Pathophysiology of polytrauma · Pathophysiology of polytrauma Marius Keel*, Otmar Trentz ......

$: Pathophysiology of polytrauma · Pathophysiology of polytrauma Marius Keel*, Otmar Trentz ... tissue injuries, or fractures. However, theseﬁrst hits represent a greater challenge,$
Injury, Int. J. Care Injured (2005) 36, 691—709

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

KEYWORDSTrauma;Injury;Pathophysiology;Host defence response;Systemic inflammatory

response syndrome(SIRS);

Compensatory anti-inflammatoryresponse syndrome(CARS);

Apoptosis;Necrosis;Multiple organ

dysfunctionsyndrome (MODS);

Multiple organ failure(MOF);

Damage control;Mortality

Summary Immediate and early trauma deaths are determined by primary braininjuries, or significant blood loss (haemorrhagic shock), while late mortality is causedby secondary brain injuries and host defence failure. First hits (hypoxia, hypotension,organ and soft tissue injuries, fractures), as well as second hits (e.g. ischaemia/reperfusion injuries, compartment syndromes, operative interventions, infections),induce a host defence response. This is characterized by local and systemic release ofpro-inflammatory cytokines, arachidonic acid metabolites, proteins of the contactphase and coagulation systems, complement factors and acute phase proteins, as wellas hormonal mediators: it is defined as systemic inflammatory response syndrome(SIRS), according to clinical parameters. However, in parallel, anti-inflammatorymediators are produced (compensatory anti-inflammatory response syndrome(CARS). An imbalance of these dual immune responses seems to be responsible fororgan dysfunction and increased susceptibility to infections.

Endothelial cell damage, accumulation of leukocytes, disseminated intravascularcoagulation (DIC) and microcirculatory disturbances lead finally to apoptosis andnecrosis of parenchymal cells, with the development of multiple organ dysfunctionsyndrome (MODS), or multiple organ failure (MOF). Whereas most clinical trials withanti-inflammatory, anti-coagulant, or antioxidant strategies failed, the implementa-tion of pre- and in-hospital trauma protocols and the principle of damage controlprocedures have reduced post-traumatic complications. However, the developmentof immunomonitoring will help in the selection of patients at risk of post-traumaticcomplications and, thereby, the choice of the most appropriate treatment protocolsfor severely injured patients.# 2005 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692Two-hit theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693Hyperinflammation–—SIRS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694

* Corresponding author. Tel.: +41 1 255 3657; fax: +41 1 255 4406.E-mail address: [email protected] (M. Keel).

0020–1383/$ — see front matter # 2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.injury.2004.12.037

692 M. Keel, O. Trentz

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

Table 1 Clinical parameters of systemic inflammatoryresponse syndrome (SIRS)

1. Heart rate > 90/min2. Breathing rate > 20/min, respectively,

hyperventilation with decrease of thearterial CO2 partial pressure (PaCO2)under 32 mmHg

3. Temperature > 38 8C or < 36 8C4. Number of leukocytes > 12,000/mm3

or < 4000/mm3 or � 10% juvenileneutrophil granulocytes

For the definition of SIRS, two or more parameters must befulfiled. Sepsis is defined as SIRS with detection of bacteremiaor bacterial focus.6

Introduction

Despite improved traffic and occupational safety,as well as significant advances in pre- and in-hospital management, severe trauma representsthe most frequent cause of death in people belowthe age of 40 years.4,38,60,128,149,168 Immediate andearly trauma deaths are determined by severeprimary 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 andhost defence failure.4,70,158,168,173,194 Direct, orindirect, mechanical forces induce organ and softtissue injuries, or fractures. However, these firsthits represent a greater challenge, as local tissuedamage, such as contusions or lacerations, hypoxiaand hypotension, induce further local and systemichost responses, to preserve the immune integrityand stimulate reparative mechanisms.164 This sys-temic inflammation was defined in 1991, throughthe consensus conference of the American Collegeof Chest Physicians/Society of Critical Care Med-icine (ACCP/SCCM), as systemic inflammatoryresponse syndrome (SIRS).6 At least two of thefour clinical parameters (Table 1) must be fulfiledfor the diagnosis of SIRS.6 It is characterized by thelocal and systemic production and release of dif-ferent mediators, such as pro-inflammatory cyto-kines, complement factors, proteins of the contactphase and coagulation systems, acute phase pro-teins, neuroendocrine mediators and an accumu-lation of immunocompetent cells at the local siteof tissue damage (Fig. 1).17,18,40,91,163,169,195 Inaddition, this systemic inflammation is augmentedby second hits, such as ischaemia/reperfusioninjuries, surgical interventions or infections(two-hit theory).163,164

However, different clinical trials and animalmodels have shown that, in parallel with avoidthe autodestructive effects of immunocompetentcells (Fig. 1).19,88,91,120,195 An imbalance betweenthese dual immune responses, with an overwhelm-

ing release of pro- or anti-inflammatory mediators,seems to be responsible for organ dysfunctionand increased susceptibility to infections andsepsis.19,116,118,155 Endothelial cell damage, accu-mulation of leukocytes, disseminated intravascularcoagulation (DIC) and microcirculatory dysfunctionfinally lead to programmed cell death (apoptosis)and necrosis of parenchymal cells (microenviron-ment theory) with the development of multipleorgan dysfunction syndrome (MODS) or multipleorgan failure (MOF).67,91,92,95,107,117,153,159,195 Inaccordance with these pathophysiological mechan-isms and definition of SIRS, the term polytraumacan be defined as a syndrome of combinedinjuries with an injury severity score (ISS) > 17and consequent SIRS for at least 1 day, leading todysfunction, or failure, of remote organs and vitalsystems, which themselves had not directly beeninjured.76,193

This review is planned to give an insight into thetriggers 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 shouldelucidate the pathophysiological basis for thedamage control concept in the surgical manage-ment of multiple injured patients, reasons for the

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-inflammatoryresponse syndrome; PMNL, polymorphonuclear leukocytes; MODS, multiple organ dysfunction syndrome; MOF, multipleorgan failure.

failure of clinical trials with immunotherapies inthe past two decades and the significance forthe development of post-traumatic immunomoni-toring.

