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  Cytokines: The balance between proinflammatory and antiinflammatory cytokines plays a key role in the maintenance of homeostasis. Following severe trauma there is an overproduction of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and IL-8 on the part of monocytes and macrophages. This constitutes part of the acute phase response, contributing to initiation and perpetuation of the local and systemic inflammatory response.7,11 TNF-α increases the production of nitric oxide (NO) and activates cyclooxygenase, resulting in an increased production and release of thromboxanes, prostaglandins and platelet activating factor (PAF)–with a consequent increase in procoagulant activity.7,12 In turn, IL-6, produced by different cells such as activated monocytes, macrophages, neutrophils and endothelial cells, plays an important role in the acute response, intervening in the production of C-reactive protein, procalcitonin, fibrinogen, α-1-antitrypsin and complement factors.6 In addition, IL-6 regulates the growth and differentiation of lymphocytes and activates natural killer (NK) cells and neutrophils. It is widely agreed that the measurement of IL-6 is a good indicator of trauma severity and outcome.13 Interleukin-8 participates in leukocyte recruitment, and facilitates the activation of these cells at the damage site. The levels of IL-8 are correlated to the development of acute respiratory distress syndrome (ARDS) following severe trauma.7 Of the different antiinflammatory cytokines, mention must be made of IL-10, which is synthesized by lymphocytes and monocytes. This cytokine fundamentally inhibits the production of TNF-α, IL-6 and IL-8.7

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  Complement system: Activation of the complement system can occur after severe trauma via any of the known pathways (alternative, classical, lectin), generating biologically active peptides that play a key role through different mechanisms7,14: the elimination of invasive pathogens via opsonization and phagocytosis (C3b, C4b), leukocyte chemotaxis (C3a, C5a), and pathogen destruction through the membrane attack complex (C5b-9). In addition, the anaphylotoxins C3a, C4a and C5a attract phagocytes and polymorphonuclear cells (PMNs) toward the damage site15,16 and induce the degranulation of mast cells, basophils and eosinophils.7,14 Experimental and clinical studies have demonstrated that complement activation takes place both locally at the damage site and systemically after trauma.14 The plasma C3 levels are correlated to the severity of trauma and to the infectious complications and mortality after trauma.16

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  Pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and alarmins: PAMPs are inflammatory molecules related to activation of the innate immune system in cases of infection, while the alarmins constitute their equivalents in the absence of infection and in the presence of tissue damage.14 Such molecules include the heat-shock proteins, annexins, defensins, HMGB1 and S100. Both families have been grouped into a larger family known as DAMPs, which are recognized by the immune system through multiligand receptors such as the toll-like receptors (TLRs).17 However, their precise role in the development of MOF remains to be fully clarified.14

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  Neutrophils: Polymorphonuclear cells, monocytes, macrophages, dendritic cells and natural killer cells play a relevant role in the cellular immune response after trauma.6–9,18 Neutrophils are attracted to the damage site by cytokines such as IL-8, and participate in the defense and debridement of the damaged tissue. In addition, these cells participate in the activation of molecules such as TNF-α, IL-8, platelet activating factor and anaphylotoxin (C5a), leading to hyper-inflammation and PMN activation and recruitment, and contributing to the development of systemic inflammatory response syndrome and MOF.6–8,19 This mobilization of PMNs results in neutrophilia three hours after injury, which represents a “vulnerability window” during which a second “hit” can give rise to MOF.6,20 In those patients that develop MOF, neutrophilia is followed by neutropenia 6–12h after trauma.6 Moreover, the PMNs induce endothelial and epithelial damage through the overregulation of adhesion molecules in the cells, and this situation results in permeability changes and cellular edema, with cellular dysfunction.7

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  Ischemia-reperfusion: This phenomenon develops in two phases following trauma: a first phase is characterized by the temporary privation of nutrients and oxygen due to the lack of blood supply, resulting in a switch from aerobic to anaerobic metabolism at cellular level. The second phase is characterized by the restoration of blood flow and oxygenation to the ischemic tissue.7 In the ischemic phase, hypoxemia implies a low production and high consumption of adenosine triphosphate, which is degraded to adenosine diphosphate. This in turn is degraded to inosine and hypoxanthine,21 triggering alterations in permeability with an increase in intracellular sodium that causes cell edema and membrane disruption.7,22 In addition, the depletion of adenosine triphosphate causes cell damage mediated by alterations in the concentrations of cytosolic calcium.23,24 The reperfusion phase is of greater importance in relation to tissue damage and MOF than the ischemia phase. In the reperfusion phase, hypoxanthine is degraded to xanthine and finally to uric acid through the mediation of xanthine oxidase, with the production of superoxide anions (O2+−) from the available oxygen. Such anions are moreover reduced to hydrogen peroxide (H2O2) and to hydroxyl ions (OH2+−) through the mediation of superoxide dismutase. These free radicals enhance the alterations in intracellular calcium homeostasis and induce lipid peroxidation, membrane disintegration and deoxyribonucleic acid alterations – with apoptosis and cell necrosis as the end result.22

