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,

Despite improved traffic and occupational safety,
as well as significant advances in pre- and in-
hospital management, severe trauma represents
the most frequent cause of death in people below
the age of 40 years.4,38,60,128,149,168 Immediate and
early trauma deaths are determined by severe
primary brain injuries, or significant blood loss
(haemorrhagic shock) after blunt, or penetrating,
trauma.4,38,60,70,128,149,158,168,173,181,194 Late mor-
tality is caused by secondary brain injuries and
host defence failure.4,70,158,168,173,194 Direct, or
indirect, mechanical forces induce organ and soft
tissue injuries, or fractures. However, these first
hits represent a greater challenge, as local tissue
damage, such as contusions or lacerations, hypoxia
and hypotension, induce further local and systemic
host responses, to preserve the immune integrity
and stimulate reparative mechanisms.164 This sys-
temic inflammation was defined in 1991, through
the consensus conference of the American College
of Chest Physicians/Society of Critical Care Med-
icine (ACCP/SCCM), as systemic inflammatory
response syndrome (SIRS).6 At least two of the
four clinical parameters (Table 1) must be fulfiled
for the diagnosis of SIRS.6 It is characterized by the
local and systemic production and release of dif-
ferent mediators, such as pro-inflammatory cyto-
kines, complement factors, proteins of the contact
phase and coagulation systems, acute phase pro-
teins, neuroendocrine mediators and an accumu-
lation of immunocompetent cells at the local site
of tissue damage (Fig. 1).17,18,40,91,163,169,195 In
addition, this systemic inflammation is augmented
by second hits, such as ischaemia/reperfusion
injuries, surgical interventions or infections
(two-hit theory).163,164
However, different clinical trials and animal
models have shown that, in parallel with avoid
the autodestructive effects of immunocompetent
cells (Fig. 1).19,88,91,120,195 An imbalance between
these dual immune responses, with an overwhelm-
seems to be responsible for organ dysfunction
and increased susceptibility to infections and
sepsis.19,116,118,155 Endothelial cell damage, accu-
mulation of leukocytes, disseminated intravascular
coagulation (DIC) and microcirculatory dysfunction
finally lead to programmed cell death (apoptosis)
and necrosis of parenchymal cells (microenviron-
ment theory) with the development of multiple
organ dysfunction syndrome (MODS) or multiple
organ failure (MOF).67,91,92,95,107,117,153,159,195 In
accordance with these pathophysiological mechan-
isms and definition of SIRS, the term polytrauma
can be defined as a syndrome of combined
injuries with an injury severity score (ISS) > 17
and consequent SIRS for at least 1 day, leading to
dysfunction, or failure, of remote organs and vital
systems, which themselves had not directly been
injured.76,193
This review is planned to give an insight into the
triggers and the mechanisms of the post-traumatic
cardiovascular shock, homeostasis, apoptosis,
organ dysfunctions and immune suppression
(CHAOS) as coined by Bone.19 In addition, it should
elucidate the pathophysiological basis for the
damage control concept in the surgical manage-
ment of multiple injured patients, reasons for the
Table 1 Clinical parameters of systemic inflammatory
response syndrome (SIRS)
1. Heart rate > 90/min
2. Breathing rate > 20/min, respectively,
hyperventilation with decrease of the
arterial CO2 partial pressure (PaCO2)
under 32 mmHg
3. Temperature > 38 8C or < 36 8C
4. Number of leukocytes > 12,000/mm3
or < 4000/mm3 or
10% juvenile
neutrophil granulocytes
For the definition of SIRS, two or more parameters must be
fulfiled. Sepsis is defined as SIRS with detection of bacteremia
or bacterial focus.6
Pathophysiology of polytrauma
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 past two decades and the significance for
the development of post-traumatic immunomoni-
toring.
Two-hit theory
The complex cascade of the host defence response is
stimulated by primary and secondary insults (two-
hit theory).163,164 The trauma impact determines
primary organ, or soft tissue, injuries and fractures
(first hit; trauma load) with local tissue damage as
well as an activation of the systemic inflammatory
response.118,135,163,164,179 In addition, secondary
endogenous and exogenous factors play a crucial
role in the initiation and severity of post-traumatic
complications.164,179,202 Typical endogenous (anti-
genic load) second hits are respiratory distress with
hypoxia, repeated cardiovascular instability, meta-
bolic acidosis, ischaemia/reperfusion injuries, dead
tissue, contaminated catheters, or tubes, and infec-
tions.46,50 Surgical interventions with severe tissue
damage, hypothermia or blood loss, inadequate, or
delayed, surgical, or intensive care, after neglected
or missed injuries, as well as massive transfusions,
represent exogenous second hits (interventional
load or surgical load).46,81,202
693
The severity of organ injuries, varying from con-
tusions to complete lacerations, and the remaining
organ perfusion influence the post-traumatic sys-
temic inflammatory response. The highest incidence
for the development of SIRS can be observed after
isolated or combined severe head injuries.55,155
Primary focal or diffuse and secondary brain
damages including ischemia/reperfusion injuries,
cerebral oedema or intracranial hypertension deter-
mine the cerebral outcome and the mortality as well
as the incidence and severity of post-traumatic
complications.169,176,181 Although the central ner-
vous system has been defined historically as an
immunologically privileged organ, due to its
separation from the peripheral circulation by the
bloodbrain barrier (BBB), different studies have
shown that the brain acts as a target and as an
effector organ.87,104,169 Glial cells, astrocytes
and neurons are potent producers of pro- and
anti-inflammatory mediators and their receptors,
leading to local tissue damage and a systemic
response.104,132,169 In addition, systemic mediators
released by peripheral immune, endothelial, or par-
enchymal cells influence the integrity of the BBB,
leading to a bi-directional communication of the
inflammatory mediators.104,132,169 Primary epidural
hematoma, or cerebral oedema, as well as post-
traumatic secondary oedema, induced by local and
694
systemic inflammatory processes, are responsible
for the development of a cerebral compartment
syndrome, which is lethal without intervention.173
Thoracic injuries, with multiple rib fractures,
lung contusions, or lacerations, are often compli-
cated by local and systemic inflammation, with or
without manifestation of pneumonia, acute lung
injury (ALI), or acute respiratory distress syndrome
(ARDS).9,120,137 Injuries of intra-abdominal organs
cause haemorrhagic shock (liver, spleen, vascular
injuries) and aseptic, or septic, peritonitis (pancrea-
tic or hollow organ injuries).11 Severe intra-abdom-
inal or retroperitoneal haemorrhage, after vascular,
renal, or pelvic injuries, as well as systemic inflam-
matory processes in septic patients, can lead to an
abdominal compartment syndrome with systemic
complications.59,125
Soft tissue injuries of the extremities, espe-
cially in patients with haemorrhagic shock, are
often complicated by decreased perfusion (low-
flow hypoxia), with a high risk for ischaemia/
reperfusion injuries and secondary infections.