Two-hit theory

The complex cascade of the host defence response isstimulated by primary and secondary insults (two-hit theory).163,164 The trauma impact determinesprimary organ, or soft tissue, injuries and fractures(first hit; trauma load) with local tissue damage aswell as an activation of the systemic inflammatoryresponse.118,135,163,164,179 In addition, secondaryendogenous and exogenous factors play a crucialrole in the initiation and severity of post-traumaticcomplications.164,179,202 Typical endogenous (anti-genic load) second hits are respiratory distress withhypoxia, repeated cardiovascular instability, meta-bolic acidosis, ischaemia/reperfusion injuries, deadtissue, contaminated catheters, or tubes, and infec-tions.46,50 Surgical interventions with severe tissuedamage, hypothermia or blood loss, inadequate, ordelayed, surgical, or intensive care, after neglectedor missed injuries, as well as massive transfusions,represent exogenous second hits (interventionalload or surgical load).46,81,202

The severity of organ injuries, varying from con-tusions to complete lacerations, and the remainingorgan perfusion influence the post-traumatic sys-temic inflammatory response. The highest incidencefor the development of SIRS can be observed afterisolated or combined severe head injuries.55,155

Primary focal or diffuse and secondary braindamages including ischemia/reperfusion injuries,cerebral oedema or intracranial hypertension deter-mine the cerebral outcome and themortality as wellas the incidence and severity of post-traumaticcomplications.169,176,181 Although the central ner-vous system has been defined historically as an‘‘immunologically privileged organ’’, due to itsseparation from the peripheral circulation by theblood—brain barrier (BBB), different studies haveshown that the brain acts as a target and as aneffector organ.87,104,169 Glial cells, astrocytesand neurons are potent producers of pro- andanti-inflammatory mediators and their receptors,leading to local tissue damage and a systemicresponse.104,132,169 In addition, systemic mediatorsreleased by peripheral immune, endothelial, or par-enchymal cells influence the integrity of the BBB,leading to a bi-directional communication of theinflammatory mediators.104,132,169 Primary epiduralhematoma, or cerebral oedema, as well as post-traumatic secondary oedema, induced by local and


systemic inflammatory processes, are responsiblefor the development of a cerebral compartmentsyndrome, 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 orwithout manifestation of pneumonia, acute lunginjury (ALI), or acute respiratory distress syndrome(ARDS).9,120,137 Injuries of intra-abdominal organscause haemorrhagic shock (liver, spleen, vascularinjuries) 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 anabdominal compartment syndrome with systemiccomplications.59,125

Soft tissue injuries of the extremities, espe-cially in patients with haemorrhagic shock, areoften 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 musclenecrosis, rhabdomyolysis and finally acute renalfailure (crush kidney).159 Fractures of the femur,multiple long bone fractures and unstable pelvicring fractures are characterized by a high bloodloss and contribute to the inflammatory acti-vity.22,49,53 Additionally, fat embolism syndromeis an infrequent clinical consequence with thetypical triad of pulmonary distress, mentalchanges and petechial rash, 24—48 h after pelvicor long-bone fractures.148

The incidence of septic complications hasincreased during the last decade.122 Closed woundswith large soft tissue damage and open wounds,or fractures, as well as neglected soft tissueinjuries, represent portal of entry for microorgan-isms.205,210 Central venous catheters, intratra-cheal tubes, chest tubes and bladder cathetersare often contaminated and raise the infection riskin severely injured patients.32 The most commonreasons for sepsis after trauma are hospitalacquired pneumonia, catheter infections, intra-abdominal and wound infections.9,140,179 Further-more, ischaemic lesions of the gastrointestinaltract after haemorrhagic shock seem to be respon-sible for bacterial translocation into the circulation(gut hypothesis).103,130

Hyperinflammation–—SIRS

Tissue damage induces in commensurate with theseverity of trauma (trauma load), genetic factors

(gene polymorphism), the general condition of thehost and the type of antigens (antigenic load), bothlocal and systemic release of pro-inflammatorycytokines and phospholipids.40,88,143,171,190 Poly-morphonuclear leukocytes (PMNL), monocytes, tis-sue macrophages (e.g. alveolar macrophages),lymphocytes, natural killer cells, and parenchymalcells are involved in a complex network of this hostdefence response.195 An overwhelming pro-inflam-matory response (hyperinflammation) leads to theclinical manifestation of SIRS and finally to hostdefence failure (MODS, MOF).55,71,135,195

Cytokines are polypeptides and act in a para- orautocrine manner.40 They are capable of exertingmany 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 1—2 h, thereexist subacute (secondary) cytokines such as IL-6,IL-8 (neutrophil activating peptide (NAF)), macro-phage migratory factor (MMF), high motility groupprotein -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 serumlevels are observed in patients with systemic inflam-mation, as well as in bronchoalveolar lavage fluids ofpatients with thoracic trauma, or acute respiratorydistress syndrome.42,43,100,121,187 In addition, IL-6serum levels correlate with the ISS, the incidenceof 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 twophenotypes, the TH1 and TH2 lymphocytes.146 TH1cells support the pro-inflammatory cascade throughsecretion of IL-2, interferon-g and TNF-b, whereasTH2 cells are important producers of anti-inflam-matory mediators. Monocytes/macrophages areinvolved in the differentiation of TH1 cells, viathe secretion of IL-12. Depressed IL-12 productionafter trauma correlated with a shift of the TH1/TH2ratio towards the TH2-type pattern, with an adverseclinical outcome.146

