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Injury, Int. J.

Care Injured (2005) 36, 691709

www.elsevier.com/locate/injury

REVIEW

Pathophysiology of polytrauma
Marius Keel *, Otmar Trentz

Division of Trauma Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland

Accepted 14 December 2004

KEYWORDS Summary Immediate and early trauma deaths are determined by primary brain
Trauma; injuries, or significant blood loss (haemorrhagic shock), while late mortality is caused
Injury; by secondary brain injuries and host defence failure. First hits (hypoxia, hypotension,
Pathophysiology; organ and soft tissue injuries, fractures), as well as second hits (e.g. ischaemia/
Host defence response; reperfusion injuries, compartment syndromes, operative interventions, infections),
Systemic inflammatory induce a host defence response. This is characterized by local and systemic release of
response syndrome pro-inflammatory cytokines, arachidonic acid metabolites, proteins of the contact
(SIRS); phase and coagulation systems, complement factors and acute phase proteins, as well
Compensatory anti- as hormonal mediators: it is defined as systemic inflammatory response syndrome
inflammatory (SIRS), according to clinical parameters. However, in parallel, anti-inflammatory
response syndrome mediators are produced (compensatory anti-inflammatory response syndrome
(CARS); (CARS). An imbalance of these dual immune responses seems to be responsible for
Apoptosis; organ dysfunction and increased susceptibility to infections.
Necrosis; Endothelial cell damage, accumulation of leukocytes, disseminated intravascular
Multiple organ coagulation (DIC) and microcirculatory disturbances lead finally to apoptosis and
dysfunction necrosis of parenchymal cells, with the development of multiple organ dysfunction
syndrome (MODS); syndrome (MODS), or multiple organ failure (MOF). Whereas most clinical trials with
Multiple organ failure anti-inflammatory, anti-coagulant, or antioxidant strategies failed, the implementa-
(MOF); tion of pre- and in-hospital trauma protocols and the principle of damage control
Damage control; procedures have reduced post-traumatic complications. However, the development
Mortality of immunomonitoring will help in the selection of patients at risk of post-traumatic
complications and, thereby, the choice of the most appropriate treatment protocols
for severely injured patients.
# 2005 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
Two-hit theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
HyperinflammationSIRS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694

* Corresponding author. Tel.: +41 1 255 3657; fax: +41 1 255 4406.
E-mail address: marius.keel@usz.ch (M. Keel).

00201383/$ see front matter # 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.injury.2004.12.037
692 M. Keel, O. Trentz

HypoinflammationCARS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
Activation of plasmatic cascade system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
Acute phase reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
Leukocyte recruitment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
Proteases, oxidative stress and capillary leakage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
Microcirculatory disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
Ischaemia/reperfusion injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
Neuroendocrine reaction and metabolic alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
Multiple organ dysfunctions or failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
Therapeutic strategies for multiply injured patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703

Introduction ing release of pro- or anti-inflammatory mediators,


seems to be responsible for organ dysfunction
Despite improved traffic and occupational safety, and increased susceptibility to infections and
as well as significant advances in pre- and in- sepsis.19,116,118,155 Endothelial cell damage, accu-
hospital management, severe trauma represents mulation of leukocytes, disseminated intravascular
the most frequent cause of death in people below coagulation (DIC) and microcirculatory dysfunction
the age of 40 years.4,38,60,128,149,168 Immediate and finally lead to programmed cell death (apoptosis)
early trauma deaths are determined by severe and necrosis of parenchymal cells (microenviron-
primary brain injuries, or significant blood loss ment theory) with the development of multiple
(haemorrhagic shock) after blunt, or penetrating, organ dysfunction syndrome (MODS) or multiple
trauma.4,38,60,70,128,149,158,168,173,181,194 Late mor- organ failure (MOF).67,91,92,95,107,117,153,159,195 In
tality is caused by secondary brain injuries and accordance with these pathophysiological mechan-
host defence failure.4,70,158,168,173,194 Direct, or isms and definition of SIRS, the term polytrauma
indirect, mechanical forces induce organ and soft can be defined as a syndrome of combined
tissue injuries, or fractures. However, these first injuries with an injury severity score (ISS) > 17
hits represent a greater challenge, as local tissue and consequent SIRS for at least 1 day, leading to
damage, such as contusions or lacerations, hypoxia dysfunction, or failure, of remote organs and vital
and hypotension, induce further local and systemic systems, which themselves had not directly been
host responses, to preserve the immune integrity injured.76,193
and stimulate reparative mechanisms.164 This sys- This review is planned to give an insight into the
temic inflammation was defined in 1991, through triggers and the mechanisms of the post-traumatic
the consensus conference of the American College cardiovascular shock, homeostasis, apoptosis,
of Chest Physicians/Society of Critical Care Med- organ dysfunctions and immune suppression
icine (ACCP/SCCM), as systemic inflammatory (CHAOS) as coined by Bone.19 In addition, it should
response syndrome (SIRS).6 At least two of the elucidate the pathophysiological basis for the
four clinical parameters (Table 1) must be fulfiled damage control concept in the surgical manage-
for the diagnosis of SIRS.6 It is characterized by the ment of multiple injured patients, reasons for the
local and systemic production and release of dif-
ferent mediators, such as pro-inflammatory cyto-
kines, complement factors, proteins of the contact Table 1 Clinical parameters of systemic inflammatory
phase and coagulation systems, acute phase pro- response syndrome (SIRS)
teins, neuroendocrine mediators and an accumu- 1. Heart rate > 90/min
lation of immunocompetent cells at the local site 2. Breathing rate > 20/min, respectively,
of tissue damage (Fig. 1).17,18,40,91,163,169,195 In hyperventilation with decrease of the
addition, this systemic inflammation is augmented arterial CO2 partial pressure (PaCO2)
by second hits, such as ischaemia/reperfusion under 32 mmHg
injuries, surgical interventions or infections 3. Temperature > 38 8C or < 36 8C
(two-hit theory).163,164 4. Number of leukocytes > 12,000/mm3
or < 4000/mm3 or  10% juvenile
However, different clinical trials and animal
neutrophil granulocytes
models have shown that, in parallel with avoid
For the definition of SIRS, two or more parameters must be
the autodestructive effects of immunocompetent
fulfiled. Sepsis is defined as SIRS with detection of bacteremia
cells (Fig. 1).19,88,91,120,195 An imbalance between or bacterial focus.6
these dual immune responses, with an overwhelm-
Pathophysiology of polytrauma 693