Furthermore, severe muscle crushing injuries pre-
dispose to a compartment syndrome with muscle
necrosis, rhabdomyolysis and finally acute renal
failure (crush kidney).159 Fractures of the femur,
multiple long bone fractures and unstable pelvic
ring fractures are characterized by a high blood
loss and contribute to the inflammatory acti-
vity.22,49,53 Additionally, fat embolism syndrome
is an infrequent clinical consequence with the
typical triad of pulmonary distress, mental
changes and petechial rash, 2448 h after pelvic
or long-bone fractures.148
The incidence of septic complications has
increased during the last decade.122 Closed wounds
with large soft tissue damage and open wounds,
or fractures, as well as neglected soft tissue
injuries, represent portal of entry for microorgan-
isms.205,210 Central venous catheters, intratra-
cheal tubes, chest tubes and bladder catheters
are often contaminated and raise the infection risk
in severely injured patients.32 The most common
reasons for sepsis after trauma are hospital
acquired pneumonia, catheter infections, intra-
abdominal and wound infections.9,140,179 Further-
more, ischaemic lesions of the gastrointestinal
tract after haemorrhagic shock seem to be respon-
sible for bacterial translocation into the circulation
(gut hypothesis).103,130
HyperinflammationSIRS
Tissue damage induces in commensurate with the
severity of trauma (trauma load), genetic factors
M. Keel, O. Trentz
(gene polymorphism), the general condition of the
host and the type of antigens (antigenic load), both
local and systemic release of pro-inflammatory
cytokines and phospholipids.40,88,143,171,190 Poly-
morphonuclear leukocytes (PMNL), monocytes, tis-
sue macrophages (e.g. alveolar macrophages),
lymphocytes, natural killer cells, and parenchymal
cells are involved in a complex network of this host
defence response.195 An overwhelming pro-inflam-
matory response (hyperinflammation) leads to the
clinical manifestation of SIRS and finally to host
defence failure (MODS, MOF).55,71,135,195
Cytokines are polypeptides and act in a para- or
autocrine manner.40 They are capable of exerting
many effects on an array of cell types (pleiotropy).40
Besides hyperacute pro-inflammatory cytokines,
such as tumor necrosis factor-a (TNF-a), or inter-
leukin-1b (IL-1b), with an effect after 12 h, there
exist subacute (secondary) cytokines such as IL-6,
IL-8 (neutrophil activating peptide (NAF)), macro-
phage migratory factor (MMF), high motility group
protein -1 (HMG-1), as well as IL-12 and IL-18,
two interferon-g (IFN-g)-modulating cytokines
(Fig. 1).40,71 Increased TNF-a, IL-1b or IL-8 serum
levels are observed in patients with systemic inflam-
mation, as well as in bronchoalveolar lavage fluids of
patients with thoracic trauma, or acute respiratory
distress syndrome.42,43,100,121,187 In addition, IL-6
serum levels correlate with the ISS, the incidence
of MODS, ARDS, or sepsis and with outcome.15,121,166
Through the influence of antigens, T-helper lym-
phocytes (TH cells, CD4+ cells) differentiate into two
phenotypes, the TH1 and TH2 lymphocytes.146 TH1
cells support the pro-inflammatory cascade through
secretion of IL-2, interferon-g and TNF-b, whereas
TH2 cells are important producers of anti-inflam-
matory mediators. Monocytes/macrophages are
involved in the differentiation of TH1 cells, via
the secretion of IL-12. Depressed IL-12 production
after trauma correlated with a shift of the TH1/TH2
ratio towards the TH2-type pattern, with an adverse
clinical outcome.146
Pro-inflammatory cytokines activate the recruit-
ment and phagocytosis activity of PMNL (priming),
the immune cells of the first hours (the first defence
line), and stimulate PMNL to release proteases and
free oxygen radicals (respiratory burst, oxidative
stress) (Fig. 1).21 Furthermore, PMNL are influenced
by colony-stimulating factors, such as granulocyte-
colony stimulating factor (G-CSF) and granulocyte
macrophage-colony stimulating factor (GM-
CSF).20,31,51,189 They enhance monocyte- or granu-
locytopoiesis, on the one hand and reduce the
spontaneous programmed cell death (apoptosis) of
PMNL during SIRS or sepsis, on the other hand.20,31,51
Other pro-inflammatory mediators contribute addi-
Pathophysiology of polytrauma
tionally to the reduction of neutrophil apoptosis,
with an accumulation of PMNL at the site of local
tissue damage.16,47,54,78,97,102,109,124
Mechanical and hypoxic cellular damage leads
further to an increase of intracellular Ca++ levels
with an activation of phospholipase A2 (PLA2) and
phospholipase C (PLC).163 These enzymes catalyse
the release of arachidonic acids from membrane
phospholipids. Through the activation of cyclooxy-
genase and 5-lipooxygenase prostaglandine E2
(PGE2) leucotriene B4 (LTB4) and thromboxane A2
(TXA2), respectively, are produced (Fig. 1).165 These
metabolites are involved in the recruitment of
inflammatory cells, regulation of vascular perme-
ability and motility, as well as the aggregation of
thrombocytes.163 Additionally, PLA2 induces the
release of the platelet activating factor (PAF).212
It supports the activation of macrophages, their
interaction with endothelial cells and the activation
and aggregation of thrombocytes.212
HypoinflammationCARS
Depending on the severity of injury and the post-
traumatic course, anti-inflammatory mediators are
also produced. TH2-cells and monocytes/macro-
phages release IL-4, IL-10, IL-13, or transforming
growth factor-b (TGF-b) (Fig. 1).30,33,57 In addition,
different cytokines (e.g. IL-6) have shown a dual
effect with pro- and anti-inflammatory activities.
