMa
10118oc!ID .......;1,...,._.. """"'"' ....
--~-wl­
pllllo at& 'IUoo - IDII10to - 1llo
22 Part I: Perioperative Care ofthe Surgical Patient
Hildebrandt U, Kessler K, Plusczyk T, et al. Com-
parison of surgical stress between laparoscopic
and open colonic resections. Surg End!Jsc
2003;17:242-6.
Hollt V. Opioid peptide processing and recep-
tor selectivity. Anna Rev Pharmacol Toxicol
1986;26:59-77.
Hoebe K, Janssen E, Beutler B. The interface be-
tween innate and adaptive immunity. Nat Im-
muno/2004;5(10):971-4.
Hoshino K, Takeuchi 0, Kawai T, et al. Cutting
edge: Toll-like receptor 4 (TLR4)-deficient mice
are hyporesponsive to lipopolysaccharide: evi-
dence for TLR4 as the Lps gene product. I Im-
muno/1999;162:3749-52.
Huber-Lang M, Sanna VJ, Lu KT, et al. Role of C5a
in multiorgan failure during sepsis. I lmmWIOl
2001;166:1193-9.
Huston JM, Gallowitsch-Puerta M, Ochani M, et
al. Transcutaneous vagus nerve stimulation
reduces serum high mobility group box 1 lev-
els and improves survival in murine sepsis. Grit
Care Med 2007:35(12):2762-8.
Jamieson T, CookDN, Nibbs RJ,etal.The chemokine
receptor D6 limits the inflammatory response
in vivo. Nat Immurw/2005;6:403-11.
Kiechl S, Lorenz E, Reindl M, et al. Toll-like recep-
tor 4 polymorphisms and atherogenesis. N Engl
I Med 2002:347:185Y192.
Klava A, Wmdsor AC, Farmery SM, et al. Interleu-
kin-10. A role in the development of postop-
erative immunosuppression. Arr:h Surg 1997:
132:425-9.
Kloosterman T, von Blomberg BM, Borgstein P,
et al. Unimpaired immune functions after
laparoscopic cholecystectomy. Surgery 1994;
115:424-8.
Labuz D, Berger S, Mousa SA, et al. Peripheral an-
tinociceptive effects of exogenous and immune
cell-derived endomorphins in prolonged in-
£1ammatory pain. I Neurosci 2006;26:4350-58.
Lamberts SW, Bruhling HA, de Jong FH. Corticos-
teroid therapy in severe illness. N Engl I Med
1997;337: 1285-92.
Lorenz E, Mira JP, Frees KL, et al. Relevance ofmu-
tations in the TLR4 receptor in patients with
gram-negative septic shock. Arr:h Intern Med
2002;162: 1028-32.
Luce JM. Physicians should administer low-dose
corticosteroids selectively to septic patients
until an ongoing trial is completed. Ann Intern
Med2004:141:70-2.
Maier SF, Goehler LE, Fleshner M, et al. The role of
the vagus nerve in cytokine-to-brain communi-
cation. Ann NYAcad Sci 1998;840:289-300.
Maldonado LS, Murata GH, HershmanJM, et al. Do
thyroid function tests independentlypredict sur-
vival in the critically ill? 1hyroid 1992;2: 119-23.
Mantovani A, Bonecchi R, Locati M. Tuning in-
£1ammation and immunity by chemokine se-
questration: decoys and more. Nat Rev Immu-
rw/2006;6:907-18.
Marik PE, Zaloga GP. Critical care review Adrenal
Insufficiency in the critically ill: a new look at
an old problem. Chest 2002;122:1784-96.
Martinez dlT, Buracchi C, Borroni EM, et al. Pro-
tection against in£1ammation- and autoan-
tibody-caused fetal loss by the chemokine
decoy receptor D6. Proc Nat/ Acad Sci USA
2007;104:2319-24.