Figure 1 Host defence response after trauma. See text for details and explanations. APC: antigen presenting cells. TH,
T-helper cells (lymphocytes); SIRS, systemic inflammatory response syndrome; CARS, compensatory anti-inflammatory
response syndrome; PMNL, polymorphonuclear leukocytes; MODS, multiple organ dysfunction syndrome; MOF, multiple
organ failure.

failure of clinical trials with immunotherapies in The severity of organ injuries, varying from con-
the past two decades and the significance for tusions to complete lacerations, and the remaining
the development of post-traumatic immunomoni- organ perfusion influence the post-traumatic sys-
toring. temic inflammatory response. The highest incidence
for the development of SIRS can be observed after
isolated or combined severe head injuries.55,155
Two-hit theory Primary focal or diffuse and secondary brain
damages including ischemia/reperfusion injuries,
The complex cascade of the host defence response is cerebral oedema or intracranial hypertension deter-
stimulated by primary and secondary insults (two- mine the cerebral outcome and the mortality as well
hit theory).163,164 The trauma impact determines as the incidence and severity of post-traumatic
primary organ, or soft tissue, injuries and fractures complications.169,176,181 Although the central ner-
(first hit; trauma load) with local tissue damage as vous system has been defined historically as an
well as an activation of the systemic inflammatory immunologically privileged organ, due to its
response.118,135,163,164,179 In addition, secondary separation from the peripheral circulation by the
endogenous and exogenous factors play a crucial bloodbrain barrier (BBB), different studies have
role in the initiation and severity of post-traumatic shown that the brain acts as a target and as an
complications.164,179,202 Typical endogenous (anti- effector organ.87,104,169 Glial cells, astrocytes
genic load) second hits are respiratory distress with and neurons are potent producers of pro- and
hypoxia, repeated cardiovascular instability, meta- anti-inflammatory mediators and their receptors,
bolic acidosis, ischaemia/reperfusion injuries, dead leading to local tissue damage and a systemic
tissue, contaminated catheters, or tubes, and infec- response.104,132,169 In addition, systemic mediators
tions.46,50 Surgical interventions with severe tissue released by peripheral immune, endothelial, or par-
damage, hypothermia or blood loss, inadequate, or enchymal cells influence the integrity of the BBB,
delayed, surgical, or intensive care, after neglected leading to a bi-directional communication of the
or missed injuries, as well as massive transfusions, inflammatory mediators.104,132,169 Primary epidural
represent exogenous second hits (interventional hematoma, or cerebral oedema, as well as post-
load or surgical load).46,81,202 traumatic secondary oedema, induced by local and
694 M. Keel, O. Trentz

systemic inflammatory processes, are responsible (gene polymorphism), the general condition of the
for the development of a cerebral compartment host and the type of antigens (antigenic load), both
syndrome, which is lethal without intervention.173 local and systemic release of pro-inflammatory
Thoracic injuries, with multiple rib fractures, cytokines and phospholipids.40,88,143,171,190 Poly-
lung contusions, or lacerations, are often compli- morphonuclear leukocytes (PMNL), monocytes, tis-
cated by local and systemic inflammation, with or sue macrophages (e.g. alveolar macrophages),
without manifestation of pneumonia, acute lung lymphocytes, natural killer cells, and parenchymal
injury (ALI), or acute respiratory distress syndrome cells are involved in a complex network of this host
(ARDS).9,120,137 Injuries of intra-abdominal organs defence response.195 An overwhelming pro-inflam-
cause haemorrhagic shock (liver, spleen, vascular matory response (hyperinflammation) leads to the
injuries) and aseptic, or septic, peritonitis (pancrea- clinical manifestation of SIRS and finally to host
tic or hollow organ injuries).11 Severe intra-abdom- defence failure (MODS, MOF).55,71,135,195
inal or retroperitoneal haemorrhage, after vascular, Cytokines are polypeptides and act in a para- or
renal, or pelvic injuries, as well as systemic inflam- autocrine manner.40 They are capable of exerting
matory processes in septic patients, can lead to an many effects on an array of cell types (pleiotropy).40
abdominal compartment syndrome with systemic Besides hyperacute pro-inflammatory cytokines,
complications.59,125 such as tumor necrosis factor-a (TNF-a), or inter-
Soft tissue injuries of the extremities, espe- leukin-1b (IL-1b), with an effect after 12 h, there
cially in patients with haemorrhagic shock, are exist subacute (secondary) cytokines such as IL-6,
often complicated by decreased perfusion (low- IL-8 (neutrophil activating peptide (NAF)), macro-
flow hypoxia), with a high risk for ischaemia/ phage migratory factor (MMF), high motility group
reperfusion injuries and secondary infections. protein -1 (HMG-1), as well as IL-12 and IL-18,
Furthermore, severe muscle crushing injuries pre- two interferon-g (IFN-g)-modulating cytokines
dispose to a compartment syndrome with muscle (Fig. 1).40,71 Increased TNF-a, IL-1b or IL-8 serum
necrosis, rhabdomyolysis and finally acute renal levels are observed in patients with systemic inflam-
failure (crush kidney).159 Fractures of the femur, mation, as well as in bronchoalveolar lavage fluids of
multiple long bone fractures and unstable pelvic patients with thoracic trauma, or acute respiratory
ring fractures are characterized by a high blood distress syndrome.42,43,100,121,187 In addition, IL-6
loss and contribute to the inflammatory acti- serum levels correlate with the ISS, the incidence
vity.22,49,53 Additionally, fat embolism syndrome of MODS, ARDS, or sepsis and with outcome.15,121,166
is an infrequent clinical consequence with the Through the influence of antigens, T-helper lym-
typical triad of pulmonary distress, mental phocytes (TH cells, CD4+ cells) differentiate into two
changes and petechial rash, 2448 h after pelvic phenotypes, the TH1 and TH2 lymphocytes.146 TH1
or long-bone fractures.148 cells support the pro-inflammatory cascade through
The incidence of septic complications has secretion of IL-2, interferon-g and TNF-b, whereas
increased during the last decade.122 Closed wounds TH2 cells are important producers of anti-inflam-
with large soft tissue damage and open wounds, matory mediators. Monocytes/macrophages are
or fractures, as well as neglected soft tissue involved in the differentiation of TH1 cells, via
injuries, represent portal of entry for microorgan- the secretion of IL-12. Depressed IL-12 production
isms.205,210 Central venous catheters, intratra- after trauma correlated with a shift of the TH1/TH2
cheal tubes, chest tubes and bladder catheters ratio towards the TH2-type pattern, with an adverse
are often contaminated and raise the infection risk clinical outcome.146
in severely injured patients.32 The most common Pro-inflammatory cytokines activate the recruit-
reasons for sepsis after trauma are hospital ment and phagocytosis activity of PMNL (priming),
acquired pneumonia, catheter infections, intra- the immune cells of the first hours (the first defence
abdominal and wound infections.9,140,179 Further- line), and stimulate PMNL to release proteases and
more, ischaemic lesions of the gastrointestinal free oxygen radicals (respiratory burst, oxidative
tract after haemorrhagic shock seem to be respon- stress) (Fig. 1).21 Furthermore, PMNL are influenced
sible for bacterial translocation into the circulation by colony-stimulating factors, such as granulocyte-
(gut hypothesis).103,130 colony stimulating factor (G-CSF) and granulocyte
macrophage-colony stimulating factor (GM-
CSF).20,31,51,189 They enhance monocyte- or granu-
HyperinflammationSIRS locytopoiesis, on the one hand and reduce the
spontaneous programmed cell death (apoptosis) of
Tissue damage induces in commensurate with the PMNL during SIRS or sepsis, on the other hand.20,31,51
severity of trauma (trauma load), genetic factors Other pro-inflammatory mediators contribute addi-
Pathophysiology of polytrauma 695