The serum levels of IL-10 correlate with ISS and post-
traumatic complications, such as MODS, ARDS, or
sepsis.88,138 In addition, natural inhibitors of recep-
tors, such as soluble TNF-receptors (TNF-RI (55 kD)
and TNF-RII (75 kD)), or IL-1 receptor antagonist
(IL-1ra) are detectable in the sera of injured
patients, correlating also with the ISS and the inci-
dence of post-traumatic complications.52,88,99
Furthermore, the readiness of blood monocytes
from injured patients to release pro-inflammatory
cytokines was decreased in in vitro studies
after stimulation with Gram-negative (endotoxin,
lipopolysaccharide (LPS)), or Gram-positive (e.g.
peptidoglycan, lipoteichonic acid), bacterial pro-
ducts and correlated with the post-traumatic
course.25,56,84,85,101,203 The mechanisms of this
endotoxin tolerance are still incompletely hours after trauma anti-inflammatory mediators
understood.203 It seems that anti-inflammatory
mediators, like IL-10, depress the activity of intra-
cellular transcription factors, such as nuclear
factor-kappa B (NF-kB), which are essential for
the synthesis of pro-inflammatory cyto-
kines.24,69,84,101,116,197,198,203 The expression of
the LPS-receptor CD14 on monocytes is decreased
after trauma, combined with an increase of the
695
soluble CD14 (sCD14), through shedding of the mem-
brane-bound CD14.203 However, the decreased
expression of CD14, as well as expression altera-
tions of the pattern-recognition receptors for bac-
terial products, the toll-like receptors, seem not to
be responsible for endotoxin tolerance.83 By
contrast, the expressions of the toll-like receptors
for Gram-positive (TLR2) and Gram-negative (TLR4)
bacterial products are increased on monocytes,
or PMNL, during systemic inflammation.80 Further-
more, antigen-presenting cells (APC), such as
monocytes/macrophages, showed a depressed
expression of the MHC (major histocompatibility
complex) class II molecule HLA-DR (human leuko-
cyte antigen) that correlated with post-traumatic
infections.71
During the early phase of the post-traumatic
course, a lymphocytopaenia has been observ-
ed.22,92,111,195 This lymphocyte depletion was asso-
ciated with morbidity and outcome after trauma.195
It may be related to increased apoptosis, triggered
by stress hormones (steroids) and cell death pro-
teins.39,111,117,145,153 Apoptosis is characterized
morphologically by cell shrinking, with cytoplas-
matic condensation (apoptotic bodies), nuclear con-
densation (pycnosis) and DNA-fragmentation (DNA
laddering).134,153 The cell membranes stay primarily
intact and no surrounding inflammatory signs can be
observed, in contrast to necrosis.153
Typical cell death proteins are TNF-a or Fas ligand
(CD95 ligand).5,134 They induce cell death after
binding with their receptors, respectively, TNF-RI
and Fas antigen (CD95 antigen) and activation
of complex intracellular cascades and effector
enzymes, such as intracellular proteases (e.g.
calpains, caspases).5,39,75,111,134,156 The cellular
expressions of TNF-RI and Fas antigen, or their soluble
molecules, were elevated in serum from injured
patients, postoperatively or during sepsis.37,145
An overwhelming anti-inflammatory response
(hypoinflammation) seems to be responsible for
post-traumatic immunosuppression, with a high
susceptibility to infections and septic complica-
tions.19,171,195 This immunological status is called
compensatory anti-inflammatory response syn-
drome.19 However, it does not look like a compen-
satory mechanism in a biphasic model; as only a few
(e.g. IL-10) were detectable in the serum of injured
patients.138 It seems that the host defence response
tries to strike a fine balance between SIRS and CARS,
to induce reparative mechanisms and limit entry
or overload of microorganisms, on the one hand, and
to avoid autoaggressive inflammation, with second-
ary tissue damage and susceptibility to infections,
on the other hand. These mixed inflammatory
696
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
syndrome (MARS).19
Activation of plasmatic cascade system
Pro-inflammatory mediators (cytokines, arachidonic
acid metabolites) and toxins activate the plasmatic
cascade system, consisting of the complement cas-
cade, the kallikreinkinin system and the coagula-
tion cascade (Fig. 2). The classical pathway of
complement activation is induced by antigenanti-
body complexes (immunoglobulins M or G (IgM,
IgG)), or activated coagulation factor XII (FXIIa),
whereas bacterial products (e.g. LPS) activate the
alternative pathway (Fig. 2).66,129,182 Cleavages of
C3, by C3 convertase, and C5, by C5 convertase,
lead to the formation of opsonins, anaphylatoxins
and, finally, the membrane attack complex
(MAC).66,129,182 The opsonins C3b and C4b are
involved in the phagocytosis of cell detritus, and
especially bacteria, by covalent binding of pathogen
surfaces (opsonization).66,129 The anaphylatoxins
C3a and C5a support different inflammatory
mechanisms, the recruitment (chemotaxis) and
activation of phagocytic cells (PMNL, monocytes,
macrophages), the enhancement of the hepatic
acute phase response, the degranulation of mast
cells and basophils, with release of vasoactive med-
M. Keel, O. Trentz
iators, such as histamine, as well as the adhesion
of leukocytes to endothelial cells, leading to
increased vascular permeability with oedema.129,169
In addition, apoptosis and cell lysis (necrosis) of
parenchymal cells, or bacteria, are induced by
C5a, through the C5a receptor (C5aR) and the
MAC (C5b-9) .129,169,182 In clinical studies, elevated
serum levels of different complement components,
or their expression in injured tissue, were observed
after trauma, or during sepsis.42,86,165,169,182,211
