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Pathophysiology in patients with polytrauma

Open AccessPublished:May 14, 2022DOI:https://doi.org/10.1016/j.injury.2022.04.009

      Abstract

      The pathophysiology after polytrauma represents a complex network of interactions. While it was thought for a long time that the direct and indirect effects of hypoperfusion are most relevant due to the endothelial permeability changes, it was discovered that the innate immune response to trauma is equally important in modifying the organ response. Recent multi center studies provided a “genetic storm” theory, according to which certain neutrophil changes are activated at the time of injury. However, a second hit phenomenon can be induced by activation of certain molecules by direct organ injury, or pathogens (damage associated molecular patterns, DAMPS - pathogen associated molecular patterns, PAMPS). The interactions between the four pathogenetic cycles (of shock, coagulopathy, temperature loss and soft tissue injuries) and cross-talk between coagulation and inflammation have also been identified as important modifiers of the clinical status. In a similar fashion, overzealous surgeries and their associated soft tissue injury and blood loss can induce secondary worsening of the patient condition. Therefore, staged surgeries in certain indications represent an important alternative, to allow for performing a “safe definitive surgery” strategy for major fractures. The current review summarizes all these situations in a detailed fashion

      Keywords

      Introduction

      Polytrauma represents a complex disease and continues to be a sustained health issue, particularly in the younger age groups [
      • Regel G.
      • Lobenhoffer P.
      • Grotz M.
      • Pape H.C.
      • Lehmann U.
      • Tscherne H.
      Treatment results of patients with multiple trauma: an analysis of 3406 cases treated between 1972 and 1991 at a German Level I Trauma Center.
      ,
      • Sauaia A.
      Epidemiology of trauma deaths: a reassessment.
      ]. The acute mortality in these patients has improved across the world, especially in developed countries, as trauma systems and preventive measures were implemented, and our understanding of the pathophysiology improved. Nevertheless, uncontrolled bleeding has been reported to cause 25% of all injury-related deaths [
      • Sauaia A.
      Epidemiology of trauma deaths: a reassessment.
      ,
      • Sobrino J.
      • Shafi S.
      Timing and causes of death after injuries.
      ] and 40–80% of potentially preventable deaths [
      • Teixeira P.G.R.
      Preventable or potentially preventable mortality at a mature trauma center.
      ], both in military and in civilian settings, as summarized recently [
      • Moore E.E.
      • Moore H.B.
      • Kornblith L.Z.
      • Neal M.D.
      • Hoffman M.
      • Mutch N.J.
      • Schöchl H.
      • Hunt B.J.
      • Sauaia A.
      Trauma-induced coagulopathy.
      ].
      For decades, an injury severity score (ISS) cutoff of ≥16 points was selected to describe the severely injured, as it implied an expected mortality rate of over 20% [
      • Champion H.R.
      • Copes W.S.
      • Sacco W.J.
      • Lawnick M.M.
      • Keast S.L.
      • Bain Jr, L.W.
      • Flanaga M.E.
      • Frey C.F.
      The Major Trauma Outcome Study: establishing national norms for trauma care.
      ]. Following the introduction of trauma systems and other improvements in care, mortality rates dropped considerably, frequently around 10–13% [
      • Mullins R.J.
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      Outcome of hospitalized injured patients after institution of a trauma system in an urban area.
      ,
      • Wong T.H.
      • Lumsdaine W.
      • Hardy B.M.
      • Lee K.
      • Balogh Z.J.
      The impact of specialist trauma service on major trauma mortality.
      ]. These and other factors lead to the development of a new, evidence-based definition of polytrauma that focuses on multiple factors that determine mortality rates. It includes five pathologic conditions and ancillary parameters [
      • Pape H.C.
      • Lefering R.
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      • Peitzman A.
      • Leenen L.
      • Marzi I.
      • Lichte P.
      • Josten C.
      • Bouillon B.
      • Schmucker U.
      • Stahel P.
      • Giannoudis P.
      • Balogh Z.
      The definition of polytrauma revisited: an international consensus process and proposal of the new 'Berlin definition.
      ] (Table 1). So far, two independent research groups confirmed its usability for objective comparison of published studies [
      • Frenzel S.1.
      • Krenn P.1.
      • Heinz T.1.
      • Negrin L.L.2.
      Does the applied polytrauma definition notably influence outcome and patient population? - a retrospective analysis.
      ] and a decent interobserver reliability (IR) in comparison to other polytrauma definitions [
      • Pothmann C.E.M.
      • Baumann S.
      • Jensen K.O.
      • Mica L.
      • Osterhoff G.
      • Simmen H.P.
      • Sprengel K
      Assessment of polytraumatized patients according to the Berlin Definition: does the addition of physiological data really improve interobserver reliability?.
      ].
      Table 1Evidence based definition of polytrauma
      • Pape H.C.
      • Lefering R.
      • Butcher N.
      • Peitzman A.
      • Leenen L.
      • Marzi I.
      • Lichte P.
      • Josten C.
      • Bouillon B.
      • Schmucker U.
      • Stahel P.
      • Giannoudis P.
      • Balogh Z.
      The definition of polytrauma revisited: an international consensus process and proposal of the new 'Berlin definition.
      .
      AIS > 2 points and at least one of the following covariables
      • hypotension (systolic blood pressure < 90 mm Hg)
      • level of consciousness (Glasgow Coma Scale [GCS] score < 8)
      • acidosis (base excess >= 6.0)
      • coagulopathy (international normalized ratio 1.4/partial thromboplastin time > 40 s)
      • age (>70 years).
      Moreover, the time and causes of post traumatic deaths have changed, most especially in late mortality. Late trauma mortality decreased over the last few decades, but its major cause remains multiple organ failure (MOF) and acute lung failure/acute respiratory distress syndrome (ALI/ARDS). Reports across the world vary regarding the magnitude and more recent temporal trends in organ failure, but all agree that it remains resource-intensive, morbid and lethal in seriously injured patients. In contrast, pre-hospital and early (<48 h) fatalities have changed little, with massive hemorrhage and head injury continue to be major causes of acute death [
      • Tisherman S.A.
      • Schmicker R.
      • Brasel K.
      • Bulger E.
      • Kerby J.
      • Minei P.
      • et al.
      Detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the Resuscitation Outcomes Consortium.
      ]. Since the 1990′s, when bleeding caused over one third of trauma fatalities [
      • Sauaia A.
      Epidemiology of trauma deaths: a reassessment.
      ], little progress has been made, as hemorrhage still accounts for 20–34% of current trauma mortality [
      Drake Establishing a regional trauma preventable/potentially preventable death rate.
      ,
      • Callcut R.
      • Kornblith L.
      • Conroy A.
      • Robles A.
      • Meizoso J.
      • Namias N.
      • et al.
      The why and how our trauma patients die: a prospective multicenter Western Trauma Association study.
      ]. While a US urban trauma center observed a reduction in bleeding deaths after implementing a bleeding-control bundle-of-care (from 36% to 25%) [
      • Oyeniyi B.
      • Blessing T.
      • Fox E.
      • Scerbo M.
      • Tomasek J.
      • Wade C.
      • et al.
      Trends in 1029 trauma deaths at a level 1 trauma center: impact of a bleeding control bundle of care.
      ], hemorrhage remained frequent among potentially preventable deaths (48% vs. 43%). Randomized controlled trials (RCT) [
      • Tisherman S.A.
      • Schmicker R.
      • Brasel K.
      • Bulger E.
      • Kerby J.
      • Minei P.
      • et al.
      Detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the Resuscitation Outcomes Consortium.
      ,
      • Moore H.B.
      • Moore E
      • Chapman M.
      • McVaney K.
      • Bryskiewicz G.
      • Blechar R.
      • Chin T.
      • Burlew Cothren
      C Sauaia A. Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial.
      ,
      • Gonzalez E.
      Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays.
      ,
      • Roberts I.
      The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients.
      ,
      • Moore E.E.
      Human polymerized hemoglobin for the treatment of hemorrhagic shock when blood is unavailable: the USA multicenter trial.
      ] and observational studies [
      • Morton A.P.
      Revisiting early postinjury mortality: are they bleeding because they are dying or dying because they are bleeding?.
      ,
      • Arslan E.D.
      Assessment of traumatic deaths in a level one trauma center in Ankara, Turkey.
      ,
      • Roberts D.J.
      One thousand consecutive in-hospital deaths following severe injury: has the etiology of traumatic inpatient death changed in Canada?.
      ] unequivocally show that hemorrhagic deaths occur within 24 h, mostly within 3–6 h. TBI competes as a dominant cause of death in the 6–24-hour period and multiple organ failure (MOF) predominates after the first week [
      • Roberts D.J.
      One thousand consecutive in-hospital deaths following severe injury: has the etiology of traumatic inpatient death changed in Canada?.
      ]. In the CRASH-2 trial, representing primarily developing countries, 34% of all deaths were attributed to bleeding and 50% within 10 h [
      • Roberts D.J.
      One thousand consecutive in-hospital deaths following severe injury: has the etiology of traumatic inpatient death changed in Canada?.
      ]. In analyses of three recent randomized controlled trials focusing on postinjury hemorrhage control, with relatively similar populations, methods, and healthcare resources, most hemorrhagic deaths occurred in the first 6 h [
      • Kalkwarf K.J.
      Bleeding to death in a big city: an analysis of all trauma deaths from hemorrhage in a metropolitan area over one year.
      ,
      • Black J.A.
      • Pierce V.S.
      • Kerby J.D.
      • Holcomb J.B.
      The evolution of blood transfusion in the trauma patient: whole blood has come full circle.
      ]. Half of all deaths in the first 3–6 h in these RCTs were due to hemorrhage. The understanding of the underlying causes of these deaths have helped to set the path for our understanding of survivable versus untreatable injuries [
      • Trunkey D.D.
      ]. Namely, a more homogenous distribution was found to occur within the first week after injury, with head and chest trauma continuing to be relevant [
      • Pfeifer R.
      • Schick S.
      • Holzmann C.
      • Graw M.
      • Teuben M.
      • Pape H.C.
      Analysis of injury and Mortality Patterns in Deceased Patients with Road Traffic Injuries: an Autopsy Study.
      ,
      • Pfeifer R.
      • Tarkin I.S.
      • Rocos B.
      • Pape H.C.
      Patterns of mortality and causes of death in polytrauma patients–has anything changed?.
      ,
      • Pfeifer R.
      • Teuben M.
      • Andruszkow H.
      • Barkatali B.M.
      • Pape H.C.
      Mortality patterns in patients with multiple trauma: a systematic review of autopsy studies.
      ].
      The effects of severe trauma are associated with acute blood loss and resulting hypoperfusion, soft tissue and injuries that activate the immune system, coagulation which provokes and inflammatory response, and loss of integument protection, especially if open wounds are present [
      • Sauaia A.
      • Moore F.A.
      • Moore E.E.
      Postinjury inflammation and organ dysfunction.
      ]. The most relevant effects were named the ‘lethal triad’, consisting of hemorrhage, acidosis and coagulopathy, originally described in Denver [
      • Kashuk J.L.
      • Moore E.E.
      • Millikan J.S.
      • Moore J.B.
      Major abdominal vascular trauma–a unified approach.
      ]. Thus, some authors suggest that in the future, biochemically targeted resuscitation strategies will be relevant [
      • Kutcher M.E.
      • Ferguson AR Cohen
      MJ A principal component analysis of coagulation after trauma.
      ].
      Depending on the given injury pattern, a variety of defense mechanisms on the cellular and humoral level are activated and can lead to specific changes in inflammatory cascades. The NIH-funded Glue grant project has emphasized the importance of the initial trauma on systemic inflammatory changes that may determine reactions relevant for later complications [
      • Xiao X.
      Seok J A genomic storm in critically injured humans.
      ]. Secondary changes modify the reactions of neutrophils and other immunologically active cells in determining secondary complications (Fig. 1). Although some aspects may be predetermined, i.e. by preexisting illness and comorbidities or genetic profile, many can be influenced by medical treatment, such as prompt control of bleeding, rapid reversal of shock, and restoration of coagulation homeostasis. The current manuscript tries to summarize the current knowledge in this difficult patient population.
      Fig. 1
      Fig. 1Endothelial damage and its cellular and clinical consequences.