tionally to the reduction of neutrophil apoptosis, soluble CD14 (sCD14), through shedding of the mem-
with an accumulation of PMNL at the site of local brane-bound CD14.203 However, the decreased
tissue damage.16,47,54,78,97,102,109,124 expression of CD14, as well as expression altera-
Mechanical and hypoxic cellular damage leads tions of the pattern-recognition receptors for bac-
further to an increase of intracellular Ca++ levels terial products, the toll-like receptors, seem not to
with an activation of phospholipase A2 (PLA2) and be responsible for endotoxin tolerance.83 By
phospholipase C (PLC).163 These enzymes catalyse contrast, the expressions of the toll-like receptors
the release of arachidonic acids from membrane for Gram-positive (TLR2) and Gram-negative (TLR4)
phospholipids. Through the activation of cyclooxy- bacterial products are increased on monocytes,
genase and 5-lipooxygenase prostaglandine E2 or PMNL, during systemic inflammation.80 Further-
(PGE2) leucotriene B4 (LTB4) and thromboxane A2 more, antigen-presenting cells (APC), such as
(TXA2), respectively, are produced (Fig. 1).165 These monocytes/macrophages, showed a depressed
metabolites are involved in the recruitment of expression of the MHC (major histocompatibility
inflammatory cells, regulation of vascular perme- complex) class II molecule HLA-DR (human leuko-
ability and motility, as well as the aggregation of cyte antigen) that correlated with post-traumatic
thrombocytes.163 Additionally, PLA2 induces the infections.71
release of the platelet activating factor (PAF).212 During the early phase of the post-traumatic
It supports the activation of macrophages, their course, a lymphocytopaenia has been observ-
interaction with endothelial cells and the activation ed.22,92,111,195 This lymphocyte depletion was asso-
and aggregation of thrombocytes.212 ciated with morbidity and outcome after trauma.195
It may be related to increased apoptosis, triggered
by stress hormones (steroids) and cell death pro-
HypoinflammationCARS teins.39,111,117,145,153 Apoptosis is characterized
morphologically by cell shrinking, with cytoplas-
Depending on the severity of injury and the post- matic condensation (apoptotic bodies), nuclear con-
traumatic course, anti-inflammatory mediators are densation (pycnosis) and DNA-fragmentation (DNA
also produced. TH2-cells and monocytes/macro- laddering).134,153 The cell membranes stay primarily
phages release IL-4, IL-10, IL-13, or transforming intact and no surrounding inflammatory signs can be
growth factor-b (TGF-b) (Fig. 1).30,33,57 In addition, observed, in contrast to necrosis.153
different cytokines (e.g. IL-6) have shown a dual Typical cell death proteins are TNF-a or Fas ligand
effect with pro- and anti-inflammatory activities. (CD95 ligand).5,134 They induce cell death after
The serum levels of IL-10 correlate with ISS and post- binding with their receptors, respectively, TNF-RI
traumatic complications, such as MODS, ARDS, or and Fas antigen (CD95 antigen) and activation
sepsis.88,138 In addition, natural inhibitors of recep- of complex intracellular cascades and effector
tors, such as soluble TNF-receptors (TNF-RI (55 kD) enzymes, such as intracellular proteases (e.g.
and TNF-RII (75 kD)), or IL-1 receptor antagonist calpains, caspases).5,39,75,111,134,156 The cellular
(IL-1ra) are detectable in the sera of injured expressions of TNF-RI and Fas antigen, or their soluble
patients, correlating also with the ISS and the inci- molecules, were elevated in serum from injured
dence of post-traumatic complications.52,88,99 patients, postoperatively or during sepsis.37,145
Furthermore, the readiness of blood monocytes An overwhelming anti-inflammatory response
from injured patients to release pro-inflammatory (hypoinflammation) seems to be responsible for
cytokines was decreased in in vitro studies post-traumatic immunosuppression, with a high
after stimulation with Gram-negative (endotoxin, susceptibility to infections and septic complica-
lipopolysaccharide (LPS)), or Gram-positive (e.g. tions.19,171,195 This immunological status is called
peptidoglycan, lipoteichonic acid), bacterial pro- compensatory anti-inflammatory response syn-
ducts and correlated with the post-traumatic drome.19 However, it does not look like a compen-
course.25,56,84,85,101,203 The mechanisms of this satory mechanism in a biphasic model; as only a few
endotoxin tolerance are still incompletely hours after trauma anti-inflammatory mediators
understood.203 It seems that anti-inflammatory (e.g. IL-10) were detectable in the serum of injured
mediators, like IL-10, depress the activity of intra- patients.138 It seems that the host defence response
cellular transcription factors, such as nuclear tries to strike a fine balance between SIRS and CARS,
factor-kappa B (NF-kB), which are essential for to induce reparative mechanisms and limit entry
the synthesis of pro-inflammatory cyto- or overload of microorganisms, on the one hand, and
kines.24,69,84,101,116,197,198,203 The expression of to avoid autoaggressive inflammation, with second-
the LPS-receptor CD14 on monocytes is decreased ary tissue damage and susceptibility to infections,
after trauma, combined with an increase of the on the other hand. These mixed inflammatory
696 M. Keel, O. Trentz