Pro-inflammatory cytokines activate the recruit-ment and phagocytosis activity of PMNL (priming),the immune cells of the first hours (the first defenceline), and stimulate PMNL to release proteases andfree oxygen radicals (respiratory burst, oxidativestress) (Fig. 1).21 Furthermore, PMNL are influencedby colony-stimulating factors, such as granulocyte-colony stimulating factor (G-CSF) and granulocytemacrophage-colony stimulating factor (GM-CSF).20,31,51,189 They enhance monocyte- or granu-locytopoiesis, on the one hand and reduce thespontaneous programmed cell death (apoptosis) ofPMNL during SIRS or sepsis, on the other hand.20,31,51

Other pro-inflammatory mediators contribute addi-


tionally to the reduction of neutrophil apoptosis,with an accumulation of PMNL at the site of localtissue damage.16,47,54,78,97,102,109,124

Mechanical and hypoxic cellular damage leadsfurther to an increase of intracellular Ca++ levelswith an activation of phospholipase A2 (PLA2) andphospholipase C (PLC).163 These enzymes catalysethe release of arachidonic acids from membranephospholipids. 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 Thesemetabolites are involved in the recruitment ofinflammatory cells, regulation of vascular perme-ability and motility, as well as the aggregation ofthrombocytes.163 Additionally, PLA2 induces therelease of the platelet activating factor (PAF).212

It supports the activation of macrophages, theirinteraction with endothelial cells and the activationand aggregation of thrombocytes.212

Hypoinflammation–—CARS

Depending on the severity of injury and the post-traumatic course, anti-inflammatory mediators arealso produced. TH2-cells and monocytes/macro-phages release IL-4, IL-10, IL-13, or transforminggrowth factor-b (TGF-b) (Fig. 1).30,33,57 In addition,different cytokines (e.g. IL-6) have shown a dualeffect with pro- and anti-inflammatory activities.The serum levels of IL-10 correlate with ISS and post-traumatic complications, such as MODS, ARDS, orsepsis.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 injuredpatients, correlating also with the ISS and the inci-dence of post-traumatic complications.52,88,99

Furthermore, the readiness of blood monocytesfrom injured patients to release pro-inflammatorycytokines was decreased in in vitro studiesafter stimulation with Gram-negative (endotoxin,lipopolysaccharide (LPS)), or Gram-positive (e.g.peptidoglycan, lipoteichonic acid), bacterial pro-ducts and correlated with the post-traumaticcourse.25,56,84,85,101,203 The mechanisms of this‘‘endotoxin tolerance’’ are still incompletelyunderstood.203 It seems that anti-inflammatorymediators, like IL-10, depress the activity of intra-cellular transcription factors, such as nuclearfactor-kappa B (NF-kB), which are essential forthe synthesis of pro-inflammatory cyto-kines.24,69,84,101,116,197,198,203 The expression ofthe LPS-receptor CD14 on monocytes is decreasedafter trauma, combined with an increase of the

soluble CD14 (sCD14), through shedding of the mem-brane-bound CD14.203 However, the decreasedexpression of CD14, as well as expression altera-tions of the pattern-recognition receptors for bac-terial products, the toll-like receptors, seem not tobe responsible for ‘‘endotoxin tolerance’’.83 Bycontrast, the expressions of the toll-like receptorsfor 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 asmonocytes/macrophages, showed a depressedexpression of the MHC (major histocompatibilitycomplex) class II molecule HLA-DR (human leuko-cyte antigen) that correlated with post-traumaticinfections.71

During the early phase of the post-traumaticcourse, 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, triggeredby stress hormones (steroids) and cell death pro-teins.39,111,117,145,153 Apoptosis is characterizedmorphologically by cell shrinking, with cytoplas-matic condensation (apoptotic bodies), nuclear con-densation (pycnosis) and DNA-fragmentation (DNAladdering).134,153 The cell membranes stay primarilyintact and no surrounding inflammatory signs can beobserved, in contrast to necrosis.153

Typical cell death proteins are TNF-a or Fas ligand(CD95 ligand).5,134 They induce cell death afterbinding with their receptors, respectively, TNF-RIand Fas antigen (CD95 antigen) and activationof complex intracellular cascades and effectorenzymes, such as intracellular proteases (e.g.calpains, caspases).5,39,75,111,134,156 The cellularexpressionsofTNF-RI andFasantigen,or their solublemolecules, were elevated in serum from injuredpatients, postoperatively or during sepsis.37,145

An overwhelming anti-inflammatory response(hypoinflammation) seems to be responsible forpost-traumatic immunosuppression, with a highsusceptibility to infections and septic complica-tions.19,171,195 This immunological status is calledcompensatory anti-inflammatory response syn-drome.19 However, it does not look like a compen-satory mechanism in a biphasic model; as only a fewhours after trauma anti-inflammatory mediators(e.g. IL-10) were detectable in the serum of injuredpatients.138 It seems that the host defence responsetries to strike a fine balance between SIRS and CARS,to induce reparative mechanisms and limit entryor overload of microorganisms, on the one hand, andto avoid autoaggressive inflammation, with second-ary tissue damage and susceptibility to infections,on the other hand. These mixed inflammatory


Figure 2 Plasmatic cascade system. Proinflammatory mediators and toxins stimulate the plasmatic cascade systemwith activtion of complement factors, kallikrein—kinin system and coagulation cascade. These mechanisms play a crucialrole in endothelial and parenchymal cell death as well in the disseminated intravascular coagulation (DIC). See text fordetails and explanations.