      Definitions and terminology specific for the posttraumatic course

      Initial stimuli

      Cellular / subcellular level

      Many different pathways are activated in a parallel fashion soon after severe trauma. Interestingly, some of them are triggered regardless of the type of injury, i.e. open versus closed, or blunt versus penetrating injury - if the general tissue injury and blood loss is severe enough. The activated molecular danger signals can be sensed by inflammatory fluid-phase pathways that contain proteins or lipids that participate in the so-called ‘first line of defense’. These factors can be host associated (“self induced”), or induced by external factors (“non self”). They can trigger pathways that lead to systemic influences and organ dysfunction. It has been emphasized to be relevant to separate between external (pathogen) versus self induced pathways, as summarized below.

      Damage associated molecular patterns (DAMPs)

      The self-induced damage associated molecular patterns (DAMPs) have been proven to derive from the host response. These factors are induced by changes in the inflammatory systems, which may be a hyper- or a hypoinflammatory host response.

      Pathogen associated molecular patterns (PAMPs)

      External (‘non-self’) factors are able to cause activation known to induce a strain of molecules, the pathogen associated molecular patterns (PAMPs) (Fig. 2) . These can derive from open wounds, infected areas or liberated endotoxins, as known to occur in intestinal ischemia reperfusion injury. Interesting DAMPS and PAMPS can activate similar inflammatory cascades.
      Fig. 2
      Fig. 2Inflammation and loss of volume into the «third space» inside the lung can set the path for secondary lung injury.

      Systemic response - early

      SIRS

      Systemic inflammatory response syndrome (SIRS) represents an early response after a variety of possible stimuli, such as trauma, burn, and infections. The hallmark of this reaction is a leak of the endothelium, which may begin in a focused body region - typically evident at first in the lung, but likely involves multiple organs.
      It is important to recognize that the purpose of innate immune response is the exaggerated defense response of the body to a noxious stressor aims at localizing and eliminate the endogenous or exogenous source of the insult. But an overwhelming stimulus provokes a non-localized response, i.e. SIRS. It involves the release of acute-phase reactants which are direct mediators of the inflammatory response and endothelial dysfunction described below. Thereby, SIRS provoked by trauma alone and can represent an early-stage complication. Its resulting dysregulated cytokine storm and subsequent inflammatory cascade reaction can lead to reversible or irreversible end-organ dysfunction [
      • Chakraborty R.K.
      • Burns B.
      2 Systemic Inflammatory Response Syndrome.
      ]. If SIRS occurs along with a bacterial source of infection, it is named sepsis (see below). Sepsis hemodynamic instability despite intravascular volume repletion is called septic shock.

      Systemic response – late

      Multiple organ failure (MOF) and multiple organ dysfunction syndrome (MODS) [
      • Shepherd J.
      • Cole E.
      Brohi J contemporary patterns of multiple organ dysfunction in trauma.
      ]

      Multiple organ dysfunction syndrome (MODS/MOF), also referred to as external challenge-induced multiple organ injury, is characterized by dysfunction of two or more organs during infection or following shock or trauma. The pathogenesis of MODS is multifactorial and involves systemic inflammation and cell stress responses including cell death; sepsis is defined as an infection with MODS/MOF [
      • Meakins J.L.
      • Marshall J.C.
      The gastrointestinal tract: the motor of multiple organ failure.
      ]. It is defined as the need for multiple internal organs supportive measures in order to function, such as artificial ventilation, dialysis, other clearing mechanisms for pathogens or support of coagulation systems. The term was used before the more precise identification of a septic state was identified. Although it was known for a long time [
      • Moore F.A.
      • Moore E.E.
      • Read R.A.
      Postinjury multiple organ failure: role of extrathoracic injury and sepsis in adult respiratory distress syndrome.
      ] that the intestinal permeability changes occur trauma patients in the absence of direct intestinal injuries [
      • Border J.R.
      • Hassett J.
      • LaDuca J.
      • Seibel R.
      • Steinberg S.
      • Mills B.
      • Losi P.
      D border the gut origin septic states in blunt multiple trauma (ISS = 40) in the ICU.
      ,
      • Sauaia A.
      • Moore E.E.
      • Johnson J.L.
      • Ciesla D.J.
      • Biffl W.L.
      • Banerjee A.
      Validation of postinjury multiple organ failure scores.
      ], it was also thought that this syndrome could develop in the absence of bacterial stimuli [
      • Roumen R.M.
      • Hendriks T.
      • van der Ven-Jongekrijg J.
      • Nieuwenhuijzen G.A.
      • Sauerwein R.W.
      • van der Meer J.W.
      Goris RJ Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure.
      ,
      • Dewar D.
      • Moore F.A.
      • Moore E.E.
      • Balogh Z.
      Postinjury multiple organ failure.
      ,
      • Minei J.P.
      • Cuschieri J.
      • Sperry J.
      • Moore E.E.
      • West M.A.
      • Harbrecht B.G.
      • O'Keefe G.E.
      • Cohen M.J.
      • Moldawer L.L.
      • Tompkins R.G.
      • Maier R.V.
      Inflammation and the Host Response to Injury Collaborative Research Program. The changing pattern and implications of multiple organ failure after blunt injury with hemorrhagic shock.
      ].

      Sepsis

      In trauma patients that are otherwise healthy and younger, the development of sepsis usually occurs at later stages of the disease and is frequently associated with MOF [
      • Bone R.C.
      • Balk R.A.
      • Cerra F.B.
      • Dellinger R.P.
      • Fein A.M.
      • Knaus W.A.
      • Schein R.M.
      • Sibbald W.J.
      The ACCP/SCCM Consensus Conference Committee
      American College of Chest Physicians/Society of Critical Care Medicine Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.
      ]. The definition has undergone several changes. The last refinement has been published by the third international conference of the Surviving Sepsis Campaign. According to this definition, sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. For quantification, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. The authors also define an acute form, named septic shock, as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities, associated with a greater risk of mortality than with sepsis alone.
      For the diagnosis of septic shock, the requirement of vasopressor treatment to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia has been suggested [
      • Singer Mervyn
      • Deutschman Clifford S
      • Seymour Christopher Warren
      • Shankar-Hari Manu
      • Annane Djillali
      • Bauer Michael
      • Bellomo Rinaldo
      • Bernard Gordon R
      • Chiche Jean-Daniel
      • Coopersmith Craig M
      • Hotchkiss Richard S
      • Levy Mitchell M
      • Marshall John C
      • Martin Greg S
      • Opal Steven M
      • Rubenfeld Gordon D
      • Poll Tom van der
      • Vincent Jean-Louis
      • Angus Derek C
      The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
      ].