Figure 2 Plasmatic cascade system. Proinflammatory mediators and toxins stimulate the plasmatic cascade system
with activtion of complement factors, kallikreinkinin system and coagulation cascade. These mechanisms play a crucial
role in endothelial and parenchymal cell death as well in the disseminated intravascular coagulation (DIC). See text for
details and explanations.

mechanisms are called mixed antagonistic response iators, such as histamine, as well as the adhesion
syndrome (MARS).19 of leukocytes to endothelial cells, leading to
increased vascular permeability with oedema.129,169
In addition, apoptosis and cell lysis (necrosis) of
Activation of plasmatic cascade system parenchymal cells, or bacteria, are induced by
C5a, through the C5a receptor (C5aR) and the
Pro-inflammatory mediators (cytokines, arachidonic MAC (C5b-9) .129,169,182 In clinical studies, elevated
acid metabolites) and toxins activate the plasmatic serum levels of different complement components,
cascade system, consisting of the complement cas- or their expression in injured tissue, were observed
cade, the kallikreinkinin system and the coagula- after trauma, or during sepsis.42,86,165,169,182,211
tion cascade (Fig. 2). The classical pathway of Similarly to some cytokines, C3a and C5a showed
complement activation is induced by antigenanti- dual effects with activation of reparative mechan-
body complexes (immunoglobulins M or G (IgM, isms too.129 Furthermore, during systemic inflam-
IgG)), or activated coagulation factor XII (FXIIa), mation, serum levels of the C1-inhibitor, produced
whereas bacterial products (e.g. LPS) activate the by hepatocytes, endothelial cells, monocytes and
alternative pathway (Fig. 2).66,129,182 Cleavages of macrophages, were decreased through a degrada-
C3, by C3 convertase, and C5, by C5 convertase, tion by PMNL-elastases. C1-inhibitor regulates the
lead to the formation of opsonins, anaphylatoxins classical complement pathway through inactivation
and, finally, the membrane attack complex of the active subunits C1s and C1r.129
(MAC).66,129,182 The opsonins C3b and C4b are The plasma proteins FXII, prekallikrein, kinino-
involved in the phagocytosis of cell detritus, and gen and the factor XI (FXI) represent the contact
especially bacteria, by covalent binding of pathogen phase system (Fig. 2).185 They are characterized by
surfaces (opsonization).66,129 The anaphylatoxins the fact, that they can be activated by negatively-
C3a and C5a support different inflammatory charged cellular surfaces (contact activation).185
mechanisms, the recruitment (chemotaxis) and FXII and prekallikrein activate mutually and form
activation of phagocytic cells (PMNL, monocytes, FXIIa and kallikrein. FXIIa stimulates the com-
macrophages), the enhancement of the hepatic plement cascade along the classical pathway.185
acute phase response, the degranulation of mast Kallikrein induces the fibrinolysis through conver-
cells and basophils, with release of vasoactive med- sion of plasminogen to plasmin, or activation of
Pathophysiology of polytrauma 697