Similarly to some cytokines, C3a and C5a showed
dual effects with activation of reparative mechan-
isms too.129 Furthermore, during systemic inflam-
mation, serum levels of the C1-inhibitor, produced
by hepatocytes, endothelial cells, monocytes and
macrophages, were decreased through a degrada-
tion by PMNL-elastases. C1-inhibitor regulates the
classical complement pathway through inactivation
of the active subunits C1s and C1r.129
The plasma proteins FXII, prekallikrein, kinino-
gen and the factor XI (FXI) represent the contact
phase system (Fig. 2).185 They are characterized by
the fact, that they can be activated by negatively-
charged cellular surfaces (contact activation).185
FXII and prekallikrein activate mutually and form
FXIIa and kallikrein. FXIIa stimulates the com-
plement cascade along the classical pathway.185
Kallikrein induces the fibrinolysis through conver-
sion of plasminogen to plasmin, or activation of
Pathophysiology of polytrauma
the urokinase-like plasminogen activator (u-PA)
(Fig. 2). The tissue-plasminogen activator (t-PA)
works as a cofactor, whereas natural inhibitors of
the fibrinolytic system are a2-antiplasmin (a2AP),
a2-macroglobulin (a2MG) and the plasminogen-
activator-inhibitor 1 (PAI-1). In addition, kallikrein
stimulates the formation of bradykinin from
kininogen. Kinins are vasodilators, increase the
vascular permeability and inhibit the functions
of thrombocytes.185
The intrinsic coagulation system is linked to the
contact activation system through the formation
of FIXa by FXIa (Fig. 2). During the host defence
response, a consumption of FXII, prekallikrein and
FXI has been observed, whereas plasma levels of
enzymeinhibitor complexes, such as FXIIaC1-
inhibitor or kallikreinC1-inhibitor, were increas-
ed.1 C1-inhibitor and a1-protease-inhibitor (a1PI)
represent the inhibitors of the intrinsic coagulation
system (Fig. 2).1,94
However, the coagulation system is initially acti-
vated over the extrinsic pathway with an increased
expression of the tissue factor (TF) on endothelial
cells and monocytes, induced by bacterial cell wall
fragments and pro-inflammatory cytokines (TNF-a,
IL-1b) (Fig. 2).61,68,94 The FVIITF complex stimu-
lates the coagulation cascade, with the formation of
FXa and finally thrombin (FIIa), from prothrombin
(FII). Thrombin activates FV, FVIII and FXI, leading to
enhanced formation of thrombin. After cleavage of
fibrinogen by thrombin, fibrin monomers polymerize
to form stable fibrin clots, via support of FXIIIa.1,94
To control the consumption of coagulation factors,
antithrombin (ATIII) produced by hepatocytes inhi-
bits thrombin and FXa, through the formation of a
thrombinantithrombin complex.1 This effect can
be enhanced by heparin. Furthermore, ATIII inhibits
the factors IXa, XIa and XIIa. Further inhibitors are
the tissue factor pathway inhibitor (TFPI) and the
activated protein C, in combination with the free
protein S.160 However, the plasma level of free
protein S is decreased during systemic inflamma-
tion, through binding to the C4b binding protein
(C4bBP).1,160
Disseminated intravascular coagulation can
occur after trauma (Fig. 2).1,68,94,113 After the initial
phase, with increased thrombin formation and
reduced fibrinolytic cascade, intra- and extra-
vascular (e.g. intra-alveolar in ARDS) fibrin clots
(hypercoagulability) and increased interaction
between endothelial cells and leukocytes was
observed.1,61,94,113 The consumption of coagulation
factors (hypocoagulability) and dysfunction of
thrombocytes are responsible for diffuse bleed-
ing (haemorrhagic diathesis).1,68 The intravascular
fibrin clots lead finally to microcirculatory distur-
697
bances with hypoxia-induced cellular damage.1,94
The consumption of coagulation factors is further
enhanced through the proteolysis of fibrin clots
to fibrin fragments by the protease plasmin
(fibrinolysis).94,115
Acute phase reaction
The local (Kupffer-cells) and systemic release of
pro-inflammatory cytokines (TNF-a, IL-1b, IL-6)
induce the acute phase reaction in the liver,
to enhance tissue protective and antimicrobial
mechanisms.204 The synthesis of positive acute
phase proteins (APP) in hepatocytes, such as
C-reactive proteins (CRP), a1-antitrypsin, a2-
macroglobulin, caeruloplasmin, lipopolysaccharide
(LPS)-binding protein (LBP), fibrinogen, prothrom-
bin or C4BP, is increased, whereas the production
of negative APP, such as albumin, high-density lipo-
proteins (HDL), protein C, protein S and ATIII, is
reduced.45,204
CRP increases the expression of TF on PMNL and
monocytes/macrophages, and thereby enhances
the activation of the extrinsic coagulation cas-
cade.45 Clinical studies have shown that the level
of CRP is relatively non-specific and not predictive
of post-traumatic complications, such as infec-
tions.74,127,165 Serial measurements appear to be
helpful however, especially in the first 2 weeks,
as, whilst the levels of CRP reduce with time in
cases of systemic inflammation, in the presence
of infection an upward trend is seen consistently.
a1-antitrypsin inactivates the proteases secreted
by PMNL or macrophages, whereas a2-macroglobu-
lin and caeruloplasmin neutralize free oxygen
radicals and pro-inflammatory cytokines.204 LBP
suppresses the effects of LPS in high concentrations,
whereas in small quantities an enhancement of the
LPS-effects can be observed.213 Serum levels of LBP
are significantly increased during the early post-
traumatic course and seem to be predictive of septic
complications.213 Furthermore, the elevated ratio
of positive APP to negative APP accelerates the
development of DIC after trauma.204
For the past decade, procalcitonin (PCT) has been
more and more of interest as a diagnostic marker.