      Effects of hypoperfusion

      General effects of endothelial dysfunction

      Endothelial damage represents one of the hallmarks of early posttraumatic changes and can be regarded as the endpoint of early hyperinflammation. Its effects occur throughout the entire body and induce changes in varying degrees [
      • Nuytink N.K.S.
      • Goris R.J.A.
      Whole body inflammation in trauma patients – an autopsy study.
      ]. The most conspicuous manifestation is the loss of fluid into the interstitial space, which has several implications. Although the permeability changes affect all organs (Table 1II and III), mainly the one occurring in the lung and the intestine, both of which are discussed separately, are associated with later complications.
      Clinically, these patients require larger volume of intravenous fluids, frequently associated with the necessity of vasopressors for maintenance of an adequate systemic perfusion pressure. In parallel, their urinary output is lowered, without signs of cardiac insufficiency or other causes of kidney failure. Frequently, there is a drop in the production or sequestration of platelets, leading to a drop in the general platelet count. This clinically evident loss of volume into the “third space” is depicted in Fig. 1 and summarizes the effects of endothelial damage, volume shift and clinical consequences.
      On the capillary level, extravascular fluid hampers the transport of oxygen and thereby diminishes regional cellular nutrition. This effect occurs in all organs of the trunk [
      • Pothmann C.E.M.
      • Baumann S.
      • Jensen K.O.
      • Mica L.
      • Osterhoff G.
      • Simmen H.P.
      • Sprengel K
      Assessment of polytraumatized patients according to the Berlin Definition: does the addition of physiological data really improve interobserver reliability?.
      ] and may be responsible for issues of wound healing and skin breakdown. In no surviving patients, clinical and autopsy studies have shown that these patients have a continuously positive I/O ratio. While in survivors the capillary leak usually is sealed within the first days to a week post injury, no survivors may never regain their level of endothelial integrity, which occurs in early deaths from HI, secondary deaths associated with ARDS and late cases or MOF. Autopsy studies have revealed that this leak occurs in all organs [
      • Pape H.-.C.
      • Remmers D.
      • Kleemann W.
      • Goris J.A.
      • Regel G.
      • Tscherne H.
      Posttraumatic multiple organ failure - a report on clinical and autopsy findings.
      ], as summarized in Tables 2 and 3.
      Table 2Regional permeability changes, mechanisms and interactions with pathogenetic pathways.
      OrganSpecificsInteraction 4 pathwaysMechanisms
      BrainImmunologically activeNeuroendocrine axis
      LungLargest visceral  capillary bed Neutrophils, Macrophages well studiedYesTransfer of permeability leak into non-injured tissue
      IntestineImmunologically active I/R injury Pathogen leakageYesPAMP activation, endotoxin induced
      LiverActivation of RES / clearance of pathogensYesActive contribution to MOF
      ExtremitiesI/R injury, regional tissue decayYesIschemia reperfusion injury
      KidneySequelae of kidney failureunknownSecondary damage after kidney failure,
      SpleenSec. permeability damageunknown
      HeartSec. permeability damageunknown
      Table 3Post mortem findings in relation to time of death (other organs or extremities were not examined)
      • Matijevic N.
      Microvesicle phenotypes are associated with transfusion requirements and mortality in subjects with severe injuries.
      .
      EdemaLungLiverHeartKidney
      HT, DIC <24 hr+++(-)
      ARDS,MOF 24hrs-7d+++(+)+(-)
      MOF, Sepsis > 7 days+++(-)
      Cell necrosis
      HT, DIC <24 hr++++
      ARDS,MOF 24hrs-7d+++++++
      MOF, Sepsis > 7 days+++++++
      Shock related  changes
      HT, DIC <24 hr+(+)+
      ARDS,MOF 24hrs-7d+(+)+
      MOF, Sepsis > 7 days++++
      In the extremities, this can set the path for further extravasation of regional fluid, which can add to the soft tissue injuries caused by the direct traumatic impact. Vascular endothelial cadherin has also been reported to play a role [
      • Vestweber D.
      How leukocytes cross the vascular endothelium.
      ]. One of the effects of this molecule is a higher risk of general tissue swelling. In the clinical scenario, it is difficult to separate effects induced by the direct impact of trauma versus the secondary inflammatory reactions leading to additional endothelial damage and swelling. It is therefore not surprising that most of these changes were examined in animal studies, namely in large animal models [
      • Horst K.
      • Greven J.
      • Lüken H.
      • Zhi Q.
      • Pfeifer R.
      • Simon T.P.
      • et al.
      Trauma Severity and its impact on local inflammation in extremity injury-insight from a combined trauma model in pigs.
      ,
      • Teuben M.P.J.
      • Hofman M.
      • Shehu A.
      • Greven J.
      • Qiao Z.
      • Jensen K.O.
      • Hildebrand F.
      • Pfeifer R.
      • Pape H.C.
      The impact of intramedullary nailing on the characteristics of the pulmonary neutrophil pool in rodents.
      ].
      The close relationship between permeability changes and immunologic changes is important and within the first hours after injury, both multiple immune system-activating features and suppressive features have been recognized [
      • Hazeldine J.
      Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: a prospective cohort study.
      ]. A balance between both these aspects of the systemic inflammatory response is crucial and serves to minimize danger reactions on the molecular level and to induce tissue-repair mechanisms for healing. As one of these mechanisms, macrophages have been found to be reprogrammed from the pro-inflammatory M1 phenotype to the anti- inflammatory M2 phenotype [
      • Matijevic N.
      Microvesicle phenotypes are associated with transfusion requirements and mortality in subjects with severe injuries.
      ]. On the cellular level, an increased expression of adhesion molecules occurs and is known to be induced by trauma-generated DAMPs (for example, mitochondrial DNA). This effect augments the endothelial damage, as endothelial expression of adhesion molecules facilitates leukocyte adhesion [
      • Sun S.
      Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways.
      ].

      Permeability changes associated with organ dysfunction: lung and intestine

      As the lung contains the largest endothelial network in the human body (size of a football field), the loss of volume into the “third space” is particularly relevant and has been a frequent explanation for the pivotal role of the lung in posttraumatic organ dysfunction (acute lung injury, ALI and adult respiratory distress syndrome, (ARDS)). it has frequently been used as an example for systemic inflammatory changes. Also, its effect on loss of volume into the “third space” is extraordinary and decreases the transport of oxygen from the alveoli into the capillaries, leading to signs of ALI and ARDS. Higher airway pressures and modifications to ventilator settings may ensue [
      • Froese A.B.
      • Bryan A.C.
      High frequency ventilation.
      ] that can set the path for secondary lung injury (Fig. 2).
      The lung contains a vast amount of both stationary and circulating immune cells. Thereby, it represents an immunologically active organ. In particular, alveolar macrophages function as conductors of the orchestrated immune response after trauma [
      • Herold S.
      • Mayer K.
      • Lohmeyer J.
      Acute lung injury: how macrophages orchestrate resolution of inflammation and tissue repair.
      ]. Pulmonary macrophages can be stationary or can enter the lung via migration. The residing macrophages have been shown to have a broad differentiation potential. A role of resident and recruited macrophages in initiating and maintaining pulmonary inflammation after pulmonary injury and contusion has been convincingly demonstrated and will be elaborated more precisely below. As discussed for the endothelial changes in the extremities, animal studies have been available to clarify certain effects. An instrumentation of the femur can cause activation of inflammatory endothelial reactions in the lung [
      • Teuben M.P.J.
      • Hofman M.
      • Shehu A.
      • Greven J.
      • Qiao Z.
      • Jensen K.O.
      • Hildebrand F.
      • Pfeifer R.
      • Pape H.C.
      The impact of intramedullary nailing on the characteristics of the pulmonary neutrophil pool in rodents.
      ].
      In addition, the pulmonary endothelial network serves as a filter for the contents (bacteria, endotoxins) deriving from adjacent intestinal leakage and the results of its microvascular permeability changes. In the setting of orthopedic trauma, multiple studies have shown that fat embolism after long bone fractures can cause an accumulation of intramedullary contents in the lung. Inside the pulmonary vasculature, several scenarios are known to occur. Initially, there may be complete blockage, thus leading to an acute rise in the influx and associated pulmonary arterial pressure [
      • Pape H.C.
      • Regel G.
      • Dwenger A.
      • Krumm K.
      • Schweitzer G.
      • Krettek C.
      • Sturm J.A.
      • Tscherne H.
      Influences of different methods of intramedullary femoral nailing on lung function in patients with multiple trauma.
      ]. Due to the presence of intrapulmonary shunts, this effect might rapidly improve the circulatory effects associated with a normalization in pulmonary arterial pressures [
      • Pape H.C.
      • Dwenger A.
      • Regel G.
      • Remmers D.
      • Tscherne H.
      Intramedullary femoral nailing in sheep: does severe injury predispose to pulmonary dysfunction?.
      ]. As seen in Figs. 1 and 2.
      It has long been known that the intestine is particularly affected by splanchnic hypoperfusion due to acute blood loss. This can cause subsequent local injury, which has lead to specific gut-directed therapies, especially regarding modifications in enteral nutrition. The connection between intestinal permeability changes / failure and intestinal reperfusion injury – both by direct injury, and by autoregulatory mechanisms – studied closer when the gut “theory of organ failure” was proposed. It became relevant for the understanding of reperfusion injury of the intestine and its systems effects [
      • Deitch E.A
      Gut failure: its role in the multiple organ failure syndrome.
      ]. The theories that help explain the role of the intestine have undergone a substantial development.
      Initially, Deitch and coworkers were among the first groups to describe findings associated with the consequences of intestinal ischemia occurring during severe trauma. According to the early pathophysiological understandings, ischemia leads to an inflammatory reaction that causes the linings of the intestine to fail, named the “leaky gut”. According to this leakiness, direct translocation of bacteria and toxins deriving from bacterial walls was thought to occur. These were then thought to be collected in the regional defense organs, such as Peyer's plaques. Subsequently, they were thought to be transferred into the liver through the “gut-liver axis”, where they could stimulate the reticuloendothelial system [
      • Pape H.-.C.
      • Remmers D.
      • Grotz M.
      • Kotzerke J.
      • Glinski S.
      • van Griensven M.
      • Dahlweid M.
      • Sznidar S.
      • Tscherne H.
      Reticuloendothelial system activity and organ failure in multiply injured patients.
      ]. The development of overwhelming inflammation and subsequent organ dysfunction were then thought to be the result of a collapse of the immune response, as part of a biphasic answer of initial hyperinflammation and subsequent immune paralysis [
      • Ayala A.
      • Wang P.
      • Ba Z.F.
      • et al.
      Differential alterations in plasma IL-6 and TNF levels after trauma and hemorrhage.
      ]. But the concept of bacterial translocation as the unifying concept was primarily based on rodent studies, and subsequently challenged in clinical studies [
      • Zhou Q.
      • Verne N.
      Intestinal hyperpermeability: a gateway to multi-organ failure?.
      ]. Moreover, it was revealed that the underlying mechanisms are by far more complex: It is evident that under physiologic conditions, there is a well functioning barrier between the intestine and the blood. It is formed by mucus, intestinal epithelial cells (IECs) and numerous other types of immunologically active cells. They separate a vast amount of both, protective commensal bacteria, and pathogenic microorganisms. The consistence and distribution of bacteria has been investigated and a -pathogen shift in the gut microbiome has been observed, which has been named ‘dysbiosis’. A modification in the composition of certain intestinal factors, such as the type of bacteria and concentration of mucus is closely repeated with septic events and organ dysfunction. This mechanism has been thought to explain a connection between the intestinal ischemia and remote organ failure [