the urokinase-like plasminogen activator (u-PA) bances with hypoxia-induced cellular damage.1,94
(Fig. 2). The tissue-plasminogen activator (t-PA) The consumption of coagulation factors is further
works as a cofactor, whereas natural inhibitors of enhanced through the proteolysis of fibrin clots
the fibrinolytic system are a2-antiplasmin (a2AP), to fibrin fragments by the protease plasmin
a2-macroglobulin (a2MG) and the plasminogen- (fibrinolysis).94,115
activator-inhibitor 1 (PAI-1). In addition, kallikrein
stimulates the formation of bradykinin from
kininogen. Kinins are vasodilators, increase the Acute phase reaction
vascular permeability and inhibit the functions
of thrombocytes.185 The local (Kupffer-cells) and systemic release of
The intrinsic coagulation system is linked to the pro-inflammatory cytokines (TNF-a, IL-1b, IL-6)
contact activation system through the formation induce the acute phase reaction in the liver,
of FIXa by FXIa (Fig. 2). During the host defence to enhance tissue protective and antimicrobial
response, a consumption of FXII, prekallikrein and mechanisms.204 The synthesis of positive acute
FXI has been observed, whereas plasma levels of phase proteins (APP) in hepatocytes, such as
enzymeinhibitor complexes, such as FXIIaC1- C-reactive proteins (CRP), a1-antitrypsin, a2-
inhibitor or kallikreinC1-inhibitor, were increas- macroglobulin, caeruloplasmin, lipopolysaccharide
ed.1 C1-inhibitor and a1-protease-inhibitor (a1PI) (LPS)-binding protein (LBP), fibrinogen, prothrom-
represent the inhibitors of the intrinsic coagulation bin or C4BP, is increased, whereas the production
system (Fig. 2).1,94 of negative APP, such as albumin, high-density lipo-
However, the coagulation system is initially acti- proteins (HDL), protein C, protein S and ATIII, is
vated over the extrinsic pathway with an increased reduced.45,204
expression of the tissue factor (TF) on endothelial CRP increases the expression of TF on PMNL and
cells and monocytes, induced by bacterial cell wall monocytes/macrophages, and thereby enhances
fragments and pro-inflammatory cytokines (TNF-a, the activation of the extrinsic coagulation cas-
IL-1b) (Fig. 2).61,68,94 The FVIITF complex stimu- cade.45 Clinical studies have shown that the level
lates the coagulation cascade, with the formation of of CRP is relatively non-specific and not predictive
FXa and finally thrombin (FIIa), from prothrombin of post-traumatic complications, such as infec-
(FII). Thrombin activates FV, FVIII and FXI, leading to tions.74,127,165 Serial measurements appear to be
enhanced formation of thrombin. After cleavage of helpful however, especially in the first 2 weeks,
fibrinogen by thrombin, fibrin monomers polymerize as, whilst the levels of CRP reduce with time in
to form stable fibrin clots, via support of FXIIIa.1,94 cases of systemic inflammation, in the presence
To control the consumption of coagulation factors, of infection an upward trend is seen consistently.
antithrombin (ATIII) produced by hepatocytes inhi- a1-antitrypsin inactivates the proteases secreted
bits thrombin and FXa, through the formation of a by PMNL or macrophages, whereas a2-macroglobu-
thrombinantithrombin complex.1 This effect can lin and caeruloplasmin neutralize free oxygen
be enhanced by heparin. Furthermore, ATIII inhibits radicals and pro-inflammatory cytokines.204 LBP
the factors IXa, XIa and XIIa. Further inhibitors are suppresses the effects of LPS in high concentrations,
the tissue factor pathway inhibitor (TFPI) and the whereas in small quantities an enhancement of the
activated protein C, in combination with the free LPS-effects can be observed.213 Serum levels of LBP
protein S.160 However, the plasma level of free are significantly increased during the early post-
protein S is decreased during systemic inflamma- traumatic course and seem to be predictive of septic
tion, through binding to the C4b binding protein complications.213 Furthermore, the elevated ratio
(C4bBP).1,160 of positive APP to negative APP accelerates the
Disseminated intravascular coagulation can development of DIC after trauma.204
occur after trauma (Fig. 2).1,68,94,113 After the initial For the past decade, procalcitonin (PCT) has been
phase, with increased thrombin formation and more and more of interest as a diagnostic marker.
reduced fibrinolytic cascade, intra- and extra- PCT is a precursor of calcitonin, which is normally
vascular (e.g. intra-alveolar in ARDS) fibrin clots produced in the C-cells of the thyroid. Different
(hypercoagulability) and increased interaction studies have shown that hepatocytes, as well as
between endothelial cells and leukocytes was immune cells, are also capable of secreting PCT.71
observed.1,61,94,113 The consumption of coagulation The biological function of this acute phase protein is
factors (hypocoagulability) and dysfunction of still unclear. However, it seems that PCT may be a
thrombocytes are responsible for diffuse bleed- useful marker for monitoring the post-traumatic
ing (haemorrhagic diathesis).1,68 The intravascular course, predicting severe SIRS, MODS and septic
fibrin clots lead finally to microcirculatory distur- complications.71,110,127,201
698 M. Keel, O. Trentz

Leukocyte recruitment organ damage by degranulation of extracellular


proteases (elastase, metalloproteinase) and forma-
The infiltration and accumulation of PMNL represent tion of reactive oxygen species (ROS, oxygen radi-
a crucial event for the development of secondary cals), the so-called respiratory burst, or oxidative
organ and tissue damage (theory of neutrophil- stress (Fig. 3).28,67,73,123,152,180 Elastases have the
mediated tissue injury).21,28,67,180 Pro-inflammatory capacity to degrade most proteins in the extracel-
mediators and toxins induce a leukocyte/endothe- lular matrix and important plasma proteins. Their
lial cell interaction (adherence) through upregula- proteolytic activity is regulated by endogenous
tion of adhesion molecules on these cells.112,144,172 protease inhibitors (PI), such as a1-antitrypsin,
During the initial phase of adherence, selectins on a2-macroglobulin, or a1-protease-inhibitor. In
leukocytes (L-selectin, leukocyte adhesion mole- addition, neutrophil elastase induces the release
cule (LAM-1)) and endothelial cells (E-selectin, of pro-inflammatory cytokines. Elevated levels of
endothelial leukocyte adhesion molecule (ELAM-1) elastase, or elastasea1-protease-inhibitor com-
and P-selectin (platelet)) are responsible for the plex (Ea1PI), were detectable in multiply injured
rolling of PMNL.172 In the second step, upregula- patients depending on the injury severity and the
tion of integrins on PMNL such as CD11a/CD18 (leu- post-traumatic course.165 In the same manner,
kocyte function associated molecule-1 or LFA-1), metalloproteinases seem to be involved in the
CD11b/CD18 (macrophage antigen-1 or Mac-1), degradation of important structural proteins after
CD11c/CD18 and intercellular adhesion molecules trauma.23,115,133,152,199
(ICAM-1), or vascular cell adhesion molecules Oxidative cell injury involves the modification of
(VCAM-1) on endothelial cells can be observed after cellular macromolecules by ROS, often leading to
trauma.172 The interaction of these adhesion mole- cell death.98,114,123 Superoxide anions (O2) are
cules leads to a stable cell-to-cell contact with a generated by membrane associated nicotinamide
PMNL-attachment, so-called sticking of PMNL. adenine dinucleotide phosphate (NADPH)-oxidase,
Through shedding increased levels of adhesion which is activated by pro-inflammatory cytokines,
receptors (selectins, soluble ICAM-1 (sICAM-1), or arachidonic acid metabolites, complement factors
sVCAM-1) are detectable in serum of injured and bacterial products.77,206 Thereafter, superoxide
patients, with a predictive value for the develop- anions are reduced in the Haber-Weiss reaction to
ment of post-traumatic complications.108 Finally, hydrogen peroxide (H2O2) by superoxide dismutase
the migration (diapedesis), accumulation and in cytosol (SOD 1), mitochondrion (SOD 2), or cell
activation of leukocytes into tissue are mediated membrane (SOD 3). H2O2 is the substrate for the
by chemoattractant factors, such as chemokines myeloperoxidase that forms the highly toxic and
and complement anaphylatoxins (C3a, C5a), after bactericidal hypochloric acid (HOCL). In addition,
binding to their corresponding receptors (chemo- accumulated H2O2 is transformed to hydroxyl ions
taxis).169 Chemokine subfamilies are distinguished (OH) in the Fenton reaction. The free ROS induce
by the position of the first two conserved cysteins, lipid peroxidation, cell membrane disintegration
which are either separated by one to three amino and DNA-damage of endothelial and parenchymal
acids, such as CXC chemokine IL-8 (CXCL8), or adja- cells.98,105,175 Furthermore, oxygen radicals and
cent, such as CC chemokine macrophage inflamma- HOCL activate PMNL to release proteases and col-
tory protein (MIP)-1a (CCL3).169 Chemokines and lagenase and to inactivate protease-inhibitors
C3a or C5a were detectable in increased local con- (PI).114 In addition, the capacity of non-enzymatic
centrations at sites of injury, as well as systemi- antioxidants, such as vitamins E or C (scavenger), or
cally.169 In addition, the accumulation of PMNL is enzymatic antioxidants, such as SOD, katalase, or
supported by reduced spontaneous apoptosis, as glutathione peroxidase, is reduced during systemic
described above.82,97,109 inflammation.136,175
In addition, reactive nitrogen species (RNS)
are involved in the pathogenesis of trauma-induced
Proteases, oxidative stress and tissue damage.107 Nitric oxide (NO) is generated
capillary leakage from the amino acid L-arginine by inducible nitric
oxide synthase (iNOS) in PMNL, or vascular muscle
Infiltrated PMNL and tissue macrophages are respon- cells, and by endothelial nitric oxide synthase
sible for the phagocytosis of microorganisms and (eNOS) in endothelial cells (Fig. 3).107 NO induces
cellular detritus. However, activated PMNL have a vasodilatation, through increase of guanosine 30 ,50 -
Janus face (Janus, the mythological gate-keeper cyclic monophosphate (cGMP) by activation of the
has two faces, looking in opposite directions).142 guanylate cyclase. The activity of iNOS is stimulated
They are also able to induce secondary tissue and by cytokines and toxins, whereas eNOS is stimulated
Pathophysiology of polytrauma 699