Martinez dlT, Locati M. Buracchi C, et al. In-
creased inflammation in mice deficient for the
chemokine decoy receptor D6. Bur I Immurwl
2005;35:1342-6.
Meakins]l. Pietsch)B, Bubenick 0, et al. Delayed
hypersensitivity: indicator of acquired failure of
host defences in sepsis and trauma. Ann Surg
1977:186:241-50.
Michalaki M. Vagenakis A, Makri M, et al. Dissocia-
tionofthe early declinein serum T3concentrstion
and serum IL-6 rise and TNFa in nonthyroidal
illness syndrome induced by abdominal surgery.
I ClinEndocrirwiMetah 2001:86:4198-205.
Molina PE, Abumrad NN. Differential effects of
hemorrhage and LPS on tissue TNF, Ilr1 and
associated neurohormonal and opioid altera-
tions. Lift Sci 2000;66:399-409.
Molina PE. Stress-specific opioid modulation of
haemodynamic counter-regulation. Clin Exp
Pharmawl Ph)'BW/2002:29:248-53.
Moore FD, Olsen KH, McMurry )D. 1he body cell
mass and iJs supporting environment. Philadel-
phia: WB Saunders: 1978.
Mukaida N. Pathophysiological roles of inter-
leukin-8/CXCL8 in pulmonary diseases. Am I
Physiol Lung CeOMol Physio/2003;284:1566-77.
Naito Y, Fukata), Tarnai S, et al. Biphasic changes
in hypothalamic-pituitary-adrenal function
during the early recovery period after major
abdominal surgery. I Clin Endccrinol Metah
1991:73:111-7.
Naito Y, Tarnai S, Shingu K, et al. Responses of
plasma adrenocorticotropic hormone, cortisol,
and cytokines during and after upper abdomi-
nal surgery. Anesthesiology 1992:77:426-31.
Oppenheim]), Yang D. Alarmins: chemotactic ac-
tivators ofimmune responses. Curr Opinlmmu-
rw/2005;17:359-65.
Parrish WR. Rosas-Ballina M, Gallowitsch-Puerta
M, et al. Modulation ofTNF release by choline
requires alpha7 subunit nicotinic acetylcho-
line receptor-mediated signaling. MJJl Med
2008;14(9-10):567-74.
Pavlov VA, Ochani M, Yang LH, et al. Selective
alpha7-nicotinic acetylcholine receptor ago-
nist GT8-21 improves survival in murine en-
dotoxemia and severe sepsis. Grit Care Med
2007:35(4):1139-44.
Riedemann NC, Neff TA, Guo RF, et al. Protective
effects of 11-6 blockade in sepsis are linked to
reduced C5a receptor expression. I Immurwl
2003;170:503-7.
Rittner HL. Brack A, Stein C. Pain and the immune
system. BrI Anaesth 2008:101:40-4.
Rivkind AI, Siegel JH, Lettleton M, et al. Neutro-
phil oxidative burst activation and the pattern
of respiratory physiologic abnormalities in the
fulminant post-traumatic adult respiratory dis-
tress syndrome. CiTe Siwek 1991;33:48-62.
Robert c, Kupper TS. Inflammatory skin diseases,
T cells, and immune surveillance. N Engll Med
1999;341(24):1817-28.
Rogers TJ, Peterson PK Opioid G protein-coupled
receptors: Signals at the crossroads of inflam-
mation. Trends Immurw/2003:24:116-21.
Rot A Contribution ofDuffy antigen to chemokine
function. Cytokine Growth Factor Rev 2005;
16:687-94.
Rouhiainen A, Kuja-Panula J, Wilkman E, et al.
Regulation of monocyte migration by amphot-
erin (HMGB1). Blood 2004; 104:1174-82.
Sakharova OV, Inzucchi SE. Endocrine assess-
ments during critical illness. Grit Care Clin 2007;
23:467-90.