      Assimakopoulos SF, et al. Gut-origin sepsis in the critically ill patient: pathophysiology and treatment [published online ahead of print July 12, 2018]. Infection. 2018 Dec;46(6):751-760 doi:10.1007/s15010-018-1178-5.

      ,
      • Haak B.W.
      • Wiersinga W.J.
      The role of the gut microbiota in sepsis.
      ].
      In a healthy individual, the system of the gut microbiota is well balanced and prevents pathological infections. In case of severe shock or direct abdominal injury, dysbiosis occurs and can be the cause of sepsis and infectious complications [
      • Liu Z.
      • Li N.
      • Fang H.
      • Chen X.
      • Guo Y.
      • Gong S.
      • Niu M.
      • Zhou H.
      • Jiang Y.
      • Chang P.
      • Chen P.
      Enteric dysbiosis is associated with sepsis in patients.
      ]. The centralization associated with systemic hemorrhage, splanchnic vasoconstriction and the associated ischemia / reperfusion injury induces malfunction of the intestinal villi, which are highly vulnerable [
      • Patel J.J.
      • Rosenthal M.D.
      • Miller K.R.
      • Martindale R.G.
      The gut in trauma.
      ].
      Currently, two main theories regarding the pathogenetic consequences of intestinal damage exist. Some authors favor the idea that bacteria translocate into the adjacent lymphatic system, where they are broken down and endotoxins are transported into the lung and other organs. They are thought to be responsible for the subsequent inflammatory changes [
      Charbonney E Endotoxemia following multiple trauma: risk factors and prognostic implications.
      ]. Others have not found evidence of endotoxemia and discuss that it is important for the further prognosis and organ dysfunction [
      • Moore F.A.
      Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma.
      ]. Experimental work suggests gut ischemia provokes remote organ dysfunction independent of bacteria [
      • Jordan J.R.
      • Moore E.E.
      • Sarin E.L.
      • Damle S.S.
      • Kashuk S.B.
      • Silliman C.C.
      • Banerjee A.
      Arachidonic acid in postshock mesenteric lymph induces pulmonary synthesis of leukotriene B4.
      ].
      Whether endotoxin does or does not play this role, it is possible that bacterial pathogens and related PAMPs penetrate the damaged intestinal tissue or translocate into the intestinal lymph nodes. It was also speculated that the reason why late organ failure develops it is the exhaustion of the regional reticuloendothelial system, being permanently overwhelmed with endotoxins and PAMPs [
      • Pape H.-.C.
      • Remmers D.
      • Grotz M.
      • Kotzerke J.
      • Glinski S.
      • van Griensven M.
      • Dahlweid M.
      • Sznidar S.
      • Tscherne H.
      Reticuloendothelial system activity and organ failure in multiply injured patients.
      ].

      Innate immune response to trauma

      The endothelial damage discussed above is augmented by a systemic inflammatory response that evolves within minutes or hours after trauma, which includes both multiple immune system-activating features and suppressive features [
      • Timmermans K.
      Plasma levels of danger-associated molecular patterns are associated withimmune suppression in trauma patients.
      ]. The inflammatory response can be induced by both, DAMPs and PAMPs. PAMPs are induced by open injuries from infectious agents (bacteria, viruses and fungi), along with the release of large amounts of ‘self’ damage-associated molecular patterns (DAMPs) such as ATP, HMGB-1, cold-inducible RNA-binding protein, histones and mitochondrial DNA.
      Ideally, there is a balanced systemic inflammatory response that is designed to clear the molecular danger and to induce tissue-repair mechanisms for healing. One example is that macrophages can be switched and reprogrammed from the pro-inflammatory M1 phenotype to the anti- inflammatory M2 phenotype [
      • Nemeth K.
      Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production.
      ]. It is important to recognize that a multi step response can occur, which is named the first and the second hit [
      • Partrick D.A.
      • Moore F.A.
      • Moore E.E.
      • Barnett Jr, C.C.
      • Silliman C.C.
      Neutrophil priming and activation in the pathogenesis of postinjury multiple organ failure.
      ,
      • Volpin G.
      • Pfeifer R Saveski J.
      • Hasani I Cohen M.
      Pape HC Damage control orthopaedics in polytraumatized patients- current concepts.
      ].
      Neutrophils play a pivotal role in transmitting signals. Both DAMPs and PAMPs are able to transmit their signals to leukocytes through certain receptors that are able to recognize certain patterns (pattern-recognition receptors, PRRs). Among these are complement receptors, purinergic receptors and others (e.g. TLRs, NLRs, RAGE). PAMPs appear to activate specific receptors named Pattern Recognition Receptors (PRRs). These PPRs are germline-encoded and have shared specificity. They are able to recognize invading pathogens and endogenous ligands released from necrotic tissue. If this mechanism is dysregulated, excessive inflammation can develop, resulting in deleterious tissue damage and impaired healing in various diseases. The mechanism is known from other diseases but has been described for trauma as well. To date, four types of PRRs have been identified, the Toll-like receptors (TLRs), the Nod-like receptors (NLRs), the RIG-like receptors (RLRs), and the C-type lectin receptors (CLRs). The most studied PRRs are the TLRs, particularly TLR 4 [
      • Robb C.T.
      • Regan K.H.
      • Dorward D.A.
      • Rossi A.G.
      Key mechanisms governing resolution of lung inflammation.
      ]. They represent a prototypical family of PRRs that can be powerful anti-inflammatory targets.
      It was shown that the immune status of the patient can be determined based on the epitopes that are deployed on the membrane of the neutrophils [
      • Pillay J.
      • Hietbrink F.
      • Koenderman L.
      • Leenen L.P.H.
      The systemic inflammatory response induced by trauma is reflected by multiple phenotypes of blood neutrophils.
      ]. Moreover, the PMN phenotype appears to be a readout for the innate immune response [
      • Hietbrink F.
      • Koenderman L.
      • Althuizen M.
      • Leenen L.P.H.
      Modulation of the innate immune response after trauma visualised by a change in functional PMN phenotype.
      ]. The early assessment of the immune status, as demonstrated by neutrophil phenotype predicted outcome. It was shown that first day neutrophil kinetics predicts late onset sepsis [
      • Groeneveld K.M.
      • Koenderman L.
      • Warren B.L.
      Early decreased neutrophil responsiveness is related to late onset sepsis in multitrauma patients: an international cohort study.
      ].