Figure 3 Oxidative stress and capillary leakage. Activated polymorphonuclear leukocytes (PMNL) release reactive
oxygen (ROS) and reactive nitrogen species (RNS). These metabolites in combination with proteases are responsible for
endothelial cell damages and the development of a capillary leakage. See text for details and explanations.

by mechanical shearing forces, or by acetylcho- sludge).12 The sludge phenomenon leads to an


line.107,178 Additional metabolites emerging from obstruction of the microcirculation with a failure of
the interaction of superoxide anions and NO, such the transcapillary exchange. The cellular oxygen
as peroxynitrite (ONOO) have been shown to med- deficiency and the accumulation of metabolites (hid-
iate cellular cytotoxicity.107 The results of the vas- den acidosis) are finally responsible for tissue and
cular dysfunction caused by ROS and RNS are a cell damage. In addition, NO (vasodilatation) and
generalized oedema, clinically manifest as capillary endothelin (vasoconstriction) induce a shock-specific
leakage syndrome, with a disturbance of nutritional microcirculatory change with a shunting of some
and metabolic exchange, cell swelling and cellular organ or tissue areas, enhancing their damage.12
dysfunctions.107

Ischaemia/reperfusion injury
Microcirculatory disturbances
Systemic hypoxaemia and hypotension during the
The microcirculation as functional unity, consisting resuscitative period after trauma, as well as local
of terminal arterioles, capillaries and venules, reg- hypoperfusion through contusions, lacerations, vas-
ulates nutritional and metabolic exchange in organs cular injuries, or compartment syndromes lead to an
and tissues.12,126 Microcirculatory disturbances dur- oxygen deficit in endothelial, parenchymal, or
ing haemorrhagic shock and systemic inflammation immune competent cells, which is partially compen-
are primary mediated through the sympathetic-adre- sated for by the intracellular degradation of the
nal reaction leading to a vasoconstriction of arterioles energy-store adenosine triphosphate (ATP) to ade-
and venules. However, through decreased catechola- nosine diphosphate (ADP) and adenosine monopho-
mine effect on arterioles, a reduced capillary flow sphate (AMP).177 As a result of the ATP-consumption,
with an increased hydrostatic pressure can be disturbances of membrane permeability and
observed.12 This microcirculatory alteration, in com- energy-dependent Na+/K+-ATPase-pump arise, with
bination with the cytokine and NO mediated capillary an intracellular Na+ increase and cellular swelling.
leakage, are responsible for a secondary hypovolae- Finally, the generation of hypoxanthine leads to a
mia and haemoconcentration, with agglutination deficit of the cellular second messenger cyclic AMP
of erythrocytes (red sludge) and thrombocytes (white (cAMP). The ATP-deficit is further responsible
700 M. Keel, O. Trentz

Figure 4 Ischemia/reperfusion injury. See text for details and explanations.

for an increase of cytosolic Ca2+ with metabolic duced in the intracranial compartment, or flowing
disturbances of glucose, proteins, release of neuro- across the damaged bloodbrain barrier after
transmitters, or hormones, and an activation of severe head injury, act as afferent signals to the
phospholipases, proteases and endonucleases, hypothalamus.90 Primary (bleeding) and secondary
with membrane disintegration and DNA-damage (capillary leakage) hypovolaemia trigger, via aortic
(Fig. 4).177 However, irreversible tissue damage or carotic baroreceptors, a sympathetic-adrenal
through apoptosis, or necrosis of parenchymal cells, response and, via juxta-glomerular baroreceptors,
caused by energy deficit, are only observed after an activation of the reninangiotensin system to
prolonged severe haemorrhagic shock, or missed support the perfusion of vital organs.90 Angiotensin
vascular injuries.10,153 is an effective vasoconstrictor, induces a renal
Of more importance for secondary tissue damage retention of sodium and fluids, and stimulates the
and organ dysfunction is the reperfusion phase adrenal release of aldosterone. In addition, osmotic
(Fig. 4). During this post-ischaemic phase, hypox- receptors in the hypothalamus are responsible for
anthine is degraded to xanthine and finally to uric the secretion of antidiuretic hormone (ADH) by the
acid by xanthine oxidase, with the generation of posterior lobe of the pituitary (neurohypophy-
superoxide anions (O2) from available oxy- sis).90,177 In addition, chemoreceptors in the central
gen.139,192 Superoxide anions are further reduced nervous system for the registration of acidosis,
to hydrogen peroxide (H2O2) and hydroxyl ions hypercapnia, hypoxaemia or hypoglycaemia, as well
(OH) by superoxide dismutase. These free oxygen as thermoreceptors, are involved in this neuroendo-
radicals enhance disturbances of the intracellular crine reaction.177,209
Ca2+ homeostasis and induce lipid peroxidation, The sympathetic nervous system and the
membrane disintegration and DNA-damage, with adrenal gland represent the efferent regulators
apoptosis and necrosis of endothelial, parenchymal of cardiovascular, respiratory and metabolic
and immune cells.35,103 responses. Signals in the sympathetic area of the
hypothalamic evoke a release of catecholamines
from the adrenal medulla.150,177 In addition, post-
Neuroendocrine reaction and metabolic ganglionic sympathetic nerve ends influence
alterations organs and vessels directly. Adrenaline stimulates
the cardiac output by increasing heart contracti-
The post-traumatic host response is also influenced lity, the heart rate and the preload (FrankStar-
by neuroendocrine and metabolic disorders.207209 ling mechanism). In addition the blood pressure is
Stress, fear, pain and inflammatory mediators pro- elevated by the increased peripheral vascular
Pathophysiology of polytrauma 701

