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Combined Hemorrhage/Trauma Models in Pigs—Current State and Future Perspectives

Hildebrand, Frank*; Andruszkow, Hagen*; Huber-Lang, Markus; Pape, Hans-Christoph*; van Griensven, Martijn

doi: 10.1097/SHK.0b013e3182a3cd74
Review Article
Editor's Choice

ABSTRACT: The majority of injury combinations in multiply injured patients entail the chest, abdomen, and extremities. Numerous pig models focus on the investigation of posttraumatic pathophysiology, organ performance monitoring and on potential treatment options. Depending on the experimental question, previous authors have included isolated insults (controlled or uncontrolled hemorrhage, chest trauma) or a combination of these injuries (hemorrhage with abdominal trauma, chest trauma, traumatic brain injury, and/or long-bone fractures). Combined trauma models in pigs can provide a high level of clinical relevance, when they are properly designed and mimicking the clinical situation. Most of these models focus on the first hours after trauma, to assess the acute sequel of traumatic hemorrhage. However, hemorrhagic shock and the associated mass transfusion are also major causes for organ failure and mortality in the later clinical course. Thus, most models lack information on the pathomechanisms during the late posttraumatic phase. Studying new therapies only during the early phase is also not reflective of the clinical situation. Therefore, a longer observation period is required to study the effects of therapeutic approaches during intensive care treatment when using animal models. These long-term studies of combined trauma models will allow the development of valuable therapeutic approaches relevant for the later posttraumatic course. This review summarizes the existing porcine models and outlines the need for long-term models to provide real effective novel therapeutics for multiply injured patients to improve organ function and clinical outcome.

*Department of Orthopedic Trauma, and Harald Tscherne Research Laboratory for Orthopedic Trauma, University of Aachen, Aachen; Department of Orthopedic Trauma, Hand-, Plastic- and Reconstructive Surgery, University of Ulm, Ulm; and Department of Experimental Trauma Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany

Received 20 May 2013; first review completed 10 Jun 2013; accepted in final form 5 Jul 2013

Address reprint requests to Frank Hildebrand, MD, Department of Orthopedic Trauma, University of Aachen, Pauwelsstrasse 30, 52075 Aachen, Germany. E-mail:

The authors have no conflicts of interest to declare.

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Clinical entity

According to epidemiologic data of different trauma databases, most injury distributions in multiply injured patients affect the head, the abdomen, the chest, and long bones (1, 2). For each injury, certain mortality rates have been shown. In this context, traumatic brain injury (TBI) and abdominal trauma represent the leading causes for early mortality (<24 h) after multiple trauma. The probability of having concomitant intra-abdominal lesions is increased by the factor 7.6 when associated chest trauma is present. Likewise, it has been reported that in about 66% of the cases, abdominal trauma is accompanied by an additional chest trauma (3). Severe chest trauma with subsequent lung contusions is associated with enhanced incidence of respiratory insufficiency and hemodynamic failure. This leads to increased mortality of up to 30%, which is higher when no severe chest trauma is present (4). Besides the direct consequences of lung contusions on pulmonary function, the lung represents a primary target organ for secondary damage due to the systemic inflammatory response after hemorrhagic shock and multiple trauma (5). Therefore, there seems to be a further important relationship between severe bleeding related to abdominal trauma and pulmonary function.

Besides their impact on early mortality, chest and abdominal trauma also represent significant risk factors for the development of multiple organ dysfunction syndrome (6, 7). Multiple organ dysfunction syndrome still represents the major cause of late deaths after severe trauma, having an incidence of 15% and a subsequent mortality of 24% in the overall trauma population (8).

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In vivo models for mimicking the clinical entity

Because of the clinical relevance of the trauma entities described above and the associated hemorrhagic shock for early and late complications, multiple large animal models have been developed to address this issue. The majority of experiments were performed in pig models because of their similarity to humans (9–14). The physiologic response to TBI, hemorrhage, and lung contusion simulates the human physiologic response more closely than any other nonprimate. Immature swine were shown to have cardiovascular, cerebrovascular, hematologic, and electrolyte profiles that are almost identical to those in young humans (15). Furthermore, ventilation parameters and the immunological system exert significant similarities to the human situation. However, the coagulation system, as an important entity during the posttraumatic period, shows significant differences. Extensive research has been performed in hemorrhagic shock models over the last decades. An additional focus on posttraumatic changes of pulmonary function can be observed since 25 years. The studies focused either on the investigation of pathophysiologic mechanisms of trauma or on the potential benefits of a wide spectrum of treatment options. Depending on the experimental question, the study focused either on isolated insults (e.g., controlled or uncontrolled hemorrhage, chest trauma) or on a combination of these injuries (hemorrhage with abdominal trauma [liver and/or spleen laceration] and/or chest trauma).