      Balanced versus imbalanced early inflammatory response

      It has been shown that certain changes in the energy metabolism of leukocytes can occur. These include a shift from oxidative phosphorylation towards aerobic glycolysis, described as the “Warburg” effect, which also has been found during septic complications after tissue trauma and infection [
      • Cheng S.C.
      Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis.
      ,
      • Denk S.
      Complement C5a functions as a master switch for the ph balance in neutrophils exerting fundamental immunometabolic effects.
      ]. This phenomenon represents the metabolic basis for induced changes in the innate immunity for monocytes and macrophages [
      • Denk S.
      Complement C5a functions as a master switch for the ph balance in neutrophils exerting fundamental immunometabolic effects.
      ] and induces a prolonged functional state after a second contact with a DAMP or PAMP, thereby representing a memory process [
      • Cheng S.C.
      mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity.
      ].
      The clinical scenario behind this effect is that if a patient arrives “in extremis” with severe trauma, the innate immune response is imbalanced [
      • Billiar T.R.
      • Vodovotz Y.
      Time for trauma immunology.
      ]. The result includes a dysregulation of several cascade systems. The relationship between ongoing low body temperature and coagulopathy has long been known. In addition, hemorrhagic shock has been shown to induce acute trauma-induced complementopathy and coagulopathy [
      • Frith D.
      Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations.
      ]. Reprogramming and rapid suppression of immunological functions, such as expression of HLA-DR. in macrophages occurs. All these mechanisms have led to the concept of the interactive four pathological cycles, consisting of shock, coagulopathy, temperature loss and secondary effects of soft tissue effects [
      • Munford R.S.
      • Pugin J.
      Normal responses to injury prevent systemic inflammation and can be immunosuppressive.
      ].

      “Genomic storm” theory

      Recently, there have been studies in animals and in a human multicenter study, that investigated the effects of trauma on genetic changes. In burn patients, it was argued that a trauma load associated with a relevant risk of mortality can induce acute genetic changes leading to functional reprioritization [
      • Lederer J.A.
      Comparison of longitudinal leukocyte gene expression after burn injury or trauma-hemorrhage in mice.
      ]. Although this response has only been proven for circulating neutrophils (“genetic storm”), the effect on the host response may be relevant for the clinical course, as they may persist during the further hospital course [
      • Xiao X.
      Seok J A genomic storm in critically injured humans.
      ]. Of note, the consequences of the genetic storm have been examined so far only in one clinical study of limited size. While the findings of the genetic storm certainly represent an important new detail in clinical trauma research, one should keep in mind that the theory is based on the following criteria:
      In a multi center study of 167 patients (out of 1637 patients with variable injuries, aged 18 to 55 years), blood leukocytes were obtained and a genome-wide expression analysis from the Affymetrix U133 Gene Chip was performed. According to the results, the degree of genetic change is associated with a trauma induced alteration over time. It includes both, an increase in the expression of certain genes, and a decrease in others with the most sustained changes occurring at the 12-hour time point. In more than half of the genes, no return to baseline was detected after 28 days in blunt trauma and until 90 days in burns injuries. Almost all gene families that were most suppressed after injury were involved in antigen presentation and T cell activation. The authors discuss that a universal genomic response to severe injury may occur, and that the return to normal gene expression correlated with clinical recovery [
      • Xiao X.
      Seok J A genomic storm in critically injured humans.
      ]. However, certain limitations apply, as the early genomic changes were highly comparable particularly between the stressors, burns, or blunt trauma:
      1. This genetic change occurred despite a markedly different clinical presentation of severe blunt trauma, burn injury, and endotoxemia. 2. Also, the fact that only neutrophil function (i.e. indicators of the mobile immune system) was selected, may me regarded as a limitation, as other immunologically active systems and secondary lymphoid organs are not covered (i.e. stationary macrophages, Reticuloendothelial system, Peyer Plaques and others). 3. The evidence of a single gene or cluster of genes whose expression changed uniquely along with different clinical outcomes was lacking.
      In summary, the results indicate that the early genetic response may be relevant but does not represent the only influencing factor regarding the clinical course, as second hit phenomena continue to be active.

      Effects of tissue injuries: chest and extremities

      Local injuries: chest

      Severe thoracic trauma also causes a significant increase in respiratory failure and length of stay in the intensive care unit. Several aspects are important that may be responsible for functional changes after chest injuries. The degree of biomechanical injury may alter dynamics of inspiration [
      • Richter M.
      • Krettek C.
      • Otte D.
      • Wiese B.
      • Stalp M.
      • Ernst S.
      • et al.
      Correlation between crash severity, injury severity, and clinical course in car occupants with thoracic trauma: a technical and medical study.
      ]. Therefore, flail chest was coined and is characterized by at least five contiguous single fractures or three adjacent segmental rib fractures occurs in approximately 15% of patients with blunt chest trauma [
      • Stellin G.
      Survival in trauma victims with pulmonary contusion.
      ]]. This results in an unstable flail segment with a paradoxical respiratory motion (inward motion during inspiration and outward motion during expiration) [
      • Clark G.C.
      • Schechter W.P.
      • Trunkey
      Variables affecting outcome in blunt chest trauma: flail chest versus pulmonary contusion.
      ]. On the other hand, especially in younger patients with elastic bony structures, the lung can be injured by contusion, even in the absence of osseous injuries. This finding may appear not until 24 to 24 hrs. on radiological exams and is typically associated with pulmonary dysfunction [
      • Fulton R.L.
      • Peter E.T.
      The progressive nature of pulmonary contusion.
      ]. Even today, polytrauma patients with thoracic injuries have a significant increase in the duration ventilation (2 vs. 8 days) and intensive care unit stay (4 vs. 11 days) when compared to trauma patients without thoracic injury [
      • Voggenreiter G.
      • Majetschak M.
      • Aufmkolk M.
      • Assenmacher S.
      • Schmit-Neuerburg K.P.
      Estimation of condensed pulmonary parenchyma from gas exchange parameters in patients with multiple trauma and blunt chest trauma.
      ]. Moreover, thoracic injuries are associated with a lethality of close to 40% and are responsible for approximately 20–25% of the deaths associated with trauma.
      Several scoring systems for the classification of blunt chest trauma have been developed. Along with the Thoracic Abbreviated Injury Scale (AIS chest), the Wagner-Score [
      • Wagner R.B.
      • Jamieson P.M.
      Pulmonary contusion. Evaluation and classification of computed tomography.
      ], the Pulmonary Contusion Score (PCS) [
      • Tyburski J.G.
      • Collinge J.D.
      • Wilson R.F.
      • Eachempati S.R.
      Pulmonary contusion : quantifing the lesions on chest x-ray filma and the factors affecting prognosis.
      ] focus on anatomic findings. Other scoring systems, such as the Thoracic Trauma Severity Score, have included physiological parameters in addition, to help provide better prediction [
      • Pape H.C.
      • Remmers D.
      • Rice J.
      • Ebisch M.
      • Krettek C.
      • Tscherne H.
      Appraisal of early evaluation of blunt chest trauma: development of a standardized scoring system for initial clinical decision making.
      ]. The Pulmonary Contusion Score (PCS, Tyburksi) was developed in 1999 and is based on the admission and 24-hour plain radiograph. It focuses on pulmonary contusion and divides the lung in 3 thirds. A high score was associate with increased mortality, prolonged mechanical ventilation, if increase in the severity of lung contusion during the first 24 h was observed. The usefulness of this score is limited due to fact that the assessment of pulmonary contusion is difficult in plain chest radiography. Wagner and Jamieson developed a thoracic trauma score based on CT scan. It divides the CT sections into pulmonary lesions of ≥ 28% of total air space, classified between (grade 1, <18%) (19–27%; grade 2 and < 19%; grade 3) and an association between a high score and a the duration of mechanical ventilation was described.
      The Thoracic Trauma Severity Score (TTS) is a CT-independent scoring system and uses and only one that underwent a validation [

      Mommsen P, Zeckey C, Andruszkow H, Weidemann J, Frömke C, Puljic P, van Griensven M, Frink M, Krettek C, Hildebrand F. J Surg Res. 2012 Jul;176(1):239-47. doi:10.1016/j.jss.2011.09.018. Epub 2011 Oct 5.PMID: 22099585 Comparison of different thoracic trauma scoring systems in regards to prediction of post-traumatic complications and outcome in blunt chesttrauma.