resistance (vasoconstriction of arterioles) and a bolic metabolism.90,150,177 In the second phase, all
centralization of the blood in favour of vital energy stores, such as glucose, fat acids and pro-
organs, such as heart and brain, established teins, are made available for the host defence
through a decrease of the perfusion of splanchnic response. The increase of the energy expenditure
area, kidneys and muscles.159 reaches a maximum after 510 days.62,90,150,177 The
Furthermore, catecholamines influence the post- increased levels of amino acids are needed for the
traumatic metabolism with an increase in the synthesis of acute phase proteins in the liver and
energy expenditure, hepatic glycogenolysis and inflammatory mediators in mononuclear cells. In
gluconeogenesis (glucose-lactate (Cori-cycle) and addition, glutamate represents a neurotransmitter
glucose-alanin cycles), as well as release of free and is the most important substrate for the meta-
fatty acids.90,150,209 Early hyperglycaemia (gluco- bolic processes of enterocytes and immune cells,
se  200 mg/dL) after trauma was associated with conserving the immune integrity of the intestinal
significantly higher infection and mortality rates.106 wall to avoid bacterial translocation during the
The natural post-traumatic insulin secretion is too systemic inflammation.90
low to cope with this post-traumatic hyperglycae-
mia. In addition, insulin secretion is partially
suppressed by catecholamines, mediated by a- Multiple organ dysfunctions or failure
receptors, whereas glucagon release is elevated
by b-receptor stimulation, contributing to hepatic The evolution of the physiological and reversible
glycogenolysis and gluconeogenesis.90 A peripheral systemic inflammation after trauma (host defence
insulin resistance has also been observed.177 Differ- response) to a host defence failure, which is asso-
ent cytokines (TNF-a, IL-1b) increase the expression ciated with irreversible organ defects and high mor-
of glucose transport systems (insulin-like activity). tality, can be described as an overload of primary
The increased intracellular glucose is oxidized to and secondary hits and an imbalance of pro- and
pyruvate and finally reduced to lactate (stress lac- anti-inflammatory mechanisms.18,19,118,159,177,188 In
tate acidosis), which contributes to the elevated addition, natural protective factors such as antiox-
lactate levels caused primarily by the metabolic idants or protease inhibitors are consumed.1
lactic acidosis (cellular hypoxia).150 Different stu- Endothelial cell damage, dysfunction of vascular
dies have shown that early increased serum levels of permeability with capillary leakage, microcircula-
lactate, or base deficit, are reliable markers for a tory disturbances with cellular hypoxia and finally
poor outcome in severely injured patients.3,36 apoptosis of parenchymal cells by cell-associated,
Pain, stress and fear cause the hypothalamus to or free, cell death proteins and/or necrosis of
release corticotropin-releasing hormone (CRH), parenchymal cells, are involved in the multiple
leading to a secretion of adrenocorticotropic hor- organ dysfunctions syndrome or multiple organ
mone (corticotropin, ACTH) from the anterior lobe failure.18,27,58,79,92,117,153,159,200 Depending on the
of pituitary (adenohypophysis).62,177 ACTH stimu- responsible insults (primary or secondary) MODS
lates the adrenal cortex to release glucocorticoids can be classified in primary, or early, MODS and
(cortisol), or mineralocorticoids (aldosterone). secondary, or late, MODS.18,27,50,95,157,159,202 Exam-
Within minutes after trauma, increased serum levels ples of early organ dysfunction are the primary
of steroids are detectable.62,177 Glucocorticoids cerebral oedema after head injury, or the primary
have different effects on the metabolism, such as ARDS after thoracic injury.15,18,95,120,137 The clinical
hepatic gluconeogenesis, glycogenesis, inhibition of manifestation of secondary MODS varies in affected
protein synthesis, increase of protein degradation in organs and dysfunction severities. Therefore, dif-
muscles and mobilization of free fatty acids by ferent scores, such as the MOF score (Goris score),
lipolysis.90,177 In addition they limit inflammatory MODS score (Marshall score), or sequential organ
processes of mononuclear cells and suppress the failure assessment (SOFA) score are available to
production of antibodies.90 In contrast, the sponta- describe dysfunctions of seven systems: respiratory,
neous apoptosis of PMNL is reduced by cortisol.34 cardiovascular, renal, hepatic, gastrointestinal,
Aldosterone increases the renal resorption of haematological and central nervous sys-
sodium-associated by fluid retention. tems.8,63,73,119 For the diagnosis of acute lung injury
The metabolic disorders after trauma are initially (ALI), or acute respiratory distress syndrome, bilat-
characterized by a reduced metabolism for about eral lung infiltrations on thoracic X-ray and a
24 h (acute, shock or ebb phase).90,150,177 This is decrease of the Horowitz ratio must be observed
followed by a flow phase with a catabolic metabo- (PaO2/ F iO2 ratio < 300 corresponds to an ALI, < 200
lism for some days to 2 weeks and a final reparative to an ARDS).137 Renal and gastrointestinal systems
phase with a turnover from a catabolic to an ana- are very sensitive to microcirculatory disorders,
702 M. Keel, O. Trentz