mechanisms are called mixed antagonistic responsesyndrome (MARS).19

Activation of plasmatic cascade system

Pro-inflammatory mediators (cytokines, arachidonicacid metabolites) and toxins activate the plasmaticcascade system, consisting of the complement cas-cade, the kallikrein—kinin system and the coagula-tion cascade (Fig. 2). The classical pathway ofcomplement activation is induced by antigen—anti-body complexes (immunoglobulins M or G (IgM,IgG)), or activated coagulation factor XII (FXIIa),whereas bacterial products (e.g. LPS) activate thealternative pathway (Fig. 2).66,129,182 Cleavages ofC3, by C3 convertase, and C5, by C5 convertase,lead to the formation of opsonins, anaphylatoxinsand, finally, the membrane attack complex(MAC).66,129,182 The opsonins C3b and C4b areinvolved in the phagocytosis of cell detritus, andespecially bacteria, by covalent binding of pathogensurfaces (opsonization).66,129 The anaphylatoxinsC3a and C5a support different inflammatorymechanisms, the recruitment (chemotaxis) andactivation of phagocytic cells (PMNL, monocytes,macrophages), the enhancement of the hepaticacute phase response, the degranulation of mastcells and basophils, with release of vasoactive med-

iators, such as histamine, as well as the adhesionof leukocytes to endothelial cells, leading toincreased vascular permeability with oedema.129,169

In addition, apoptosis and cell lysis (necrosis) ofparenchymal cells, or bacteria, are induced byC5a, through the C5a receptor (C5aR) and theMAC (C5b-9) .129,169,182 In clinical studies, elevatedserum levels of different complement components,or their expression in injured tissue, were observedafter trauma, or during sepsis.42,86,165,169,182,211

Similarly to some cytokines, C3a and C5a showeddual effects with activation of reparative mechan-isms too.129 Furthermore, during systemic inflam-mation, serum levels of the C1-inhibitor, producedby hepatocytes, endothelial cells, monocytes andmacrophages, were decreased through a degrada-tion by PMNL-elastases. C1-inhibitor regulates theclassical complement pathway through inactivationof the active subunits C1s and C1r.129

The plasma proteins FXII, prekallikrein, kinino-gen and the factor XI (FXI) represent the contactphase system (Fig. 2).185 They are characterized bythe fact, that they can be activated by negatively-charged cellular surfaces (contact activation).185

FXII and prekallikrein activate mutually and formFXIIa 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


the urokinase-like plasminogen activator (u-PA)(Fig. 2). The tissue-plasminogen activator (t-PA)works as a cofactor, whereas natural inhibitors ofthe fibrinolytic system are a2-antiplasmin (a2AP),a2-macroglobulin (a2MG) and the plasminogen-activator-inhibitor 1 (PAI-1). In addition, kallikreinstimulates the formation of bradykinin fromkininogen. Kinins are vasodilators, increase thevascular permeability and inhibit the functionsof thrombocytes.185

The intrinsic coagulation system is linked to thecontact activation system through the formationof FIXa by FXIa (Fig. 2). During the host defenceresponse, a consumption of FXII, prekallikrein andFXI has been observed, whereas plasma levels ofenzyme—inhibitor complexes, such as FXIIa—C1-inhibitor or kallikrein—C1-inhibitor, were increas-ed.1 C1-inhibitor and a1-protease-inhibitor (a1PI)represent the inhibitors of the intrinsic coagulationsystem (Fig. 2).1,94

However, the coagulation system is initially acti-vated over the extrinsic pathway with an increasedexpression of the tissue factor (TF) on endothelialcells and monocytes, induced by bacterial cell wallfragments and pro-inflammatory cytokines (TNF-a,IL-1b) (Fig. 2).61,68,94 The FVII—TF complex stimu-lates the coagulation cascade, with the formation ofFXa and finally thrombin (FIIa), from prothrombin(FII). Thrombin activates FV, FVIII and FXI, leading toenhanced formation of thrombin. After cleavage offibrinogen by thrombin, fibrin monomers polymerizeto 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 athrombin—antithrombin complex.1 This effect canbe enhanced by heparin. Furthermore, ATIII inhibitsthe factors IXa, XIa and XIIa. Further inhibitors arethe tissue factor pathway inhibitor (TFPI) and theactivated protein C, in combination with the freeprotein S.160 However, the plasma level of freeprotein S is decreased during systemic inflamma-tion, through binding to the C4b binding protein(C4bBP).1,160

Disseminated intravascular coagulation canoccur after trauma (Fig. 2).1,68,94,113 After the initialphase, with increased thrombin formation andreduced fibrinolytic cascade, intra- and extra-vascular (e.g. intra-alveolar in ARDS) fibrin clots(hypercoagulability) and increased interactionbetween endothelial cells and leukocytes wasobserved.1,61,94,113 The consumption of coagulationfactors (hypocoagulability) and dysfunction ofthrombocytes are responsible for diffuse bleed-ing (haemorrhagic diathesis).1,68 The intravascularfibrin clots lead finally to microcirculatory distur-

bances with hypoxia-induced cellular damage.1,94

The consumption of coagulation factors is furtherenhanced through the proteolysis of fibrin clotsto fibrin fragments by the protease plasmin(fibrinolysis).94,115

Acute phase reaction

The local (Kupffer-cells) and systemic release ofpro-inflammatory cytokines (TNF-a, IL-1b, IL-6)induce the acute phase reaction in the liver,to enhance tissue protective and antimicrobialmechanisms.204 The synthesis of positive acutephase proteins (APP) in hepatocytes, such asC-reactive proteins (CRP), a1-antitrypsin, a2-macroglobulin, caeruloplasmin, lipopolysaccharide(LPS)-binding protein (LBP), fibrinogen, prothrom-bin or C4BP, is increased, whereas the productionof negative APP, such as albumin, high-density lipo-proteins (HDL), protein C, protein S and ATIII, isreduced.45,204