      ]. It includes five anatomical and physiological parameters at the time of admission: extension of pulmonary contusion, rib fractures, pleural lesion, age and the Horowitz ratio PaO2/FiO2.
      It was discussed whether improvements in passive car safety and prophylactic measures have caused a reduction in the severity of thoracic trauma and its complications, namely ARDS. A trauma registry analysis revealed that mortality rates were unchanged although there was a decrease in the duration of mechanical ventilation, the need for emergency surgery, lung failure, sepsis, and multi organ failure [
      • Horst K.
      • Andruszkow H.
      • Herren C.
      • Hildebrand F.
      • Pape H.C.
      Thoracic trauma now and then: a 10 year experience from 16,773 severely injured patients.
      ]. These findings are in line with a meta-analysis that discarded the hypothesis of reduced ARDS incidences over time [
      • Pfeifer R.
      • Heussen N.
      • Michalewicz E.
      • Hilgers R.D.
      • Pape H.C.
      Incidence of adult respiratory distress syndrome in trauma patients: a systematic review and meta- analysis over a period of three decades.
      ]. Due to the ongoing importance of chest trauma, a closer look at the pathophysiology appears to be justified.
      The role of local blood flow changes following chest trauma has long been described. Direct pulmonary trauma or contusion disrupts lung tissue and vessels, followed by immediate bleeding into the bronchoalveolar space and pulmonary interstitium, which immediately results in compromised oxygenation and a decrease in the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2). This disruption leads to rapid activation of the coagulation system and thrombus formation, which compromises both perfusion and gas exchange.
      In addition, opening of A-V shunts and the influence of artificial ventilation does not require further explanation. However, inflammatory stimuli can modify the regional response. After fracture and experimental trauma, a release of mitochondrial DAMPs has been shown. These DAMPs mimic bacterial PAMPs and are thought to suppress the remote neutrophil-driven pulmonary immune response: after lung contusion, neutrophils relocate from the contused lungs to sites of extra-pulmonary damage and cause a decrease in pulmonary antibacterial defense and an increased risk of pneumonia [
      • Zhao C.
      Mitochondrial damage-associated molecular patterns released by abdominal trauma suppress pulmonary immune responses.
      ]. Neutrophils located in normal lung vasculature are “marginating”, i.e. rolling along vascular walls as a result of weak attractive forces and particle flow characteristics [
      • Hogg C.J.
      • Doerschuck C.M.
      • Wiggs B.
      • et al.
      Neutrophil retention during a single transit through the pulmonary circulation.
      ]. This marginating phenomenon has been demonstrated in post-capillary venules in the systemic vascular beds. According to recent evidence, the pulmonary circulation is unique in this respect, in that the majority of neutrophils in the lung are found in capillaries [
      • MacNee W.
      • Selby C.
      Neutrophil kinetics in the lungs.
      ]. Lien et al. used videomicroscopy and reported that the neutrophils were held up in the capillary beds but not in postcapillary venules [
      • Lien D.C.
      • Wagner Jr, W.W.
      • Capen R.L.
      • Haslett C.
      • et al.
      Physiological neutrophil sequestration in the lung: visual evidence for localisation in capillaries.
      ]. It appears that the physical restraints of the pulmonary capillary bed, stiffness of the activated neutrophil cytoskeleton, and adhesion receptor mechanisms, play a role in the early neutrophil kinetic responses to acute lung injury.
      Likewise, alveolar macrophages can sense DAMPs and PAMPs and extracellular matrix fragments such as hyaluronan [
      • Jiang D.
      • et al.
      Regulation of lung injury and repair by Toll-like receptors and hyaluronan.
      ] via PRRs and react to pulmonary and extra-pulmonary trauma with initially accentuated pro-inflammatory and pro-coagulatory responses. After lung contusion, alveolar macrophages upregulate their expression of the innate immunoreceptor TLR4. This effect appears to support defense mechanisms against bacteria and the direct versus indirect lung injury has different consequences, as depicted in Fig. 3.
      Fig. 3
      Fig. 3Direct and indirect lung injury caused by DAMPs and PAMPs.

      Peripheral soft tissue injuries

      Local inflammation leads to cellular soft tissue changes with subsequently systemic effects [
      • Kobbe P.
      • Vodovotz Y.
      • Kaczorowski D.J.
      • Billiar T.R.
      • Pape H.-.C.
      The role of fracture-associated soft tissue injury in the induction of systemic inflammation and remote organ dysfunction after bilateral femur fracture.
      ]. As adenosine triphosphate (ATP) supplies dwindle due to local hypoxia, cellular homeostasis is altered and necrosis can occur through direct cell destruction, subsequent membrane rupture, apoptosis or necroptosis [
      • Singer A.J.
      • Clark R.A.
      Cutaneous wound healing.
      ]. When the hemostatic function of platelets is activated, platelets also secrete several mediators - such as PDGF - thereby promoting and activating macrophages and fibroblasts in injured tissue. Macrophages secrete further growth factors such as PDGF or VEGF, proinflammatory cytokines and nitric oxide [
      • Tidball J.G.
      Villalta SAJAJoP-R. Regulatory interactions between muscle and the immune system during muscle regeneration.
      ]. Injured tissue cells secrete vasoactive and chemotactic mediators that recruit inflammatory leukocytes to the site of injury; here, platelets provide a provisional matrix for cell migration [
      • Clark R.A.
      The molecular and cellular biology of wound repair.
      ]. Infiltrated neutrophils clean the injured site of foreign particles and bacteria and are either extruded or digested by macrophages. Through various proinflammatory mediators, macrophages appear to play a pivotal role in the transition from tissue inflammation to tissue repair. Granulation tissue invades the wound four days after injury. Regeneration of the skin usually starts with the formation of granulation tissue and the initiation of vascularization []. These physiological changes have a sustained clinical relevance and can induce a second hit phenomenon (Fig. 2).

      Soft tissue crush injury as a source of a second hit phenomenon

      Severe prolonged tissue compression in the form of crush injuries is rare (1.4 to 13.7% of all injuries) and represent a special threat. In crush injuries, force is applied or energy transmitted over an extended period of time to an immobilized portion of the body. The disrupted tissue perfusion leads to cellular hypoperfusion and/or hypoxia with subsequent ischemia and necrosis [
      • Malinoski D.J.
      • Slater M.S.
      • Mullins R.J.
      Crush injury and rhabdomyolysis.
      ,
      • Gonzalez D.
      Crush syndrome.
      ]. Rhabdomyolysis results, and may induce myoglobinuric acute renal failure, dependent on the degree of involved muscle mass, duration of compression and level of compromise in local circulation. However, even after rapid rescue, acute renal failure in the setting of rhabdomyolysis commonly occurs and is associated with a sustained mortality rate of up to approximately 20% [
      • Erek E.
      • Sever M.S.
      • Serdengeçti K.
      • Vanholder R.
      • Akoğlu E.
      • Yavuz M.
      • et al.
      An overview of morbidity and mortality in patients with acute renal failure due to crush syndrome: the Marmara earthquake experience.
      ]. Associated conditions include electrolyte abnormalities, metabolic acidosis, hypovolemia and disseminated intravascular coagulation. orthopedic surgeons are well aware of local sequelae of severe tissue injuries and the importance for a second hit phenomenon. These are usually respected and lead to changes in the type of surgical tactics, such as limited soft tissue release and appreciation of minimal invasive techniques. In this line, the triade of death described above has been expanded by soft tissue injuries, as discussed in the next section.

      Interaction of pathogenetic cycles and cross-talk between coagulation and inflammation