Salomon F, Cuneo RC, Hesp R, et al. The effects of
treatment with recombinant human growth
hormone on body composition and metabo-
lism in adults with growth hormone deficiency.
N Engl!Med 1989;321:1797-803.
Scaffidi P. Misteli T, Bianchi ME. Release of chro-
matin protein HMGB1 by necrotic cells triggers
inflammation. Nature 2002:418:191-5.
Schmidt H, Miiller-Werdan U, Hoffmann T, et al.
Autonomic dysfunction predicts mortality in
patients with multiple organ dysfunction syn-
drome of different age groups. Grit Care Med
2005;33(9):1994-2002.
Schmidt R Werdan K. Miiller-Werdan U. Auto-
nomic dysfunction in the ICU patient. Curr
Optn Grit Care 2001:7(5):314-22.
Schwandner R. Dziarski R. Wesche H, et al. Pep-
tidoglycan- and lipoteichoic acid-induced cell
activation is mediated by toll-like receptor 2.
I Bioi Chern 1999;274:17406-9.
Shatney CH, Benner C. Sequential serum comple-
ment (C3)andimmunoglobulinlevels in shock/
trauma patients developing acute fulminant
systemic sepsis. CiTe Siwek 1985:16:9-17.
Slag MF, Morley JE, Elson MK, et al. Hypothyrox-
inemia in critically ill patients as a predictor of
high mortality.IAM-11981;245:43-5.
Stein C, Schafer M. Machelska H. Attacking pain
at its source: new perspectives on opioids. Nat
Med 2003;9: 1003-8
Takala J, Ruokonen E, Webster NR, et al. Increased
mortality associated with growth hormone
treatment in critically ill adults. N Eng/ I Med
1999;341:785-92.
Taylor BE, Buchman TG. Is there a role for growth
hormone therapy in refractory critical illness?
Curr Opin Grit Care 2008;14(4):438-44.
The FO, Boeckxstaens GE, Snoek SA, et al. Activa-
tion ofthe cholinergic anti-in£1ammatory path-
way ameliorates postoperative ileus in mice.
Gastroentero/ogy2007;133(4):1219-28.
Tilg H, Trehu E, Atkins MB, et al. lnterleukin-6
(IIr6) as an anti-inflammatory cytokine: in-
duction of circulating Ilr 1 receptor antagonist
and soluble tumor necrosis factor receptor p55.
Blood 1994;83:113-8.
Turnbull AV, Rivier CL. Regulation of the hypo-
thalamic-pituitary-adrenal axis by cytokines:
Actions and mechanisms of action. Ph)'SWl Rev
1999;79:1-71.
Ueo H, Honda M. Adachi M, et al. Minimal in-
crease in serum interleukin- 6 levels during
laparoscopic cholecystectomy. Am I Surg 1994:
168:358-60.
Ulloa L, Ochani M, Yang H, et al. Ethyl pyruvate
prevents lethality in mice with established le-
thal sepsis and systemic inflammation. Proc
Nat/ Acad Sci USA 2002;99:12351-6.
van Westerloo DJ, Giebelen lA, Florquin S, et al.
The vagus nerve and nicotinic receptors modu-
late experimental pancreatitis severity in mice.
Gastroenterology2006;130(6): 1822-30.
Venet F, Bohe J, Debard AL, et al. Both percentage
of gammadelta. T lymphocytes and CD3 ex-
pression are reduced during septic shock. Grit
Care Med 2005:33:2836-40.
Vermes I, Beishuizen A, Hampsink RM, et al.
Dissociation of plasma adrenocorticotropin
and cortisol levels in critically ill patients:
possible role of endothelin and atrial natri-
uretic hormone. I Clin End!Jcrinol Metab 1995:
80:1238-42.

Wang H. Bloom 0, Zhang M. et ai. HMG-1 as a late
mediator ofendotoxin lethality in mice. Science
1999;285;248-51.