CRP increases the expression of TF on PMNL andmonocytes/macrophages, and thereby enhancesthe activation of the extrinsic coagulation cas-cade.45 Clinical studies have shown that the levelof CRP is relatively non-specific and not predictiveof post-traumatic complications, such as infec-tions.74,127,165 Serial measurements appear to behelpful however, especially in the first 2 weeks,as, whilst the levels of CRP reduce with time incases of systemic inflammation, in the presenceof infection an upward trend is seen consistently.

a1-antitrypsin inactivates the proteases secretedby PMNL or macrophages, whereas a2-macroglobu-lin and caeruloplasmin neutralize free oxygenradicals and pro-inflammatory cytokines.204 LBPsuppresses the effects of LPS in high concentrations,whereas in small quantities an enhancement of theLPS-effects can be observed.213 Serum levels of LBPare significantly increased during the early post-traumatic course and seem to be predictive of septiccomplications.213 Furthermore, the elevated ratioof positive APP to negative APP accelerates thedevelopment of DIC after trauma.204

For the past decade, procalcitonin (PCT) has beenmore and more of interest as a diagnostic marker.PCT is a precursor of calcitonin, which is normallyproduced in the C-cells of the thyroid. Differentstudies have shown that hepatocytes, as well asimmune cells, are also capable of secreting PCT.71

The biological function of this acute phase protein isstill unclear. However, it seems that PCT may be auseful marker for monitoring the post-traumaticcourse, predicting severe SIRS, MODS and septiccomplications.71,110,127,201


Leukocyte recruitment

The infiltration and accumulation of PMNL representa crucial event for the development of secondaryorgan and tissue damage (theory of neutrophil-mediated tissue injury).21,28,67,180 Pro-inflammatorymediators 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 onleukocytes (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 aftertrauma.172 The interaction of these adhesion mole-cules leads to a stable cell-to-cell contact with aPMNL-attachment, so-called ‘‘sticking’’ of PMNL.Through shedding increased levels of adhesionreceptors (selectins, soluble ICAM-1 (sICAM-1), orsVCAM-1) are detectable in serum of injuredpatients, with a predictive value for the develop-ment of post-traumatic complications.108 Finally,the migration (‘‘diapedesis’’), accumulation andactivation of leukocytes into tissue are mediatedby chemoattractant factors, such as chemokinesand complement anaphylatoxins (C3a, C5a), afterbinding to their corresponding receptors (chemo-taxis).169 Chemokine subfamilies are distinguishedby the position of the first two conserved cysteins,which are either separated by one to three aminoacids, such as CXC chemokine IL-8 (CXCL8), or adja-cent, such as CC chemokine macrophage inflamma-tory protein (MIP)-1a (CCL3).169 Chemokines andC3a 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 issupported by reduced spontaneous apoptosis, asdescribed above.82,97,109

Proteases, oxidative stress andcapillary leakage

Infiltrated PMNL and tissue macrophages are respon-sible for the phagocytosis of microorganisms andcellular detritus. However, activated PMNL have aJanus face (Janus, the mythological gate-keeperhas two faces, looking in opposite directions).142

They are also able to induce secondary tissue and

organ damage by degranulation of extracellularproteases (elastase, metalloproteinase) and forma-tion of reactive oxygen species (ROS, oxygen radi-cals), the so-called respiratory burst, or oxidativestress (Fig. 3).28,67,73,123,152,180 Elastases have thecapacity to degrade most proteins in the extracel-lular matrix and important plasma proteins. Theirproteolytic activity is regulated by endogenousprotease inhibitors (PI), such as a1-antitrypsin,a2-macroglobulin, or a1-protease-inhibitor. Inaddition, neutrophil elastase induces the releaseof pro-inflammatory cytokines. Elevated levels ofelastase, or elastase—a1-protease-inhibitor com-plex (Ea1PI), were detectable in multiply injuredpatients depending on the injury severity and thepost-traumatic course.165 In the same manner,metalloproteinases seem to be involved in thedegradation of important structural proteins aftertrauma.23,115,133,152,199

Oxidative cell injury involves the modification ofcellular macromolecules by ROS, often leading tocell death.98,114,123 Superoxide anions (O2

��) aregenerated by membrane associated nicotinamideadenine dinucleotide phosphate (NADPH)-oxidase,which is activated by pro-inflammatory cytokines,arachidonic acid metabolites, complement factorsand bacterial products.77,206 Thereafter, superoxideanions are reduced in the Haber-Weiss reaction tohydrogen peroxide (H2O2) by superoxide dismutasein cytosol (SOD 1), mitochondrion (SOD 2), or cellmembrane (SOD 3). H2O2 is the substrate for themyeloperoxidase that forms the highly toxic andbactericidal hypochloric acid (HOCL). In addition,accumulated H2O2 is transformed to hydroxyl ions(OH��) in the Fenton reaction. The free ROS inducelipid peroxidation, cell membrane disintegrationand DNA-damage of endothelial and parenchymalcells.98,105,175 Furthermore, oxygen radicals andHOCL activate PMNL to release proteases and col-lagenase and to inactivate protease-inhibitors(PI).114 In addition, the capacity of non-enzymaticantioxidants, such as vitamins E or C (scavenger), orenzymatic antioxidants, such as SOD, katalase, orglutathione peroxidase, is reduced during systemicinflammation.136,175

In addition, reactive nitrogen species (RNS)are involved in the pathogenesis of trauma-inducedtissue damage.107 Nitric oxide (NO) is generatedfrom the amino acid L-arginine by inducible nitricoxide synthase (iNOS) in PMNL, or vascular musclecells, and by endothelial nitric oxide synthase(eNOS) in endothelial cells (Fig. 3).107 NO inducesvasodilatation, through increase of guanosine 30,50-cyclic monophosphate (cGMP) by activation of theguanylate cyclase. The activity of iNOS is stimulatedby cytokines and toxins, whereas eNOS is stimulated