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  Intestinal hypothesis: The alterations in the structure and permeability of the intestinal mucosa play a key role as a source of bacterial products and antiinflammatory mediators that penetrate the systemic circulation and damage different organs. Two basic factors may contribute to this phenomenon: intestinal stasis allowing bacterial overgrowth, and ischemia-reperfusion, which increases intestinal permeability. However, the precise mechanisms involved have not been well established.6

The SOFA was developed in 1994 under the auspices of the European Society of Intensive Care Medicine as an objective tool for quantitatively assessing organ dysfunction or failure over time, and thus also for evaluating patient response to treatment.23 The SOFA scores 6 organs from 0 to 4 according to the degree of dysfunction in each of them (Table 1). Multiorgan failure is defined as the alteration of two or more organs with a score of ≥3.23 Although the initial aim of the scale was to evaluate morbidity, a good correlation has been observed between the maximum score obtained and mortality. In this regard, the mortality rate is over 90% in those patients presenting a total score of over 15 (with a specificity of almost 99%).24

Antonelli et al.25 evaluated the SOFA in trauma patients and found non-survivors to have poorer respiratory, cardiovascular and neurological scores, particularly during the first 5 days of admission. In this context, neurological function is the most complicated dimension to evaluate in certain cases, due to both the potential interferences of sedating drugs and the presence of traumatic brain injury. The SOFA has recently been used by a German group in the largest series of trauma patients published to date, with the assessment of MOF in 31,154 patients.26 The authors recorded an incidence of MOF of 32%, which suggests that the SOFA may overestimate the incidence of post-trauma MOF. The scale, developed at European level, is used in the Spanish national trauma registry (RETRAUCI) for assessing the incidence of MOF.27

In 1987, the Denver group for the first time developed a scale for assessing MOF.28 This instrument evaluates four systems, each of which are scored from 0 to 3 (Table 2). Organ failure is defined by a score of over 0, while MOF is defined as the failure of two or more organs, with a total score of ≥4 as determined 48h after trauma.28 The Denver scale has been revised on several occasions since its introduction, and some of the original parameters have received modifications–fundamentally in relation to the respiratory and cardiovascular dimensions. The current version of the scale evaluates the parameters described in Table 2.

In the 1990s, Marshall et al. presented a new scale for assessing MOF.29 The authors evaluated 6 systems, each of which were scored from 0 to 4 (Table 3). The parameters are always recorded at the same time of day (the first value in the morning). The Marshall scale does not consider specific values as indicators of MOF as such; rather, it establishes degrees of severity defined by the observed mortality. Thus, no mortality is observed in patients with a score of 0, while the mortality rate is 25% in those with a score of 9–12; 50% in those with a score of 13–16; 75% in those with a score of 17–20; and 100% in the case of a score of over 20. A good correlation is observed between the score and hospital stay. In the same way as the SOFA, the Marshall scale evaluates neurological status. In this case, a Glasgow coma score of 15 is assumed in sedated patients. On the other hand, because of the difficulty of defining the optimum parameter for assessing patient hemodynamics, a new variable was introduced in the updated version of 1995: the pressure adjusted heart rate (PAR). This variable is the ratio between the product of heart rate and central venous pressure, and the mean blood pressure (PAR=HR×CVP/MBP).

Some studies have compared the different scales described above. A German study analyzing the performance of the Goris, Marshall and Denver scales found the latter instrument to offer the best performance, with a sensitivity of 81% and a specificity of 88%.30 The authors highlighted that the Denver scale does not include more complex evaluations such as aspartate transaminase levels (GOT) or PAR, which had a scant impact upon the calculations made. Some years later, the Denver group compared their scale with the Marshall scale in patients of their severe trauma database and excluding pure traumatic brain injury cases and patients with an extracranial Abbreviated Injury Score of under 2. The receiver operator characteristic (ROC)-based analysis yielded similar results for both scales, though the Denver scale had greater specificity and a greater capacity to evaluate patient response to treatment.31 Different studies in turn have compared the SOFA with the Marshall scale, though not in specific trauma patient groups.

A new scale has recently been developed: the Denver Emergency Department Trauma Organ Failure Score (Denver ED TOF Score).32 This is the first scale designed to allow early prediction (within the first 4h after trauma) of the development of MOF in the first 7 days of admission. The instrument includes pre-hospital variables and parameters collected during first care in the emergency room (Table 4). The score ranges from 0 to 9, and an increased risk of MOF is associated to higher scores, with excellent calibration and discrimination. The Denver ED TOF Score could be useful not only in identifying patients in early stages of MOF but also as a screening tool for patient transfer to a reference center. Its main limitation is lesser patient severity (median Injury Severity Score [ISS] 9, with an interquartile range of 4–16), since it was developed from secondary analysis of a database not designed for this purpose, and the lack of external validation.