Wang H. Liao H. Ochani M. et al. Cholinergic
agonists inhibit HMGB1 release and improve
survival in experimental sepsis. Nat Med 2004;
10(11):1216-21.
Wang H. Yu M. Ochani M. et ai. Nicotinic ace-
tylcholine receptor alpha7 rnbunit is an
....,....~ ~· ... EDITOR'S COMMENT
'lhis ie an encyclopedic chapter conceming the
metabolic and inflammatory componentB «.
trauma and infection. R is probably the most
complete and e:ocyclopedic chapter that has ever
been written in any literature including both
surgical and medical literature. As will be clear
to the reader. there are an eoormol18 number «
components to the inflammatory and metabolic
mponse to tnwma and Infection. To a collllder-
able alent, they are synergistic. The moat promi-
nent of the cJasalaJ that we deal with are the cy-
toklnea, lnterleukln& and transporting facton. If
you will, such 88 NF-kB. Many of them have very
short half-lives, IJU.Ch 88 TNF with a half-life of
20 mlnu~ and then among the cytoklnea D:.-1
with a half-Hfe of 6 minutes. 'Ihe entire proceaa le
to acolllldemble enentlntegmted and comblnee
to have a &«<ee of mponsea, which Indicate In
the responee what the orpnlml pm:e:lvee.ln thle
case the human orpnl8m.ls the degree of Insult.
For onllnarily elective surge~ for ewnple, of
mther amalllma&lveneea, there lea programmed
retponse, which I will diBCI18s, but it ie emall,. and
it is temporary. Ifthe mrgery ielarge:t;. or if there
ill an infectiol18 postoperative complication. or if
thie ill a moderate traumatic episode, the cytok.-
inee, iDtetleukinll, lbU m:eptors and other pro-
cesaee bt!£in to bring about a response which is
close to .life-threatening.
On the other hand. a DUmber « theee very
same facton which bring about the responee,
which. when it gets out of hand. is deleterioue,
on the obm:se side of the response aid in the
survival mechanism « the olpi1iml.. such 88
8Cilte-phase protein syntheeill. Other aspects «
the responee include the relea.se of nt!111rophile
arer a few houn, in which it is proposed that
10 bllllon are released. which have a half-life of
appronmately a few hours and then undergo
apotoela or prognunmed cell death, which brlngll
about a utllltatlon of some of the components of
neutrophlla to partldpate In synthem oharlo118
proteins and other components which aid In the
healing and In the positive mponse to tmlma
and the metabolic and Inflammatory mponee
which helps the orpnlam survive. In the Initial
comple.: from a mther minor InJury or compara-
tively minor surgery. or even ellghtly more major
surgery which goes well and doee not have any
postopemtlve compHcatlona, the entire duretlon
1111-2 days. It then IJUbaldes.
One of the problems in this area is what I call
the •holy-gail syndrome". It will be obviol18 alter
reading this chapter that it ill highly 1IDiikely that
there is a •holy p•. 'Ihere may be eome com-
ponents of the inflam!DIItory responee which are
critical or central to the respoDBe, but. to myWIJ.1
of thinkin& there ie no central or enential com-
Chapter 1: Metabolic and Inflammatory Responses to Tnluma and Infection
essential regulator of inflammation. NatuTB
20031421(6921);384-8.
Wurfel MM. Gordon AC. Holden TD, et al. Toll-like
Receptor 1 Po1ym.01phisms Affect Innate Im-
mune Responses and Outcomes in Sepsis. Am
] ReapiT Crit CmeMed 2008;178;710-20.