Figure 3 Oxidative stress and capillary leakage. Activated polymorphonuclear leukocytes (PMNL) release reactiveoxygen (ROS) and reactive nitrogen species (RNS). These metabolites in combination with proteases are responsible forendothelial 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 fromthe interaction of superoxide anions and NO, suchas peroxynitrite (ONOO�) have been shown to med-iate cellular cytotoxicity.107 The results of the vas-cular dysfunction caused by ROS and RNS are ageneralized oedema, clinically manifest as capillaryleakage syndrome, with a disturbance of nutritionaland metabolic exchange, cell swelling and cellulardysfunctions.107

Microcirculatory disturbances

The microcirculation as functional unity, consistingof terminal arterioles, capillaries and venules, reg-ulates nutritional and metabolic exchange in organsand tissues.12,126 Microcirculatory disturbances dur-ing haemorrhagic shock and systemic inflammationare primarymediated through the sympathetic-adre-nal reaction leading to a vasoconstrictionof arteriolesand venules. However, through decreased catechola-mine effect on arterioles, a reduced capillary flowwith an increased hydrostatic pressure can beobserved.12 This microcirculatory alteration, in com-bination with the cytokine and NOmediated capillaryleakage, are responsible for a secondary hypovolae-mia and haemoconcentration, with agglutinationof erythrocytes (red sludge) and thrombocytes (white

sludge).12 The sludge phenomenon leads to anobstruction of the microcirculation with a failure ofthe transcapillary exchange. The cellular oxygendeficiency and the accumulation of metabolites (hid-den acidosis) are finally responsible for tissue andcell damage. In addition, NO (vasodilatation) andendothelin (vasoconstriction) induce a shock-specificmicrocirculatory change with a shunting of someorgan or tissue areas, enhancing their damage.12

Ischaemia/reperfusion injury

Systemic hypoxaemia and hypotension during theresuscitative period after trauma, as well as localhypoperfusion through contusions, lacerations, vas-cular injuries, or compartment syndromes lead to anoxygen deficit in endothelial, parenchymal, orimmune competent cells, which is partially compen-sated for by the intracellular degradation of theenergy-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 andenergy-dependent Na+/K+-ATPase-pump arise, withan intracellular Na+ increase and cellular swelling.Finally, the generation of hypoxanthine leads to adeficit of the cellular second messenger cyclic AMP(cAMP). The ATP-deficit is further responsible


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

for an increase of cytosolic Ca2+ with metabolicdisturbances of glucose, proteins, release of neuro-transmitters, or hormones, and an activation ofphospholipases, proteases and endonucleases,with membrane disintegration and DNA-damage(Fig. 4).177 However, irreversible tissue damagethrough apoptosis, or necrosis of parenchymal cells,caused by energy deficit, are only observed afterprolonged severe haemorrhagic shock, or missedvascular injuries.10,153

Of more importance for secondary tissue damageand organ dysfunction is the reperfusion phase(Fig. 4). During this post-ischaemic phase, hypox-anthine is degraded to xanthine and finally to uricacid by xanthine oxidase, with the generation ofsuperoxide anions (O2

��) from available oxy-gen.139,192 Superoxide anions are further reducedto hydrogen peroxide (H2O2) and hydroxyl ions(OH��) by superoxide dismutase. These free oxygenradicals enhance disturbances of the intracellularCa2+ homeostasis and induce lipid peroxidation,membrane disintegration and DNA-damage, withapoptosis and necrosis of endothelial, parenchymaland immune cells.35,103

Neuroendocrine reaction and metabolicalterations

The post-traumatic host response is also influencedby neuroendocrine and metabolic disorders.207—209

Stress, fear, pain and inflammatory mediators pro-

duced in the intracranial compartment, or flowingacross the damaged blood—brain barrier aftersevere head injury, act as afferent signals to thehypothalamus.90 Primary (bleeding) and secondary(capillary leakage) hypovolaemia trigger, via aorticor carotic baroreceptors, a sympathetic-adrenalresponse and, via juxta-glomerular baroreceptors,an activation of the renin—angiotensin system tosupport the perfusion of vital organs.90 Angiotensinis an effective vasoconstrictor, induces a renalretention of sodium and fluids, and stimulates theadrenal release of aldosterone. In addition, osmoticreceptors in the hypothalamus are responsible forthe secretion of antidiuretic hormone (ADH) by theposterior lobe of the pituitary (neurohypophy-sis).90,177 In addition, chemoreceptors in the centralnervous system for the registration of acidosis,hypercapnia, hypoxaemia or hypoglycaemia, as wellas thermoreceptors, are involved in this neuroendo-crine reaction.177,209

The sympathetic nervous system and theadrenal gland represent the efferent regulatorsof cardiovascular, respiratory and metabolicresponses. Signals in the sympathetic area of thehypothalamic evoke a release of catecholaminesfrom the adrenal medulla.150,177 In addition, post-ganglionic sympathetic nerve ends influenceorgans and vessels directly. Adrenaline stimulatesthe cardiac output by increasing heart contracti-lity, the heart rate and the preload (Frank—Star-ling mechanism). In addition the blood pressure iselevated by the increased peripheral vascular


resistance (vasoconstriction of arterioles) and acentralization of the blood in favour of vitalorgans, such as heart and brain, establishedthrough a decrease of the perfusion of splanchnicarea, kidneys and muscles.159

Furthermore, catecholamines influence the post-traumatic metabolism with an increase in theenergy expenditure, hepatic glycogenolysis andgluconeogenesis (glucose-lactate (Cori-cycle) andglucose-alanin cycles), as well as release of freefatty acids.90,150,209 Early hyperglycaemia (gluco-se � 200 mg/dL) after trauma was associated withsignificantly higher infection and mortality rates.106