PCT is a precursor of calcitonin, which is normally
produced in the C-cells of the thyroid. Different
studies have shown that hepatocytes, as well as
immune cells, are also capable of secreting PCT.71
The biological function of this acute phase protein is
still unclear. However, it seems that PCT may be a
useful marker for monitoring the post-traumatic
course, predicting severe SIRS, MODS and septic
complications.71,110,127,201
698
Leukocyte recruitment
The infiltration and accumulation of PMNL represent
a crucial event for the development of secondary
organ and tissue damage (theory of neutrophil-
mediated tissue injury).21,28,67,180 Pro-inflammatory
mediators and toxins induce a leukocyte/endothe-
lial cell interaction (adherence) through upregula-
tion of adhesion molecules on these cells.112,144,172
During the initial phase of adherence, selectins on
leukocytes (L-selectin, leukocyte adhesion mole-
cule (LAM-1)) and endothelial cells (E-selectin,
endothelial leukocyte adhesion molecule (ELAM-1)
and P-selectin (platelet)) are responsible for the
rolling of PMNL.172 In the second step, upregula-
tion of integrins on PMNL such as CD11a/CD18 (leu-
kocyte function associated molecule-1 or LFA-1),
CD11b/CD18 (macrophage antigen-1 or Mac-1),
CD11c/CD18 and intercellular adhesion molecules
(ICAM-1), or vascular cell adhesion molecules
(VCAM-1) on endothelial cells can be observed after
trauma.172 The interaction of these adhesion mole-
cules leads to a stable cell-to-cell contact with a
PMNL-attachment, so-called sticking of PMNL.
Through shedding increased levels of adhesion
receptors (selectins, soluble ICAM-1 (sICAM-1), or
sVCAM-1) are detectable in serum of injured
patients, with a predictive value for the develop-
ment of post-traumatic complications.108 Finally,
the migration (diapedesis), accumulation and
activation of leukocytes into tissue are mediated
by chemoattractant factors, such as chemokines
and complement anaphylatoxins (C3a, C5a), after
binding to their corresponding receptors (chemo-
taxis).169 Chemokine subfamilies are distinguished
by the position of the first two conserved cysteins,
which are either separated by one to three amino
acids, such as CXC chemokine IL-8 (CXCL8), or adja-
cent, such as CC chemokine macrophage inflamma-
tory protein (MIP)-1a (CCL3).169 Chemokines and
C3a or C5a were detectable in increased local con-
centrations at sites of injury, as well as systemi-
cally.169 In addition, the accumulation of PMNL is
supported by reduced spontaneous apoptosis, as
described above.82,97,109
Proteases, oxidative stress and
capillary leakage
Infiltrated PMNL and tissue macrophages are respon-
sible for the phagocytosis of microorganisms and
cellular detritus. However, activated PMNL have a
Janus face (Janus, the mythological gate-keeper
has two faces, looking in opposite directions).142
They are also able to induce secondary tissue and
M. Keel, O. Trentz
organ damage by degranulation of extracellular
proteases (elastase, metalloproteinase) and forma-
tion of reactive oxygen species (ROS, oxygen radi-
cals), the so-called respiratory burst, or oxidative
stress (Fig. 3).28,67,73,123,152,180 Elastases have the
capacity to degrade most proteins in the extracel-
lular matrix and important plasma proteins. Their
proteolytic activity is regulated by endogenous
protease inhibitors (PI), such as a1-antitrypsin,
a2-macroglobulin, or a1-protease-inhibitor. In
addition, neutrophil elastase induces the release
of pro-inflammatory cytokines. Elevated levels of
elastase, or elastasea1-protease-inhibitor com-
plex (Ea1PI), were detectable in multiply injured
patients depending on the injury severity and the
post-traumatic course.165 In the same manner,
metalloproteinases seem to be involved in the
degradation of important structural proteins after
trauma.23,115,133,152,199
Oxidative cell injury involves the modification of
cellular macromolecules by ROS, often leading to
cell death.98,114,123 Superoxide anions (O2) are
generated by membrane associated nicotinamide
adenine dinucleotide phosphate (NADPH)-oxidase,
which is activated by pro-inflammatory cytokines,
arachidonic acid metabolites, complement factors
and bacterial products.77,206 Thereafter, superoxide
anions are reduced in the Haber-Weiss reaction to
hydrogen peroxide (H2O2) by superoxide dismutase
in cytosol (SOD 1), mitochondrion (SOD 2), or cell
membrane (SOD 3). H2O2 is the substrate for the
myeloperoxidase that forms the highly toxic and
bactericidal hypochloric acid (HOCL). In addition,
accumulated H2O2 is transformed to hydroxyl ions
(OH) in the Fenton reaction. The free ROS induce
lipid peroxidation, cell membrane disintegration
and DNA-damage of endothelial and parenchymal
cells.98,105,175 Furthermore, oxygen radicals and
HOCL activate PMNL to release proteases and col-
lagenase and to inactivate protease-inhibitors
(PI).114 In addition, the capacity of non-enzymatic
antioxidants, such as vitamins E or C (scavenger), or
enzymatic antioxidants, such as SOD, katalase, or
glutathione peroxidase, is reduced during systemic
inflammation.136,175
In addition, reactive nitrogen species (RNS)
are involved in the pathogenesis of trauma-induced
tissue damage.107 Nitric oxide (NO) is generated
from the amino acid L-arginine by inducible nitric
oxide synthase (iNOS) in PMNL, or vascular muscle
cells, and by endothelial nitric oxide synthase
(eNOS) in endothelial cells (Fig. 3).107 NO induces
vasodilatation, through increase of guanosine 30 ,50 -
cyclic monophosphate (cGMP) by activation of the
guanylate cyclase. The activity of iNOS is stimulated
by cytokines and toxins, whereas eNOS is stimulated
Pathophysiology of polytrauma
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-
line.107,178 Additional metabolites emerging from
the interaction of superoxide anions and NO, such
as peroxynitrite (ONOO) have been shown to med-
iate cellular cytotoxicity.107 The results of the vas-
cular dysfunction caused by ROS and RNS are a
generalized oedema, clinically manifest as capillary
leakage syndrome, with a disturbance of nutritional
and metabolic exchange, cell swelling and cellular
dysfunctions.107
Microcirculatory disturbances