Wurtman RJ. Stress and the adrenocortical control
ofepinephrine synthesis.Metaboli3m 2002;51(6,
SUppll):ll-14.
ponent,. although there maybe components with-
out which the inflammatory retponse will not
take place, or at least will DOt resemble what we
actuallysee DOW. 'Iherefore I geta little deprened,
when I go to surgical meefinsa, and particulaJ:Iy
when I see a bright young !DIID or WO!DIID pre-
eenting a paper as if to say that this is the holy
grail of inflam!DIItory and metabolic retponse
to injury <r lmlma. 1t ill highly unlila.!ly that it
is, and some bit rl. modesty probably ehould be
maintained. Let ue go through the components
In outline form and point out some of the lllauee
that have come to light. I would urge the reader
to bear In mind that. as the result of these "91Ut-
oua components which see:mlnglycome together,
MODS {multiple organ dylfunctlon syndrome)
and SIRS {systemic Inflammatory mponse syn-
drome) accrue. Thlllle covered nlcdy In Chapter
8 by Dr. Manhall. and I do like hla approach. that
mucll of what happene to patients we In fact~
ate by the way we take care of them.
In the overview, the amhors preaem a Hat
of the Immune. !nflammawry and metaboHc
responaee to InJury. It starts 88 a local activa-
tion but then Ill followed shortly thereafter by a
I!Jilemic inflammatory and endocrine respoDBe.
Theee can be m811ifest to 118 as mrges in plasma
catecho.lamiDe. cortieol and aldosterone levele
resulting in taclrJcardia,. tachypnea, '98BOCOI1-
etriction,. reduced cardiac output, lower azygen
collBIImption,.lower basal metabolic rate. eodium
and water retention,. tramJocation of blood. from
the peripheral to the central 'rita! organe, and
acute-phase protein production. 'lhis ie the •ebb•
phase origiDally proposed by Sir Da'rid Cuthbert-
eon in the 19308.. If the organiem and the organe
rurme, we then transition to a ·now" phase. 'Ihe
duration and the DUmber of organs inrolved re-
ally depende on. fint,. how eltensive the injury or
insult is and. second. whether or not the organe
have survived the Initial ebb phase. The stress re-
eponee here Ia, 88 the authors say, •dlaracterlzed
by explolllve metabolic activit,;• which Ia ·medi-
ated by a ma.a.rlve neuroendocrine ftux lnvolvln.g
the production and secretion of catecholamlnea,
antidiuretic hormone. cortisol. Insulin, glucagon
and growth hormone. The Increased adrene:rglc
lltlmtilatlon causes an Increase In the glucagon
to ln8ulln ratio and. combined with ••• cortisol
and cytoklnee, lnducee the state ofenhanced pr~
teolyala and llpolyal.:' 'This Ia the nub of the Issue.
There are other partll that will be cove:red by Dr.
Haaselgren In Chapter 2 and by Dr. Marahaii In
Chapter&
Furthermore, a critical part of the inue here
is that there is no iDa.ctive Btore of protein. 'Ihe
etorehou.seforprotein. 88 we mowit, is the m.u.s-
cle. 'Ihe protein content of organe such 88 heart,
liver or kidneye may also •etore this proteiD",
when the litrells is high enoush. and may lead to
the failure of the organ and then the organism, 88
23
Yang H. Ocbani M. LiJ, et al. Reversing established
sepsis with antagonists of endogenous high
mobility group box 1. Proc Nat/ Acad Sci lJ.YA
2004;101:296-301.
in liver failure.Mauive destruction,. catabolism of
skeletal muscle to the point where the abilities of
the patient to move and breathe are threatened.
is al8o part and parcel of this m~ponee. I auume
that in the evolutionary component, skeletal
m.uade ill seen 88leee val.uahle to the organism
than, for e:umple. heart. brain. kidneye and lim:;
howem;. continued. datntction of lean body
!DII.U,ofwhich theeelatter areallpart.illpartand
parcel of the hypermetabolic response.
The other major deetructive impulse, at least
It see!DII to me It Ill. Ia the wldeepread caplllary
leak and the opening up of 11gbt Junctions of the
caplllarlee and al8o perilaps enlaJ:ie:ment of the
pores or the spacee In the endotheHum, which
keep materlal In the drculatlng compartment.