      The four pathogenic changes that can interact have been described before in detail. They consist of the triade of death with the addition of soft tissue injuries (chest trauma and extremity injuries, namely those with vascular injury), (Fig. 4) [
      • Hazeldine J.
      Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: a prospective cohort study.
      ]. All four pathways may interact and can stimulate the three remaining pathways, thus inducing separate vicious cycles. One common endpoint exists for these pathways, since all of them lead to a systemic inflammatory response, subsequently to a generalized endothelial damage. In this line, autopsy studies clearly document an increase in organ size and interstitial edema in all organs after severe trauma being the best described organs [
      • Sturm J.A.
      • Wisner H.D.
      Oestern HJ Trentz O Increased lung capillary permeability after trauma: a prospective clinical study.
      ,
      • Lewis F.R.
      • Ellings V.B.
      • Sturm J.A.
      Bedside measurement of lung water.
      ,
      • Shepard G.H.
      • Ferguson J.L.
      • Foster J.H.
      Pulmonary contusion.
      ]. As a result of the pathogenetic changes induced by the initial primary injury, the development of the interstitial edema increases over time, i.e. within the first days. Shock, soft tissue injuries, lung contusions and coagulopathy have been described above in detail.
      Fig. 4
      Fig. 4Four pathogenic changes that interact with each other and may interfere with the clinical course
      [
      • Hazeldine J.
      Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: a prospective cohort study.
      ]
      .
      Severe hemorrhage is also associated with haemostatic abnormalities that have sustained effects on the loss of fibrinogen, on thrombin generation, impaired platelet function - assessed by low admission platelet numbers - and dysregulated fibrinolysis. All these changes interfere with the acid base balance, body temperature and other soft tissue injury hypoperfusion, and have been named the four vicious cycles of polytrauma [
      • Pape H.C.
      • Giannoudis P.
      • Krettek C.
      The timing of fracture treatment in polytrauma patients – relevance of damage control orthopaedic surgery.
      ,
      • Pape H.C.
      • Giannoudis P.V.
      • Krettek C.
      • Trentz O.
      Timing of fixation of major fractures in blunt polytrauma: role of conventional indicators in clinical decision making.
      ,
      • Pape H.C.
      • Rixen D.
      • Morley J.
      • Husebye E.E.
      • Mueller M.
      • Dumont C.
      • Gruner A.
      • Oestern H.J.
      • Bayeff-Filoff M.
      • Garving C.
      • Pardini D.
      • van Griensven M.
      • Krettek C.
      • Giannoudis P.
      E.P.O.F.F. Study Group
      Impact of the method of initial stabilization for femoral shaft fractures in patients with multiple injuries at risk for complications (borderline patients).
      ,
      • Pape H.C.
      • Tornetta 3rd, P.
      • Tarkin I.
      • Tzioupis C.
      • Sabeson V.
      • Olson S.A
      Timing of fracture fixation in multitrauma patients: the role of early total care and damage control surgery.
      ]. Although the low initial platelet count may be a helpful parameter, it is crucial to have a more detailed analysis by conventional or viscoelastic haemostatic assays. Among the management priorities, surgical and nonsurgical techniques are differentiated [
      • Pape H.C.
      • Halvachizadeh S.
      • Leenen L.
      • Velmahos G.D.
      • Buckley R.
      • Giannoudis P.V.
      Timing of major fracture care in polytrauma patients - An update on principles, parameters and strategies for 2020.
      ]. Surgical hemorrhage control is the first line of defense, and paralleled by restoration of circulating blood volume. Although various blood products can be used, there is no international agreement on the optimal composition of transfusion components. Tranexamic acid seems to play a growing role in terms of prehospital and ER use [
      CRASH-2 Trial Collaborators
      Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo- controlled trial.
      ].
      In lung contusions, the following aspects may be relevant: The indirect chest trauma results in immediate regional coagulopathy by activation of the complement system. It has been shown that the direct injury generates the liberation of regional C5a, which correlates with the volume of lung contusion [
      • Hoth J.J.
      • Wells J.D.
      • Jones S.E.
      • Yoza B.K.
      • McCall C.E.
      Complement mediates a primed inflammatory response after traumatic lung injury.
      ]. In both primary lung injury and secondary lung injury, complement-induced upregulation of leukocyte and endothelial adhesion molecules (for example, ICAM-1), together with a degraded pulmonary endothelial glycocalyx, results in the recruitment of leukocytes to the damaged area, a hallmark of ALI and ARDS [
      • Schmidt E.P.
      • et al.
      The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis.
      ] and activation of inflammatory cells that may migrate from the endothelium to the alveoli and induce further secondary inflammation [
      • Niesler U.
      • Palmer A.
      • Radermacher P.
      • Huber-Lang M.S.
      Role of alveolar macrophages in the inflammatory response after trauma.
      ].
      Hypothermia is also relevant, as mmaintaining euthermia when ambient temperature is below this level requires an increase in heat production. Therefore, additional oxygen is needed as substrate. When the ambient temperature is below the thermoneutral zone and tissue oxygen consumption is limited due to hemorrhagic shock, heat production cannot offset ongoing losses, and hypothermia occurs. Decreased thermogenesis is often complicated by anesthetic and paralyzing agents. These can cause a decrease in heat production by as much as one third. Finally, heat loss is also known to be exacerbated by administration of unwarmed intravenous fluids. Due to inadequate blood flow to the thermoregulatory hypothalamus during shock, the set point would be altered to a low temperature level for initiating physiological thermogenesis.
      Markers of the adequacy of shock reversal, such as serum lactate, are measured routinely in major trauma centers. It is undoubted that the shock state must be fully reversed, before definitive fracture surgery is performed. This implies that surgical causes of hemorrhage (e.g. major vascular lesions) are ruled out. The value of initial lactate levels has undergone a change, since Dezman et al. showed that serial measurements of lactate levels are more accurate in the prediction survival than the initial values only (lactate clearance). Therefore, although lactate is a decent acute indicator for acute hemorrhage, it is unable to predict late complications, such as SIRS or MOF [
      • Halvachizadeh S.
      • Baradaran L.
      • Cinelli P.
      • Pfeifer R.
      • Sprengel K.
      • Pape H.C.
      How to detect a polytrauma patient at risk of complications: a validation and database analysis of four published scales.
      ]. Lactate alone can be affected by various metabolites of metabolic acidosis [
      • Moviat M.
      • Terpstra A.M.
      • Ruitenbeek W.
      • Kluijtmans L.A.
      • Pickkers P.
      • van der Hoeven J.G.
      Contribution of various metabolites to the "unmeasured" anions in critically ill patients with metabolic acidosis.
      ] and, given the increasing numbers of elderly polytrauma patients with chronic diseases (such as renal failure), chronically elevated lactate values prevent lactate values alone from being predictive [
      • Kaplan L.J.
      • Frangos S.
      Clinical review: acid-base abnormalities in the intensive care unit – part II.
      ].
      Among multiple factors that can influence the course, hypothermia is known to affect coagulation and should not be addressed alone [
      • Hildebrand F.
      • Giannoudis P.V.
      • van Griensven M.
      • Chawda M.
      • Pape H.-C.
      Pathophysiologic changes and effects of hypothermia on outcome in elective surgery and trauma patients.
      ]. Coagulopathy affects several other pathways, such as the cellular energy turnover, the cardiac effects induced by hypothermia [
      • Pape H.C.
      • Andruszkow H.
      • Pfeifer R.
      • Hildebrand F.
      Options and hazards to use the early appropriate care protocol in trauma patients with major fractures.
      ]. In addition to the static and dynamic parameters listed in Table 4, inflammatory markers have been used although it is evident that the use of a single parameter is insufficient .
      Table 4Parameters relevant to perform a risk profiling for the likelihood of complications (borderline status)
      • Gonzalez E.
      Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays.
      .
      Parameters
      Static parametersInjury combination• Polytrauma ISS > 20 and AIS chest > 2

      • Thoracic Trauma Score (TTS) > grade 2
      Local injury chest• Chest X ray: Bilateral lung contusion: 1st plain film or

      • Chest CT: unilateral bisegmental contusion

      • bilateral  uni- or bisegmental contusion flail chest
      Local injury trunk/extremities• Multiple long bone fractures + truncal injury AIS 2 or more
      Truncal• Polytrauma with abdominal/pelvic

      • trauma RR ,90 mm Hg)

      • (Moore 3) and hem. shock
      Major Surgery for non life saving conditions• “non life saving” surgeries: flexible (day 1, 2, 3) after reassessment according to individual patient physiology:

      • Safe definitive surgery (SDS) or damage control (DCO)
      Duration of 1st operative intervention• Presumed operation time > 6 h

      • intraoperative reassessment:

      • coagulopathy (ROTEM/FIBTEM)

      • lactate (< 2.0 - 2.5 mmol/L)

      • body temperature stable

      • requirement > 3 pRBC / hour
      Dynamic parametersBlood transfusion requirements• Massive transfusion (10 units RBCs per 6 h)

      • initiates “goal directed therapy” (massive transfusion protocols)
      Intra/ perioperative• ROTEM/FIBTEM

      • Lactate clearance < 2.5 mmol/l ( 24 hrs.)
      Table 5Nomenclature for resuscitation strategies and surgical fixation strategies [(Ref.
      • Pfeifer R.
      • Pape H.C.
      Trends in nomenclature to describe concepts in trauma patients: time for standardization.
      )].
      NomenclatureIndicationInjury distribution
      Acute Traumatic Coagulopathy (ATC)Acute hemorrhageUndefined
      Damage control resuscitation (DCR)14Acute hemorrhageUndefined
      Resuscitation associated coagulopathy (RAC)Acute hemorrhageUndefined
      MuST-Surgery: “MusculoSkeletal Temporary Surgery”Unstable major fractureMonotrauma
      Early Total Care (ETC)Unstable major fractureIsolated or multiple fractures
      Damage Control OrthopedicsUnstable major fractureMultiple fractures, Polytrauma
      Early Appropriate Care (EAC)Unstable major fractureIsolated or multiple fractures
      Safe definitive Surgery (SDS)Unstable major fractureMultiple fractures, Polytrauma

      Implications for surgical management

      On arrival of a severely injured patient, it is crucial to differentiate between injuries that require immediate surgical interventions (life saving procedures, usually for hemorrhage control) and those that can be done in planned, semi-urgent fashion [
      • Pape H.C.
      • Pfeifer R.
      Safe definitive orthopaedic surgery (SDS): repeated assessment for tapered application of Early Definitive Care and Damage Control?: an inclusive view of recent advances in polytrauma management.
      ]. After completion of initial assessment (ATLS principles), the treating physician should be aware of whether a patient is at risk for acute hemorrhage, or other issues that may be associated with complications [
      • Pape H.-.C.
      • Regel G.
      • Tscherne H.
      Controversies regarding early musculoskeletal management in the multiple trauma patient.
      ].
      Decision making includes the utilization of several parameters to allow for assessment of the patient, judgement of the surgical procedures required, and the patient perspective. In addition to the anatomical injury description (e.g. ‘severe injury at least in two body regions’), usually scoring systems include several other parameters, such as physiologic variables (hypotension, level of consciousness, acidosis, coagulopathy) [
      • Pape H.C.
      • Lefering R.
      • Butcher N.
      • Peitzman A.
      • Leenen L.
      • Marzi I.
      • Lichte P.
      • Josten C.
      • Bouillon B.
      • Schmucker U.
      • Stahel P.
      • Giannoudis P.
      • Balogh Z.
      The definition of polytrauma revisited: an international consensus process and proposal of the new 'Berlin definition.
      ]. The degree of soft tissue injury has been added and may include chest trauma, severe extremity injury, or complex pelvic trauma. The sum or any of the variable components is relevant for certain risk profiles (Table 6) [
      • Pape H.C.
      • Halvachizadeh S.
      • Leenen L.
      • Velmahos G.D.
      • Buckley R.
      • Giannoudis P.V.
      Timing of major fracture care in polytrauma patients - An update on principles, parameters and strategies for 2020.
      ]. The relevance of a second hit phenomenon is widely accepted. Clinically, multiple causes can induce a second hit. Early after injury, the magnitude of reperfusion injuries in the case of vascular injuries, or the surgical impact has been identified to play a role. At later stages, infectious complications are more frequent, and their secondary complications (pneumonia, Sepsis, septic MOF) are crucial [
      • Teixeira P.G.R.
      Preventable or potentially preventable mortality at a mature trauma center.
      ].
      Table 6Adaptation of patient selection for immediate versus later (>24 hrs) definitive fracture fixation according to the Injury severity score before and after 2000.
      AuthoryearMean ISSMean ISSExplanation
      surgery <24 hsurgery>24h
      ETC/SDSDCO
      Johnson19854953subgroup (ISS > 40)
      Bone198931.831.3randomized
      Charash199425/2724/29chest / no chest injury, ISS
      Bosse1997n.a.n.a.compares nail vs plate
      Bone1998n.a.n.a.compares nail vs plate
      Carlson1998n.a.n.a.reamed vs unreamed nailing
      Scalea200016,826,8Damage Control Orthopaedics
      Nowotarsky2000n.a.n.a.DCO causes no harm
      Taeger200530.437.3ISS difference:6.9 points
      Pape200723.329ISS difference:5.7 points
      Morshed200927.232.3ISS difference:5.1 points
      O'Toole200927.436.2ISS difference:8.8 points
      Nahm201128.836.4ISS difference:7.6 points
      Steinhausen201423.531.1ISS difference:7.6 points
      Dukan2019n.an.a.Patients withISS 16–25
      There have been several changes in the nomenclature to describe treatment surgical concepts in trauma patients. These appear to represent the fact that both, the quality of resuscitation strategies, and the surgical concepts can minimize secondary complications (Table 5) [
      • Pfeifer R.
      • Pape H.C.
      Trends in nomenclature to describe concepts in trauma patients: time for standardization.
      ].