leading to a necrosis of renal tubules with increase decrease the early and late mortality.13 Patients
of serum creatinine concentrations and oliguria with a borderline state after primary survey, or
(< 0.5 ml/kg KG/h) or anuria, and to necrosis of patients with a high trauma impact, or at risk of
intestinal villi.103,159 The alteration of the intestinal adverse outcome, such as head injury, bilateral lung
mucosa seems to be responsible for a bacterial contusions, multiple long bone fractures, coagulo-
translocation and explains the high rate of bacter- pathy, hypothermia or a presumed operation
aemia in the absence of a detectable infective focus time > 6 h, should be supplied with a staged
in lethal septic complications after trauma (gut sequential surgical management as damage control,
hypothesis).103,130,159 The gastrointestinal tract after the further work up in the secondary survey, to
often represents the source for the development avoid or limit the influence of second hits (inter-
of secondary multiple organ failure after trauma, ventional or antigenic loads).147,202 Damage control
whereas the liver represents the engine, with an includes haemorrhage control through tamponade,
acute phase and cytokine response, and decreased vascular repair or vessel ligation, and organ resec-
function of hepatocytes (increase of serum bilirubin tions.59 In addition, a reduction of contamination
concentration).130,157,162 Repeated scoring is help- after hollow organ injuries, or open fractures, as
ful for identifying categories of injured patients at well as decompression of compartment syndromes
major risk of death, or complications, after surgical of the extremities by fasciotomy, or of the abdomen
interventions.8 by decompressive laparotomy, should contribute to
the limitation of secondary inflammatory pro-
cesses.11,49,89,154 Furthermore, the temporary sta-
Therapeutic strategies for multiply bilization of pelvic and long bone fractures, or
injured patients dislocations of large joints, by rapidly assembled
and applied external fixators seem to be benefi-
Hypoxia and severe haemorrhagic shock correlate cal.49,53,89,141,147,154 This concept decreases the sys-
with high mortality rates, as well as with an high temic release of pro- and anti-inflammatory
incidence of SIRS, sepsis and organ dysfunction.95 To mediators, in comparison with definitive interven-
reduce these high mortality and morbidity rates in tions, such as reamed nailing (early total care).147
the post-traumatic course, early preventive Debridement of open wounds and fractures, with
interventions are necessary. According to the guide- resection of non-viable tissues, temporary closure
lines of advanced trauma life support (ATLS#), early by vacuum assisted closure therapy and second look
oxygenation therapy by intubation and controlled interventions, contribute to a limited antigenic
assisted ventilation and an adequate volume ther- load, with a decrease in septic complications.89,186
apy with crystalloids, colloids and/or blood products However, the early stabilization of major skeletal
are essential.29 However, the large-volume loading injuries (early total care) represents still the
scheme is the subject of controversial debate in concept for patients with isolated fractures and in
severe haemorrhagic shock.131,174 Patients with the absence of high traumatic impact and the risk
blood loss > 2 l should not be overwhelmed by factors mentioned above.147
crystalloids or colloids until surgical management With regard to strategies for post-traumatic
of bleeding is undertaken, whereas in septic shock intensive care, only supportive therapies are estab-
early, goal-directed, high volume therapy is success- lished to avoid secondary organ damage and hits.95
ful.161 In contrast, small volume resuscitation in Secondary brain injuries, with elevated intracranial
severe traumatic shock seems to avoid a reduced pressure (ICP) due to cerebral oedema, or ischae-
O2 transport capacity, coagulopathy, and infusion- mia/reperfusion injuries, can be limited by applying
induced hypothermia.131,174 different neuroprotective strategies, such as con-
After the primary survey, with basic imaging, trolled hyperventilation, moderate hypothermia,
multiply injured patients are graded as non-respon- and release of cerebrospinal fluid (CSF).167,183
ders, borderlines and responders, according to Whenever these therapeutic regimens fail to reduce
the initial response to volume therapy, or pharma- ICP, intravenous administration of barbiturate may
ceutical resuscitation.29 Life saving surgical proce- become necessary.183 The beneficial effect of bar-
dures, such as decompressing pneumothorax, biturates, in terms of lowering elevated ICP, is
cardiac tamponade or acute epidural haematoma, thought to be due to decreased cerebral metabolism
and surgical control of massive haemorrhage in the and blood flow.41 Other supportive therapies include
thoracic or abdominal cavities and from pelvic frac- mechanical ventilation, inotropes and haemofiltra-
tures, or traumatic amputations are carried out tion for renal failure.159,177 Furthermore, a single
without delay.29,53,60,154 These early interventions shot of an antibiotic (cephalosporin) after trauma
seem to limit the systemic inflammation and reduces the post-traumatic wound infection rate.196
Pathophysiology of polytrauma 703

Further antibiotics should only be given according Although some successful progress in clinical
to an antibiogram of an infectious focus.196 Early trials is obvious, better understanding of the patho-
enteral nutrition, via gastric or duodenal tubes, logical mechanisms at local site of injury would
reduces the accumulation of pathogenic bacteria identify exact primary targets for drug interven-
in the intestinal tract and avoids atrophy of intest- tions. However, progress in diagnostic tools for
inal mucosa,.177,184 Additional arginine, glutamine, the monitoring of the immune status (beside immu-
nucleotides, or unsaturated omega-3-fatty acids nomonitoring) may become more successful for the
(immune-enhanced enteral nutrition (IEEN)) re- management of severely injured patients in the near
duce post-traumatic hypermetabolism and improve future. Parallel monitoring of pro- (e.g. IL-6) and
immune competence.26 anti-inflammatory (e.g. IL-10) cytokines, as well as
Despite thorough insights into the pathophysio- acute phase proteins (e.g. CRP, procalcitonin), or
logical mechanisms of post-traumatic systemic other factors, could help us in the decision making
inflammation and hopeful results of animal studies, for optimal secondary operative interventions to
multiple prospective clinical trials performed in the limit second hits.71,170 However, more prospective
past decades, especially in patients with sepsis, diagnostic studies have to be conducted, to under-
have failed to provide a benefit of anti-inflamma- stand the kinetics and significance of these factors
tory, anti-coagulant, or antioxidant strategies in order to optimize the concept of damage
with regard to the mortality, whereas the incidence control.
of post-traumatic complications, such as infections,
or multiple organ dysfunctions, has partially
decreased.2,13,33,64,65,72,91,113,136,151 However, the
magic bullet is still not found. Reasons for these References
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