The capillary leak would deplete If allowed to go
on, and !fit does f!1J on, endogenous resources and
Ia maladapted 88 the author says. The eyete:mlc
!n&mmatory reaponee, eevere metaboHc deple-
tion, and possible eecondary Infection all cauee
dam.ap to vital Olpn&, but were not Initially
compromised by the InJury. 'Iheee Include adlllt
resplmtory dlaueas syndrome, which I believe
has bwo component~. the ftnt Ia the capillary leak
and the eecond ill the use ofGceuive crystalloid
in re811.BCitation.llappi!J m.anypeople taking care
of patients with severe injury and with infectim
nowrealize that theCOD.tiD.ued.retll.8citation ofpa-
tientBwhoaretndferiD.g&amac:apillaryleakisnot
heJpful and contribute. not ODiy to ARDS but re-
nal inru1licieoc:J hepatic dylfunctian,. loes of duct
epithelial-barrier fimctian,. immunoparalJ&is and
the multi oqpm. dylfunction after eepm develope,.
which can be fatal. 'lhe siren retpCID.H, hawtM!%;.
with the appropriate rupport and pnmded the
Blrees retponse ill DOt complicated by later~
lion u.ruaUy J.'e80.Iml without complication. The
catabolic proceii81Uill.8lly peaks at 48 to 72 hours
post injury.
If the catabolic response le resolved It then
leads to the beginnings of an anabolic 8tate with
Insulin, growth hormone. lnauHn like growth
factor 1. and perhaps ln8ulln like growth factor
2 within frve days of InJury. 88 the author says.
The mechanistic change Ill a flux of protein, fluid,
and electrolytes returning ro the depleted cellu-
lar space. particularly muscle. and cellular space
eKpanda.
There Ia much that le new In this chapter.
which has not made Its appearence In the lltaD-
dard tenbook of surgery. 'Ihese Include from this
point on a number of headlnge. Including ·The
Innate Immune syete:m•, which Include the .'Ibll
Like Receptors", which are the To1kignaling
pathway initiallydeecribed in Drosophila in 1985,.
88 the amhor BllJI and fiDally J:eCO&Dized in hu-
!DIID8 in 1997; at least 11 human toll-like recep-
rors have been identified. 'Iheee, which have not
received a sreat deal of recognition in the COD-
temporary surgical literature at least appears
(conlinued)
24 Part 1: Perioperative Care ofthe Surgical Patient
to play an adaptive role on adaptive immune
systems. They are expressed on dendritic cells,
T-lymphocytes, a number of parenchymal cells,
including adrenals, liver and spleen and which
in the adrenal-expressed TLRs (toll-like recep-
tors~ the systemic inflammatory response. NF-Jl,
which is a major facilitator to all of this migrates
from the cytoplasm, where it usually resides with
the destruction of the inhibiting IkB and tranll-
migrates to the nucleus. Here. it mediates gene
transcription and the production of inflamma-
tory mediators, such as chemokines, adhesion
molecules, tumor necrosis factor, interleukin-1,
and TNF-a receptors.
Other new terminology. which will be new or
at least unfiuniliar to the average surgeon read-
ing this chapter includes complement. which is
recognizable. except for the fact that what is new
is that the complement system consists of more
than 30 proteins. These are divided into three
main pathways:
1. classic
2.alternative
3. mannan-binding lectin pathways.
Another relatively new term is alarmins,
which is triggered by injury or trauma without
evidence of a bacterial focus. They are released
after a non-programmed cell death or by cells
of the immune system. Heat shock proteins, de-
fensins, cathelicidin, eosinophil-derived neuro-
toxin (EDN), and others. There are a number of
systems which ordinarily do not receive a great
deal of attention in a standard textbook version
of the acute phase reaction. These are systems
such as the adaptive immune system, which is a
secondary and more efficient response to invad-
ers, and which is made up of cellular immunity.