The microcirculation as functional unity, consisting
of terminal arterioles, capillaries and venules, reg-
ulates nutritional and metabolic exchange in organs
and tissues.12,126 Microcirculatory disturbances dur-
ing haemorrhagic shock and systemic inflammation
are primary mediated through the sympathetic-adre-
nal reaction leading to a vasoconstriction of arterioles
and venules. However, through decreased catechola-
mine effect on arterioles, a reduced capillary flow
with an increased hydrostatic pressure can be
observed.12 This microcirculatory alteration, in com-
bination with the cytokine and NO mediated capillary
leakage, are responsible for a secondary hypovolae-
mia and haemoconcentration, with agglutination
of erythrocytes (red sludge) and thrombocytes (white
699
sludge).12 The sludge phenomenon leads to an
obstruction of the microcirculation with a failure of
the transcapillary exchange. The cellular oxygen
deficiency and the accumulation of metabolites (hid-
den acidosis) are finally responsible for tissue and
cell damage. In addition, NO (vasodilatation) and
endothelin (vasoconstriction) induce a shock-specific
microcirculatory change with a shunting of some
organ or tissue areas, enhancing their damage.12
Ischaemia/reperfusion injury
Systemic hypoxaemia and hypotension during the
resuscitative period after trauma, as well as local
hypoperfusion through contusions, lacerations, vas-
cular injuries, or compartment syndromes lead to an
oxygen deficit in endothelial, parenchymal, or
immune competent cells, which is partially compen-
sated for by the intracellular degradation of the
energy-store adenosine triphosphate (ATP) to ade-
nosine diphosphate (ADP) and adenosine monopho-
sphate (AMP).177 As a result of the ATP-consumption,
disturbances of membrane permeability and
energy-dependent Na+/K+-ATPase-pump arise, with
an intracellular Na+ increase and cellular swelling.
Finally, the generation of hypoxanthine leads to a
deficit of the cellular second messenger cyclic AMP
(cAMP). The ATP-deficit is further responsible
700
Figure 4 Ischemia/reperfusion injury. See text for details and explanations.
for an increase of cytosolic Ca2+ with metabolic
disturbances of glucose, proteins, release of neuro-
transmitters, or hormones, and an activation of
phospholipases, proteases and endonucleases,
with membrane disintegration and DNA-damage
(Fig. 4).177 However, irreversible tissue damage
through apoptosis, or necrosis of parenchymal cells,
caused by energy deficit, are only observed after
prolonged severe haemorrhagic shock, or missed
vascular injuries.10,153
Of more importance for secondary tissue damage
and organ dysfunction is the reperfusion phase
(Fig. 4). During this post-ischaemic phase, hypox-
anthine is degraded to xanthine and finally to uric
acid by xanthine oxidase, with the generation of
superoxide anions (O2) from available oxy-
gen.139,192 Superoxide anions are further reduced
to hydrogen peroxide (H2O2) and hydroxyl ions
(OH) by superoxide dismutase. These free oxygen
radicals enhance disturbances of the intracellular
Ca2+ homeostasis and induce lipid peroxidation,
membrane disintegration and DNA-damage, with
apoptosis and necrosis of endothelial, parenchymal
and immune cells.35,103
Neuroendocrine reaction and metabolic
alterations
The post-traumatic host response is also influenced
by neuroendocrine and metabolic disorders.207209
Stress, fear, pain and inflammatory mediators pro-
M. Keel, O. Trentz
duced in the intracranial compartment, or flowing
across the damaged bloodbrain barrier after
severe head injury, act as afferent signals to the
hypothalamus.90 Primary (bleeding) and secondary
(capillary leakage) hypovolaemia trigger, via aortic
or carotic baroreceptors, a sympathetic-adrenal
response and, via juxta-glomerular baroreceptors,
an activation of the reninangiotensin system to
support the perfusion of vital organs.90 Angiotensin
is an effective vasoconstrictor, induces a renal
retention of sodium and fluids, and stimulates the
adrenal release of aldosterone. In addition, osmotic
receptors in the hypothalamus are responsible for
the secretion of antidiuretic hormone (ADH) by the
posterior lobe of the pituitary (neurohypophy-
sis).90,177 In addition, chemoreceptors in the central
nervous system for the registration of acidosis,
hypercapnia, hypoxaemia or hypoglycaemia, as well
as thermoreceptors, are involved in this neuroendo-
crine reaction.177,209
The sympathetic nervous system and the
adrenal gland represent the efferent regulators
of cardiovascular, respiratory and metabolic
responses. Signals in the sympathetic area of the
hypothalamic evoke a release of catecholamines
from the adrenal medulla.150,177 In addition, post-
ganglionic sympathetic nerve ends influence
organs and vessels directly. Adrenaline stimulates
the cardiac output by increasing heart contracti-
lity, the heart rate and the preload (FrankStar-
ling mechanism). In addition the blood pressure is
elevated by the increased peripheral vascular
Pathophysiology of polytrauma
resistance (vasoconstriction of arterioles) and a
centralization of the blood in favour of vital
organs, such as heart and brain, established
through a decrease of the perfusion of splanchnic
area, kidneys and muscles.159
Furthermore, catecholamines influence the post-
traumatic metabolism with an increase in the
energy expenditure, hepatic glycogenolysis and
gluconeogenesis (glucose-lactate (Cori-cycle) and
glucose-alanin cycles), as well as release of free
fatty acids.90,150,209 Early hyperglycaemia (gluco-
se
200 mg/dL) after trauma was associated with
significantly higher infection and mortality rates.106
The natural post-traumatic insulin secretion is too
low to cope with this post-traumatic hyperglycae-
mia. In addition, insulin secretion is partially
suppressed by catecholamines, mediated by a-
receptors, whereas glucagon release is elevated
by b-receptor stimulation, contributing to hepatic
glycogenolysis and gluconeogenesis.90 A peripheral
insulin resistance has also been observed.177 Differ-
ent cytokines (TNF-a, IL-1b) increase the expression
of glucose transport systems (insulin-like activity).
