REVIEWPathophysiology of polytrauma
Introduction
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 mortality 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 systemic inflammation was defined in 1991, through the consensus conference of the American College of Chest Physicians/Society of Critical Care Medicine (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 different mediators, such as pro-inflammatory cytokines, complement factors, proteins of the contact phase and coagulation systems, acute phase proteins, neuroendocrine mediators and an accumulation 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 the pro-inflammatory reaction, anti-inflammatory mediators are produced (compensatory anti-inflammatory response syndrome (CARS)) to avoid the autodestructive effects of immunocompetent cells (Fig. 1).19, 88, 91, 120, 195 An imbalance between these dual immune responses, with an overwhelming release of pro- or anti-inflammatory mediators, seems to be responsible for organ dysfunction and increased susceptibility to infections and sepsis.19, 116, 118, 155 Endothelial cell damage, accumulation of leukocytes, disseminated intravascular coagulation (DIC) and microcirculatory dysfunction finally lead to programmed cell death (apoptosis) and necrosis of parenchymal cells (microenvironment 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 mechanisms 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 management of multiple injured patients, reasons for the failure of clinical trials with immunotherapies in the past two decades and the significance for the development of post-traumatic immunomonitoring.
Section snippets
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
Hyperinflammation—SIRS
Tissue damage induces in commensurate with the severity of trauma (trauma load), genetic factors (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 Polymorphonuclear leukocytes (PMNL), monocytes, tissue macrophages (e.g. alveolar macrophages), lymphocytes, natural killer cells, and parenchymal cells are involved in a complex network of this host
Hypoinflammation—CARS
Depending on the severity of injury and the post-traumatic course, anti-inflammatory mediators are also produced. TH2-cells and monocytes/macrophages release IL-4, IL-10, IL-13, or transforming growth factor-β (TGF-β) (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
Activation of plasmatic cascade system
Pro-inflammatory mediators (cytokines, arachidonic acid metabolites) and toxins activate the plasmatic cascade system, consisting of the complement cascade, the kallikrein–kinin system and the coagulation cascade (Fig. 2). The classical pathway of complement activation is induced by antigen–antibody 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
Acute phase reaction
The local (Kupffer-cells) and systemic release of pro-inflammatory cytokines (TNF-α, IL-1β, 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), α1-antitrypsin, α2-macroglobulin, caeruloplasmin, lipopolysaccharide (LPS)-binding protein (LBP), fibrinogen, prothrombin or C4BP, is increased, whereas the production of negative APP, such
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/endothelial cell interaction (adherence) through upregulation of adhesion molecules on these cells.112, 144, 172 During the initial phase of adherence, selectins on leukocytes (L-selectin, leukocyte adhesion molecule (LAM-1)) and endothelial cells
Proteases, oxidative stress and capillary leakage
Infiltrated PMNL and tissue macrophages are responsible 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 organ damage by degranulation of extracellular proteases (elastase, metalloproteinase) and formation of reactive oxygen species (ROS, oxygen radicals), the so-called respiratory burst, or oxidative
Microcirculatory disturbances
The microcirculation as functional unity, consisting of terminal arterioles, capillaries and venules, regulates nutritional and metabolic exchange in organs and tissues.12, 126 Microcirculatory disturbances during haemorrhagic shock and systemic inflammation are primary mediated through the sympathetic-adrenal reaction leading to a vasoconstriction of arterioles and venules. However, through decreased catecholamine effect on arterioles, a reduced capillary flow with an increased hydrostatic
Ischaemia/reperfusion injury
Systemic hypoxaemia and hypotension during the resuscitative period after trauma, as well as local hypoperfusion through contusions, lacerations, vascular injuries, or compartment syndromes lead to an oxygen deficit in endothelial, parenchymal, or immune competent cells, which is partially compensated for by the intracellular degradation of the energy-store adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and adenosine monophosphate (AMP).177 As a result of the ATP-consumption,
Neuroendocrine reaction and metabolic alterations
The post-traumatic host response is also influenced by neuroendocrine and metabolic disorders.207, 208, 209 Stress, fear, pain and inflammatory mediators produced in the intracranial compartment, or flowing across the damaged blood–brain 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
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 associated with irreversible organ defects and high mortality, 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 antioxidants or protease inhibitors are consumed.1 Endothelial cell damage, dysfunction of
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 guidelines of advanced trauma life support (ATLS©), early oxygenation therapy by intubation and controlled assisted ventilation and an adequate volume therapy with crystalloids, colloids and/or blood
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