The natural post-traumatic insulin secretion is toolow to cope with this post-traumatic hyperglycae-mia. In addition, insulin secretion is partiallysuppressed by catecholamines, mediated by a-receptors, whereas glucagon release is elevatedby b-receptor stimulation, contributing to hepaticglycogenolysis and gluconeogenesis.90 A peripheralinsulin resistance has also been observed.177 Differ-ent cytokines (TNF-a, IL-1b) increase the expressionof glucose transport systems (insulin-like activity).The increased intracellular glucose is oxidized topyruvate and finally reduced to lactate (stress lac-tate acidosis), which contributes to the elevatedlactate levels caused primarily by the metaboliclactic acidosis (cellular hypoxia).150 Different stu-dies have shown that early increased serum levels oflactate, or base deficit, are reliable markers for apoor outcome in severely injured patients.3,36

Pain, stress and fear cause the hypothalamus torelease corticotropin-releasing hormone (CRH),leading to a secretion of adrenocorticotropic hor-mone (corticotropin, ACTH) from the anterior lobeof pituitary (adenohypophysis).62,177 ACTH stimu-lates the adrenal cortex to release glucocorticoids(cortisol), or mineralocorticoids (aldosterone).Withinminutes after trauma, increased serum levelsof steroids are detectable.62,177 Glucocorticoidshave different effects on the metabolism, such ashepatic gluconeogenesis, glycogenesis, inhibition ofprotein synthesis, increase of protein degradation inmuscles and mobilization of free fatty acids bylipolysis.90,177 In addition they limit inflammatoryprocesses of mononuclear cells and suppress theproduction of antibodies.90 In contrast, the sponta-neous apoptosis of PMNL is reduced by cortisol.34

Aldosterone increases the renal resorption ofsodium-associated by fluid retention.

The metabolic disorders after trauma are initiallycharacterized by a reduced metabolism for about24 h (acute, shock or ebb phase).90,150,177 This isfollowed by a flow phase with a catabolic metabo-lism for some days to 2 weeks and a final reparativephase with a turnover from a catabolic to an ana-

bolic metabolism.90,150,177 In the second phase, allenergy stores, such as glucose, fat acids and pro-teins, are made available for the host defenceresponse. The increase of the energy expenditurereaches a maximum after 5—10 days.62,90,150,177 Theincreased levels of amino acids are needed for thesynthesis of acute phase proteins in the liver andinflammatory mediators in mononuclear cells. Inaddition, glutamate represents a neurotransmitterand is the most important substrate for the meta-bolic processes of enterocytes and immune cells,conserving the immune integrity of the intestinalwall to avoid bacterial translocation during thesystemic inflammation.90

Multiple organ dysfunctions or failure

The evolution of the physiological and reversiblesystemic inflammation after trauma (host defenceresponse) to a host defence failure, which is asso-ciated with irreversible organ defects and high mor-tality, can be described as an overload of primaryand secondary hits and an imbalance of pro- andanti-inflammatory mechanisms.18,19,118,159,177,188 Inaddition, natural protective factors such as antiox-idants or protease inhibitors are consumed.1

Endothelial cell damage, dysfunction of vascularpermeability with capillary leakage, microcircula-tory disturbances with cellular hypoxia and finallyapoptosis of parenchymal cells by cell-associated,or free, cell death proteins and/or necrosis ofparenchymal cells, are involved in the multipleorgan dysfunctions syndrome or multiple organfailure.18,27,58,79,92,117,153,159,200 Depending on theresponsible insults (primary or secondary) MODScan be classified in primary, or early, MODS andsecondary, or late, MODS.18,27,50,95,157,159,202 Exam-ples of early organ dysfunction are the primarycerebral oedema after head injury, or the primaryARDS after thoracic injury.15,18,95,120,137 The clinicalmanifestation of secondary MODS varies in affectedorgans and dysfunction severities. Therefore, dif-ferent scores, such as the MOF score (Goris score),MODS score (Marshall score), or sequential organfailure assessment (SOFA) score are available todescribe 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 adecrease of the Horowitz ratio must be observed(PaO2/ FiO2 ratio < 300 corresponds to an ALI,< 200to an ARDS).137 Renal and gastrointestinal systemsare very sensitive to microcirculatory disorders,


leading to a necrosis of renal tubules with increaseof serum creatinine concentrations and oliguria(< 0.5 ml/kg KG/h) or anuria, and to necrosis ofintestinal villi.103,159 The alteration of the intestinalmucosa seems to be responsible for a bacterialtranslocation and explains the high rate of bacter-aemia in the absence of a detectable infective focusin lethal septic complications after trauma (guthypothesis).103,130,159 The gastrointestinal tractoften represents the source for the developmentof secondary multiple organ failure after trauma,whereas the liver represents the engine, with anacute phase and cytokine response, and decreasedfunction of hepatocytes (increase of serum bilirubinconcentration).130,157,162 Repeated scoring is help-ful for identifying categories of injured patients atmajor risk of death, or complications, after surgicalinterventions.8