The cellular immunity is the cellular response of
the organism. namely the patient that is a local
host response against invading organillms. Local
mediators of inflammation, such as cytokines,
histamine, kinins, and arachadonic acid metabo-
lites allow increased capillary leakage. which in
this sense is a good thing as it allows diapedesis
of cells to infiltrate into the site of injury. These
are primarily neutrophils and also to a lesser
extent monocyte macrophages. The humeral
community is much more diffuse and involves
toll-like receptor activation, which causes secre-
tion of cytokines including our friends TNF and
IL-l and the chemokines, especially derived from
macrophage&. There are a variety of other compo-
nents in this including cytokine receptors, which
are on the surface of the majority of human cells
and intracellular signaling pathways that regulate
gene transcription. We have already heard of the
nuclear factor-..B (NF,B) activating protein API
and the C!EBP family of transcription factors, in
particular C/EBP-~ and 8.
NF-..B is studied because it is central in the
inflammatory process as a transcription fac-
tor once its inhibitor has been metabolized
will translocate to the nucleus. The number of
cytokines is legion but the important ones for
our purposes, TNF, IL-1(3, IL-6, IL-8, IL-12 and
IFN-A, are pro-inflammatory cytokines and IL-4,
IL-10, and IL-13 are considered to be inhibitory
or anti-inflammatory. Interleukin-1 is ancient
as compared with some of these other factors
as it was described as a pyrogen a half century
ago. It does have a short half life of six minutes,
as mentioned earlier. Of the two forms, IL-1(3 is
regulated by different antigens, IL-1(3 is the more
common and more involved in what its role is.
IL~ is another popular cytokine, as it were, and it
peaks and 4 to 48 hours. It is induced partially by
TNF and partially by IL-l. Its function is operant
by the proliferation and differentiation of B and
T-lymphocytes. It also regulates the synthesis of
another acute phase protein, such as C-reactive
protein and fibrinogen and other complement
factors. One of the significant findings of laparo-
scopic procedures is that there is less elevation of
IL~ following laparoscopic cholecystectomy as
well as abdominal, aortic. and colorectal surgery.
Similarly.llmall bowel and colonic resections car-
ried out laparoscopically have lower elevations
of IL-6. Another feature of IL~ is that it seems to
have a prognostic significance in patients with
SIRS. sepsis, or MODS and has been tested in the
ICU in this regard and has come to be a prognos-
tic indicator.
Of the chemokines, these have not had much
presence, on the surgical scene at least, and there
are 18 chemokine receptors and 43 chemokines.
Their role is still being elucidated. but some have
suggested that some of these are •decoy recep-
tors·.
A major and relatively novel discussion in a
surgical text is the neuro-immune axis. We re-
main very concerned about what the accurate
sensory input to the brain is during stress. We
know that there are neural routes, mostly by
afferent vagal fibers and then there are blood-
borne inflammatory mediators. Elsewhere in this
volume we have called attention to the fact that
vagal pathways pass from the peritoneal cavity to
the CNS and in a paper that appeared in Scknce
in 2000 as discussed elsewhere, there was a ben-
efit to subdiaphragmatic vagotomy. The stimulus
for the vagus is activated it seems, at least in part
by IL-l in peripheral tissues. IL-l binding and an
intact vagus nerve seem to be required for the
generation of the fever following intraperitoneal
IL-l. However, vagotomy alone does not block the
effects of various cytokines on CNS despite the
protective character of the blood brain barrier.
However, in the third ventricle the blood brain
barrier may be deficient and thus there may be
places where the cytokine may damage the cen-
tral blood brain barrier. giving results of continu-
ing inflammation.
We have talked about the afferent effects of
the neuro-immune axis, but one should not lose
sight ofthe fact that there is an efferent regulation
going through the sympathetic and suppressing
the parasympathetic portion of the autonomic
nervous system.