The increased intracellular glucose is oxidized to
pyruvate and finally reduced to lactate (stress lac-
tate acidosis), which contributes to the elevated
lactate levels caused primarily by the metabolic
lactic acidosis (cellular hypoxia).150 Different stu-
dies have shown that early increased serum levels of
lactate, or base deficit, are reliable markers for a
poor outcome in severely injured patients.3,36
Pain, stress and fear cause the hypothalamus to
release corticotropin-releasing hormone (CRH),
leading to a secretion of adrenocorticotropic hor-
mone (corticotropin, ACTH) from the anterior lobe
of pituitary (adenohypophysis).62,177 ACTH stimu-
lates the adrenal cortex to release glucocorticoids
(cortisol), or mineralocorticoids (aldosterone).
Within minutes after trauma, increased serum levels
of steroids are detectable.62,177 Glucocorticoids
have different effects on the metabolism, such as
hepatic gluconeogenesis, glycogenesis, inhibition of
protein synthesis, increase of protein degradation in
muscles and mobilization of free fatty acids by
lipolysis.90,177 In addition they limit inflammatory
processes of mononuclear cells and suppress the
production of antibodies.90 In contrast, the sponta-
neous apoptosis of PMNL is reduced by cortisol.34
Aldosterone increases the renal resorption of
sodium-associated by fluid retention.
The metabolic disorders after trauma are initially
characterized by a reduced metabolism for about
24 h (acute, shock or ebb phase).90,150,177 This is
followed by a flow phase with a catabolic metabo-
lism for some days to 2 weeks and a final reparative
phase with a turnover from a catabolic to an ana-
701
bolic metabolism.90,150,177 In the second phase, all
energy stores, such as glucose, fat acids and pro-
teins, are made available for the host defence
response. The increase of the energy expenditure
reaches a maximum after 510 days.62,90,150,177 The
increased levels of amino acids are needed for the
synthesis of acute phase proteins in the liver and
inflammatory mediators in mononuclear cells. In
addition, glutamate represents a neurotransmitter
and is the most important substrate for the meta-
bolic processes of enterocytes and immune cells,
conserving the immune integrity of the intestinal
wall to avoid bacterial translocation during the
systemic inflammation.90
Multiple organ dysfunctions or failure
The evolution of the physiological and reversible
systemic inflammation after trauma (host defence
response) to a host defence failure, which is asso-
ciated with irreversible organ defects and high mor-
tality, can be described as an overload of primary
and secondary hits and an imbalance of pro- and
anti-inflammatory mechanisms.18,19,118,159,177,188 In
addition, natural protective factors such as antiox-
idants or protease inhibitors are consumed.1
Endothelial cell damage, dysfunction of vascular
permeability with capillary leakage, microcircula-
tory disturbances with cellular hypoxia and finally
apoptosis of parenchymal cells by cell-associated,
or free, cell death proteins and/or necrosis of
parenchymal cells, are involved in the multiple
organ dysfunctions syndrome or multiple organ
failure.18,27,58,79,92,117,153,159,200 Depending on the
responsible insults (primary or secondary) MODS
can be classified in primary, or early, MODS and
secondary, or late, MODS.18,27,50,95,157,159,202 Exam-
ples of early organ dysfunction are the primary
cerebral oedema after head injury, or the primary
ARDS after thoracic injury.15,18,95,120,137 The clinical
manifestation of secondary MODS varies in affected
organs and dysfunction severities. Therefore, dif-
ferent scores, such as the MOF score (Goris score),
MODS score (Marshall score), or sequential organ
failure assessment (SOFA) score are available to
describe dysfunctions of seven systems: respiratory,
cardiovascular, renal, hepatic, gastrointestinal,
haematological and central nervous sys-
tems.8,63,73,119 For the diagnosis of acute lung injury
(ALI), or acute respiratory distress syndrome, bilat-
eral lung infiltrations on thoracic X-ray and a
decrease of the Horowitz ratio must be observed
(PaO2/ F iO2 ratio < 300 corresponds to an ALI, < 200
to an ARDS).137 Renal and gastrointestinal systems
are very sensitive to microcirculatory disorders,
702
leading to a necrosis of renal tubules with increase
of serum creatinine concentrations and oliguria
(< 0.5 ml/kg KG/h) or anuria, and to necrosis of
intestinal villi.103,159 The alteration of the intestinal
mucosa seems to be responsible for a bacterial
translocation and explains the high rate of bacter-
aemia in the absence of a detectable infective focus
in lethal septic complications after trauma (gut
hypothesis).103,130,159 The gastrointestinal tract
often represents the source for the development
of secondary multiple organ failure after trauma,
whereas the liver represents the engine, with an
acute phase and cytokine response, and decreased
function of hepatocytes (increase of serum bilirubin
concentration).130,157,162 Repeated scoring is help-
ful for identifying categories of injured patients at
major risk of death, or complications, after surgical
interventions.8
Therapeutic strategies for multiply
injured patients
Hypoxia and severe haemorrhagic shock correlate
with high mortality rates, as well as with an high
incidence of SIRS, sepsis and organ dysfunction.95 To
reduce these high mortality and morbidity rates in
the post-traumatic course, early preventive
interventions are necessary. According to the guide-
lines of advanced trauma life support (ATLS#), early
oxygenation therapy by intubation and controlled
assisted ventilation and an adequate volume ther-
apy with crystalloids, colloids and/or blood products
are essential.29 However, the large-volume loading
scheme is the subject of controversial debate in
severe haemorrhagic shock.131,174 Patients with
blood loss > 2 l should not be overwhelmed by
crystalloids or colloids until surgical management
of bleeding is undertaken, whereas in septic shock
early, goal-directed, high volume therapy is success-
ful.161 In contrast, small volume resuscitation in
severe traumatic shock seems to avoid a reduced
O2 transport capacity, coagulopathy, and infusion-
induced hypothermia.131,174
After the primary survey, with basic imaging,
multiply injured patients are graded as non-respon-
ders, borderlines and responders, according to
the initial response to volume therapy, or pharma-
ceutical resuscitation.29 Life saving surgical proce-
dures, such as decompressing pneumothorax,
cardiac tamponade or acute epidural haematoma,