Therapeutic strategies for multiplyinjured patients

Hypoxia and severe haemorrhagic shock correlatewith high mortality rates, as well as with an highincidence of SIRS, sepsis and organ dysfunction.95 Toreduce these high mortality and morbidity rates inthe post-traumatic course, early ‘‘preventive’’interventions are necessary. According to the guide-lines of advanced trauma life support (ATLS#), earlyoxygenation therapy by intubation and controlledassisted ventilation and an adequate volume ther-apy with crystalloids, colloids and/or blood productsare essential.29 However, the large-volume loadingscheme is the subject of controversial debate insevere haemorrhagic shock.131,174 Patients withblood loss > 2 l should not be overwhelmed bycrystalloids or colloids until surgical managementof bleeding is undertaken, whereas in septic shockearly, goal-directed, high volume therapy is success-ful.161 In contrast, small volume resuscitation insevere traumatic shock seems to avoid a reducedO2 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 tothe 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 thethoracic or abdominal cavities and from pelvic frac-tures, or traumatic amputations are carried outwithout delay.29,53,60,154 These early interventionsseem to limit the systemic inflammation and

decrease the early and late mortality.13 Patientswith a borderline state after primary survey, orpatients with a high trauma impact, or at risk ofadverse outcome, such as head injury, bilateral lungcontusions, multiple long bone fractures, coagulo-pathy, hypothermia or a presumed operationtime > 6 h, should be supplied with a stagedsequential surgical management as damage control,after the further work up in the secondary survey, toavoid or limit the influence of second hits (inter-ventional or antigenic loads).147,202 Damage controlincludes haemorrhage control through tamponade,vascular repair or vessel ligation, and organ resec-tions.59 In addition, a reduction of contaminationafter hollow organ injuries, or open fractures, aswell as decompression of compartment syndromesof the extremities by fasciotomy, or of the abdomenby decompressive laparotomy, should contribute tothe limitation of secondary inflammatory pro-cesses.11,49,89,154 Furthermore, the temporary sta-bilization of pelvic and long bone fractures, ordislocations of large joints, by rapidly assembledand 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-inflammatorymediators, in comparison with definitive interven-tions, such as reamed nailing (early total care).147

Debridement of open wounds and fractures, withresection of non-viable tissues, temporary closureby vacuum assisted closure therapy and second lookinterventions, contribute to a limited antigenicload, with a decrease in septic complications.89,186

However, the early stabilization of major skeletalinjuries (early total care) represents still theconcept for patients with isolated fractures and inthe absence of high traumatic impact and the riskfactors mentioned above.147

With regard to strategies for post-traumaticintensive care, only supportive therapies are estab-lished to avoid secondary organ damage and hits.95

Secondary brain injuries, with elevated intracranialpressure (ICP) due to cerebral oedema, or ischae-mia/reperfusion injuries, can be limited by applyingdifferent neuroprotective strategies, such as con-trolled hyperventilation, moderate hypothermia,and release of cerebrospinal fluid (CSF).167,183

Whenever these therapeutic regimens fail to reduceICP, intravenous administration of barbiturate maybecome necessary.183 The beneficial effect of bar-biturates, in terms of lowering elevated ICP, isthought to be due to decreased cerebral metabolismand blood flow.41 Other supportive therapies includemechanical ventilation, inotropes and haemofiltra-tion for renal failure.159,177 Furthermore, a singleshot of an antibiotic (cephalosporin) after traumareduces the post-traumatic wound infection rate.196


Further antibiotics should only be given accordingto an antibiogram of an infectious focus.196 Earlyenteral nutrition, via gastric or duodenal tubes,reduces the accumulation of pathogenic bacteriain 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-duce post-traumatic hypermetabolism and improveimmune competence.26

Despite thorough insights into the pathophysio-logical mechanisms of post-traumatic systemicinflammation and hopeful results of animal studies,multiple prospective clinical trials performed in thepast decades, especially in patients with sepsis,have failed to provide a benefit of anti-inflamma-tory, anti-coagulant, or antioxidant strategieswith regard to the mortality, whereas the incidenceof post-traumatic complications, such as infections,or multiple organ dysfunctions, has partiallydecreased.2,13,33,64,65,72,91,113,136,151 However, themagic bullet is still not found. Reasons for theseequivocal results may include individual injury pat-terns, inappropriate timing of drug administration,or suboptimal drug levels at the target site.35,65 Inaddition, the study protocols have focused onsingle mechanisms only, whereas the immunenetwork is more complex and individual (genepolymorphism, sexual dimorphism), as describedabove.13,64,65,93,151 Nevertheless, some successfulclinical studies are available, especially for septicpatients, although the underlying mechanisms havenot been clearly defined.91 Trauma patients receiv-ing high doses of intravenous immunoglobulinsexhibit a reduction in septic complications andan 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 withsevere sepsis.14 However, criticisms concern dataconsistence, unclear mechanism of action and theincreased risk of bleeding, which restricts its use ininjured patients, especially with severe head inju-ries.14,48 Although the effects of steroids in patientswith sepsis are controversial, low doses of corti-costeroids seem to reduce the mortality rate inpatients with septic complications.7,191 Insulinhas recently been shown to decrease mortalityand to prevent the incidence of multiple organfailure in critically ill patients.96 It seems thatinsulin attenuates the inflammatory response bydecreasing the pro-inflammatory, and increasingthe anti-inflammatory, cascades, thus restoringsystemic homeostasis, which has been shownto be critical for organ function and survival incritically ill patients.96

Although some successful progress in clinicaltrials is obvious, better understanding of the patho-logical mechanisms at local site of injury wouldidentify exact primary targets for drug interven-tions. However, progress in diagnostic tools forthe monitoring of the immune status (beside immu-nomonitoring) may become more successful for themanagement of severely injured patients in the nearfuture. Parallel monitoring of pro- (e.g. IL-6) andanti-inflammatory (e.g. IL-10) cytokines, as well asacute phase proteins (e.g. CRP, procalcitonin), orother factors, could help us in the decision makingfor optimal secondary operative interventions tolimit second hits.71,170 However, more prospectivediagnostic studies have to be conducted, to under-stand the kinetics and significance of these factorsin order to optimize the concept of damagecontrol.

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Pathophysiology of polytrauma · Pathophysiology of polytrauma Marius Keel*, Otmar Trentz ......

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