Another novel discussion is the immunosup-
pression following trauma, which we have been
aware of in a vague way and find that there is
a cholinergic anti-inflammatory pathway and
some cytokine immunosuppressant such as IL-6.
Immune dysfunction may also be cell mediated
and cellular immunoincompetence, which is also
defined as immune paralysis, may be induced by
PGE2, IL-10 and other anti-inflammatory media-
tors. IL-10 and TGF(3 may induce monocyte im-
mune paralysis. Another form of dysfunction is
lymphocyte dysfunction. in which T-helper lym-
phocytes may also be involved in immunosup-
pression following surgical trauma.
In the development of SIRS and MODS. the
·second hit phenomenon· has become part of
our normal language. For example, there may
be initial trauma and a complication may result,
which may be the second hit. The second hit may
be sterile. for example the need for an operation
in general, or it may be infectious with a pathogen
induced infection. Whatever causes the second
hit, however, has now become synonymous with
the development of MODS. This is further cov-
ered in Chapter 8. There is a very extensive dis-
cussion of hormonal relationships in trauma and
inflammation. but I do want to mention adrenal
insufficiency. which may occur in prolonged stay
in the ICU The point is that one must think about
this in order to rule it out. Patients with transient
adrenal insufficiency basically may have a de-
creased blood pressure, decreased urine output,
other inexplicable hypoglycemia. hyponatremia.
hyperkalemia metabolic acidosis, eosiniphilia,
and a hypodynamic circulation as well. To think
of adrenal insufficiency should give one a very ag-
gressive response to this. A250 microgram ACTH
stimulation test. which is recognized as being of
a very high level, is probably the best way to tell
whether the patient has a hypoadrenal response.
This seems to be much more accurate than ran-
dom cortisol levels.
Another hormonal deficiency that can oc-
cur after prolonged ICU stay is hypothyroidillm.
There is a low T3 syndrome. and interestingly
enough, there is an inverse correlation between
T3 levels and mortality. In prolonged critical ill-
ness, an ·euthyroid sick syndrome· may present.
in which the TSH exhaustion is what would best
be identified. and there would be reduced TSH se-
cretion and reduced levels ofT3 and T4. Low TRH
expression in the hypothalamus has been seen in
patients who have been chronically ill, as if this
particular function has been depleted.
The sympathetic nerves and the whole sym-
pathetic system are extremely important in pro-
longed trauma and stress. The catecholamine
immune secretion from the adrenals takes place
within seconds of stimulation. Since both Norepi-
nephrine and Epinephrine are stored in granules
within the adrenal medulla and their exocytosis
is initiated by acetylcholine secretion in the adre-
nal medulla. The sympathetic system is involved
in almost every possible body system, which is
important in the response to trauma, including
cardiac output. myocardial contractility. main-
tenance of blood pressure, bronchodilatation,
thermoregulation, retention of water and sodium
in the kidneys, and not paradoxically-almost
purposefully-decrease in bowel motility. The
dysfunction ofthe adrenal system, such as exhaus-
tion. probably presages a poor outcome.
Metabolic alterations are extremely impor-
tant. but there is one concept here, which is also
brought on in Chapter 8, that is mitochondrial
dysfunction. The mitochondrial dysfunction may
be the result offailure ofthe mitochondrial energy
production butless and less likely so. The basic is-
sue appears to be the failure of adequate supplies
to the mitochondria. ATP is not contained in a
depot. Any of the components such as glucose,
fat. other sugars, and protein to mitochondria
because of decreased cardiac output and blood
flow, oxygenation by the lung. glucose transport
leads to a rapid onset of mitochondrial dysfunc-
tion. If the mitochondrial transitional pore open-
ing are open, large molecules such as cytochrome
C can enter the cytosol and triMer apoptosis-
progranuned cell death. This results in the failure
to produce ATP in a period of crisis.