      Extremity injuries

      It appears that the controversy whether all fractures should be stabilized within 24 h after admission (Early Total Care), or a temporizing approach is beneficial in certain subgroups (Damage Control Orthopaedics) has been solved, as most authors agree that major fractures are in the focus of treatment and modifications have been made since the change of the millennium, as listed in Table 5. It summarizes all publications dealing with major extremity fractures as of 2000. They all list the ISS on admission, thus allowing for comparison and it reveals that all available manuscripts use early definitive fracture fixation in patients with more moderate injury severity scores, suggesting that process of clearance for surgery has been installed.
      More recently, clear cut parameters were described based on the calculation in larger patient populations. O'Toole was the first to define endpoints of resuscitation to assess whether the initial operation for a major fracture should include definitive fixation, or a temporizing approach [
      • O'Toole R.V.
      • O'BrienM Scalea TM
      • Habashi N.
      • Pollak A.N.
      • Turen C.H
      Resuscitation before stabilization of femoral fractures limits acute respiratory distress syndrome in patients with multiple traumatic injuries despite low use of damage control orthopedics.
      ]. Vallier et al. introduced the Early Appropriate Care protocol and utilized parameters of the acid base status on admission to rule out patients that underwent insufficient resuscitation [
      • Vallier H.A.
      • et al.
      Early definitive stabilization of unstable pelvis and acetabulum fractures reduces morbidity.
      ]. Later, Dezman et al. describe that serial lactate levels are helpful in determining patients at risk and coined the term “lactate clearance” [
      • Dezman Z.D.W.
      • Corner A.C.
      • Smith G.S.
      • Hu P.F.
      • Mackenzie C.F.
      • Scalea T.M.
      • et al.
      Repeat lactate level predicts mortality better than rate of clearance.
      ]. The Safe Definitive Surgery uses components indicative of four pathogenetic cycles to separate borderline from unstable patients [
      • Pape H.C.
      • Pfeifer R.
      Safe definitive orthopaedic surgery (SDS): repeated assessment for tapered application of Early Definitive Care and Damage Control?: an inclusive view of recent advances in polytrauma management.
      ,
      • Tscherne H.
      • Regel G.
      • Pape H.-.C.
      • Pohlemann T.
      • Krettek C.
      Internal fixation of multiple fractures in patients with polytrauma.
      ].
      Historically, the number of blood units administered were used as one of the markers for adverse outcomes [
      • Wilson R.F.
      • Dulchavsky S.A.
      • Soullier G.
      • Beckman B.
      Problems with 20 or more blood transfusions in 24 h.
      ]. With the implementation of defined resuscitation protocols, the adverse outcomes have been reduced [

      Stein P, Kaserer A, Sprengel K, Wanner GA, Seifert B, Theusinger OM, Spahn DR. Anaesthesia. 2017 Nov;72(11):1317-1326. doi:10.1111/anae.13920. Epub 2017 May 23.

      ].
      It appears that the most important change from the surgical principles to stabilize long bone fractures is from a rather strict concept of day 1 surgery (window of opportunity) became more modular. Days 2 to 5 after injury were believed to be unsafe, as they were thought to be most vulnerable in terms of the inflammatory cascade [
      • Pape H.C.
      • Barthels M.
      • van Griensven M.
      • Krettek C.
      • Das Gupta R.
      • Tscherne H
      Biochemical changes following trauma and skeletal surgery of the lower extremity – quantification of the operative burden.
      ]. Along with improvements in resuscitation, inflammatory control and coagulation management, the approach has become more modular, with the focus on stabilizing the osseous injury with the highest potential for systemic impact first. As not all fractures are addressed during day one anymore, it is then possible to sequentially stabilize fractures as soon as the physiology is stable, regardless the day of injury [

      Stein P, Kaserer A, Sprengel K, Wanner GA, Seifert B, Theusinger OM, Spahn DR. Anaesthesia. 2017 Nov;72(11):1317-1326. doi:10.1111/anae.13920. Epub 2017 May 23.

      ] (Fig. 5).
      Fig. 5
      Fig. 5Fixation of major fractures is not performed during a “window of opportunity” any more, but tapered to the patient condition any day during the first week
      [

      Stein P, Kaserer A, Sprengel K, Wanner GA, Seifert B, Theusinger OM, Spahn DR. Anaesthesia. 2017 Nov;72(11):1317-1326. doi:10.1111/anae.13920. Epub 2017 May 23.

      ]
      .
      Due to repeated re-evaluation and assessment of patients regarding their physiology, dynamic classification and adaptation of the treatment strategy is achieved. The current understanding avoids the use of a “window of opportunity”, where surgery was avoided on days 2-4 after injury. Instead, the Safe definitive Surgery approach focuses on the initial suriocal hemorrhage control, followed by daily reassessments and daily decision making regarding further fixation of major fractures.
      Finally, in intraarticular fractures, those with sustained soft tissue injuries, or severely open fractures, the terminology of temporizing fracture fixation should be independent of the one describing the general condition of a polytrauma patient on admission, as temporary external fixation may be recommended for isolated musculoskeletal injuries [

      Pfeifer R, Kalbas Y, Coimbra, R Leenen L, Komadina R, Hildebrand F, Halvachizadeh S, Akhtar M, Peralta R, Fattori L, Mariani D, Hasler R, Lefering R, Marzi I, Pitance F, Osterhoff G, Volpin G, Weil Y, Wendt K, Pape H-C. Indications and interventions of damage control orthopedic surgeries: an expert opinion survey. Eur J Trauma Emerg Sur. 2021 Dec;47(6):2081-2092 doi:10.1007/s00068-020-01386-1.

      ]. Among these are fractures accompanied by severe closed soft tissue injuries, severe vascular injuries, open fractures with gross bacterial contamination, sustained segmental bone loss and complex articular fractures. In these cases, although patients are physiologically stable, an indication for a staged procedure exists. This concept closed the gap of listing indications, as had been done previously for truncal injuries [
      • Roberts D.J.
      • Bobrovitz N.
      • Zygun D.A.
      • Ball C.G.
      • Kirkpatrick A.W.
      • Faris P.D.
      • et al.
      Indications for use of damage control surgery in civilian trauma patients: a Content analysis and expert appropriateness rating study.
      ].

      Pelvic ring injuries

      In patients with pelvic ring injuries, the instability may be the primary reason for hemodynamic instability and surgical hemorrhage control should be part of the resuscitation strategies. Usually, most bleeding is associated with the injury to the posterior pelvic ring, thus requiring special attention. According to local preferences, the treatment may entail the use of “anti shock” C clamp or “rescue screws”, others have described to apply posterior compression even through anterior external fixators [
      • Sellei R.M.
      • Schandelmaier P.
      • Kobbe P.
      • Knobe M.
      • Pape H.C.
      Can a modified anterior external fixator provide posterior compression of AP Compression type III pelvic injuries?.
      ]. Although the latter strategy has not made it to widespread acceptance, and although some centers continue to include angioembolization as their first line of defense, addressing the posterior pelvic ring has become the routine for most centers. In those that use pelvic packing, their protocol may foresee closing the anterior pelvic ring as well after posterior hemorrhage has been controlled if the patient is improving [
      • Höch A.
      • Zeidler S.
      • Pieroh P.
      • Josten C.
      • Stuby F.M.
      • Herath S.C.
      German Pelvic Trauma Registry Trends and efficacy of external emergency stabilization of pelvic ring fractures: results from the German Pelvic Trauma Registry.
      ].

      Conclusion

      Decision making should be performed rapidly and may be subject to revision before, during or after the first surgical phase. Some trigger factors are known that require damage control or abbreviated surgeries. Among these are severe head and chest trauma, multiple fractures if the patient is unstable, or uncontrollable exsanguination. Damage control orthopaedics is recommended for an unstable patient or a patient in extremis, and it has some utility for the borderline patient as well. Specific injury combinations for which damage control orthopaedics should be considered are femoral fractures, if bilateral, pelvic ring injuries with profound hemorrhage, and multiple injuries in elderly patients.
      This process of decision-making may be defined as “injury-patient tailored” for damage control orthopedics, e.g. a Safe Definitive Surgery approach. Regarding this strategy, it continues to be essential to validate prognostic criteria, as achieved in scores. Further studies should be undertaken to better understand the role of damage control orthopaedics in the treatment of patients that sustained a combination of orthopedic trauma and concomitant injuries to the chest and head.

      Source of funding

      No funding was received.

      Declaration of Competing Interest

      None of the authors have any conflicts of interest to declare.

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