and surgical control of massive haemorrhage in the
thoracic or abdominal cavities and from pelvic frac-
tures, or traumatic amputations are carried out
without delay.29,53,60,154 These early interventions
seem to limit the systemic inflammation and
M. Keel, O. Trentz
decrease the early and late mortality.13 Patients
with a borderline state after primary survey, or
patients with a high trauma impact, or at risk of
adverse outcome, such as head injury, bilateral lung
contusions, multiple long bone fractures, coagulo-
pathy, hypothermia or a presumed operation
time > 6 h, should be supplied with a staged
sequential surgical management as damage control,
after the further work up in the secondary survey, to
avoid or limit the influence of second hits (inter-
ventional or antigenic loads).147,202 Damage control
includes haemorrhage control through tamponade,
vascular repair or vessel ligation, and organ resec-
tions.59 In addition, a reduction of contamination
after hollow organ injuries, or open fractures, as
well as decompression of compartment syndromes
of the extremities by fasciotomy, or of the abdomen
by decompressive laparotomy, should contribute to
the limitation of secondary inflammatory pro-
cesses.11,49,89,154 Furthermore, the temporary sta-
bilization of pelvic and long bone fractures, or
dislocations of large joints, by rapidly assembled
and applied external fixators seem to be benefi-
cal.49,53,89,141,147,154 This concept decreases the sys-
temic release of pro- and anti-inflammatory
mediators, in comparison with definitive interven-
tions, such as reamed nailing (early total care).147
Debridement of open wounds and fractures, with
resection of non-viable tissues, temporary closure
by vacuum assisted closure therapy and second look
interventions, contribute to a limited antigenic
load, with a decrease in septic complications.89,186
However, the early stabilization of major skeletal
injuries (early total care) represents still the
concept for patients with isolated fractures and in
the absence of high traumatic impact and the risk
factors mentioned above.147
With regard to strategies for post-traumatic
intensive care, only supportive therapies are estab-
lished to avoid secondary organ damage and hits.95
Secondary brain injuries, with elevated intracranial
pressure (ICP) due to cerebral oedema, or ischae-
mia/reperfusion injuries, can be limited by applying
different neuroprotective strategies, such as con-
trolled hyperventilation, moderate hypothermia,
and release of cerebrospinal fluid (CSF).167,183
Whenever these therapeutic regimens fail to reduce
ICP, intravenous administration of barbiturate may
become necessary.183 The beneficial effect of bar-
biturates, in terms of lowering elevated ICP, is
thought to be due to decreased cerebral metabolism
and blood flow.41 Other supportive therapies include
mechanical ventilation, inotropes and haemofiltra-
tion for renal failure.159,177 Furthermore, a single
shot of an antibiotic (cephalosporin) after trauma
reduces the post-traumatic wound infection rate.196
Pathophysiology of polytrauma
Further antibiotics should only be given according
to an antibiogram of an infectious focus.196 Early
enteral nutrition, via gastric or duodenal tubes,
reduces the accumulation of pathogenic bacteria
in the intestinal tract and avoids atrophy of intest-
inal mucosa,.177,184 Additional arginine, glutamine,
nucleotides, or unsaturated omega-3-fatty acids
(immune-enhanced enteral nutrition (IEEN)) re- management of severely injured patients in the near
duce post-traumatic hypermetabolism and improve
immune competence.26
Despite thorough insights into the pathophysio-
logical mechanisms of post-traumatic systemic
inflammation and hopeful results of animal studies,
multiple prospective clinical trials performed in the
past decades, especially in patients with sepsis,
have failed to provide a benefit of anti-inflamma-
tory, anti-coagulant, or antioxidant strategies
with regard to the mortality, whereas the incidence
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
equivocal results may include individual injury pat-
terns, inappropriate timing of drug administration,
or suboptimal drug levels at the target site.35,65 In
addition, the study protocols have focused on
single mechanisms only, whereas the immune
network is more complex and individual (gene
polymorphism, sexual dimorphism), as described
above.13,64,65,93,151 Nevertheless, some successful
clinical studies are available, especially for septic
patients, although the underlying mechanisms have
not been clearly defined.91 Trauma patients receiv-
ing high doses of intravenous immunoglobulins
exhibit a reduction in septic complications and
an improvement in serum bactericidal activity.44
Treatment with recombinant human activated pro-
tein C (drotrecogin alfa activated) showed a sig-
nificant reduction of mortality in patients with
severe sepsis.14 However, criticisms concern data
consistence, unclear mechanism of action and the
increased risk of bleeding, which restricts its use in
injured patients, especially with severe head inju-
ries.14,48 Although the effects of steroids in patients
with sepsis are controversial, low doses of corti-
costeroids seem to reduce the mortality rate in
patients with septic complications.7,191 Insulin
has recently been shown to decrease mortality
and to prevent the incidence of multiple organ
failure in critically ill patients.96 It seems that
insulin attenuates the inflammatory response by
decreasing the pro-inflammatory, and increasing
the anti-inflammatory, cascades, thus restoring
systemic homeostasis, which has been shown
to be critical for organ function and survival in
critically ill patients.96
703
Although some successful progress in clinical
trials is obvious, better understanding of the patho-
logical mechanisms at local site of injury would
identify exact primary targets for drug interven-
tions. However, progress in diagnostic tools for
the monitoring of the immune status (beside immu-
nomonitoring) may become more successful for the
future. Parallel monitoring of pro- (e.g. IL-6) and
anti-inflammatory (e.g. IL-10) cytokines, as well as
acute phase proteins (e.g. CRP, procalcitonin), or
other factors, could help us in the decision making
for optimal secondary operative interventions to
limit second hits.71,170 However, more prospective
diagnostic studies have to be conducted, to under-
stand the kinetics and significance of these factors
in order to optimize the concept of damage
control.
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