In general, diverse criteria for a relevant trauma model have been summarized by Cho et al. (16) and by the recommendations of the 2000 Military Medicine Workshop on Animals Models in Hemorrhage and Resuscitation Research (16, 17). Key points are as follows: (a) the need for models that have the potential for uncontrolled bleeding, (b) surgical manipulation coinciding with hemorrhage seen clinically, (c) significant soft-tissue injury to better approximate the postinjury inflammatory state, and (d) the severity of trauma with lethality that closely mimics clinical situations. Finally, the duration of hypotension before resuscitation should be comparable to the clinical scenario. Majde et al. (17) underlined these findings by indicating that the induction of a defined and reproducible trauma with sufficient hemorrhage is a key factor in the development of a relevant animal trauma model. Furthermore, it is important to adapt the duration of hypotension before resuscitation to the clinical scenario (17). Furthermore, despite the similarities between humans and pigs in the response to hemorrhagic shock, the species-specific differences (coagulation system, different receptor status for drugs, etc.) require further studies. In this context, an impaired oxygenation has been observed in the nonphysiologic supine position because of increased edema formation and higher ventilation/perfusion heterogeneity (18–20).

In this review, the authors aim to provide an overview of isolated or combined trauma models in swine characterized over the last two decades. A special focus was set on long-term models suitable to investigate therapeutic approaches for the prevention and treatment of late posttraumatic complications (multiple organ dysfunction syndrome, sepsis). In this review, a focus was set on a critical analysis and a comparison of the methodological background (controlled vs. uncontrolled vs. combined trauma model) rather than an assessment of the importance or relevance of every single study. The authors feel that this approach might be more feasible as the conditions of every study are a little different, because in every case, the purpose of the study or the experimental question is a little different. Therefore, it seems that every model has strengths and weaknesses and that there is no intrinsic value to a model, per se. The same model could either be good or bad, depending on the experimental question (e.g., focusing either on fundamental pathophysiologic mechanisms or therapeutic interventions).

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One has to differentiate between controlled and uncontrolled hemorrhage. The former can be divided in pressure-controlled and volume-controlled hemorrhage. Regardless of a controlled or uncontrolled approach, some studies performed a splenectomy before induction of trauma hemorrhage to prevent autotransfusions from pooled blood in the spleen that is well known in pigs (21).

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The pathophysiology following hemorrhagic shock includes endocrine, cardiovascular, coagulatory, and immune responses. Therefore, the induction of a well-defined and reproducible trauma that includes significant hemorrhage is a significant factor in the establishment of a relevant trauma model. There are also some studies that to some extent combine pressure and volume control by choosing either a primary volume-controlled setup (e.g., withdrawal of 35% of the total blood volume), which will be stopped when a specific mean arterial blood pressure (MAP) falls below a specific limit (22), or vice versa (23).

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Differences in models of volume controlled vs. pressure controlled

Most porcine models use a volume-controlled shock and withdraw a defined blood volume over a set period after anesthesia (Table 1). The advantage of a volume-controlled model is the ability to assess compensatory hemodynamic mechanisms. However, as the degree of hypotension is not well defined, it also offers some disadvantages (14, 24). In most studies, a 30% to 50% reduction in total blood volume has been induced, resulting in mortality rates up to 20% (22, 25–28). However, depending on the study design as lethal models, mortality rates of up to 100% have been described (10, 12, 29, 30). Some volume-controlled hemorrhage models focused on the effects of resuscitation fluids (12, 22, 31); others observed the effects of hypothermia on outcome (10, 26, 29, 32).

However, Gomez et al. (33) proposed that a defined level of hypotension driven by blood pressure measurements might be clinically more relevant than volume-controlled hemorrhage. The degree and duration of hypotension can be better controlled as blood pressure can be reliably measured, and the blood volume is an estimation, and the remaining volume cannot be measured online. The majority of the studies had a target MAP between 30 and 45 mmHg, which was generally maintained for 30 to 45 min (33–35). Only in a study by Roch et al. (36) the time to resuscitation was 120 min, which is clinically less relevant.

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Pressure-controlled hemorrhage

Pressure-controlled hemorrhage has been used to investigate physiologic mechanisms and organ dysfunction depending on the intensity of hypotension. However, variable outcomes are possible despite constant hypotension. This may be due to interindividual differences in cardiovascular reserves. Gomez et al. (33) also stated that pressure-controlled models might be advantageous, as the MAP rather than the volume of blood loss is available clinically. However, the use of pressure-controlled hemorrhage also has some negative side effects. To keep the artificial pressure point at the set level, decompensation of the individual animal might occur at different time points. This might result in more blood withdrawal when the animal compensates or various amounts of resuscitation in case of decompensation. Furthermore, despite a set pressure, these models might also exert various effects on the physiologic and immunologic response. An additional disadvantage is the artificial nature of pressure control, as the animals are bled to a predetermined fixed pressure and are maintained at that pressure for a fixed time period. This does not resemble the clinical situation of traumatized patients.

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Problems of controlled models

Independently of the use of volume- or pressure-controlled models, there is usually minimal decompensation if no exsanguination of the animal is performed. Furthermore, decompensation from isolated hemorrhage might in general be recoverable without many consequences when resuscitation is performed with shed blood or fresh whole blood. The observed disturbances in the models are significantly influenced by the method and content of resuscitation (e.g., crystalloids or artificial colloids). The absence of uncontrolled sources of bleeding (e.g., solid organ injuries) has been identified as a further limitation of studies with controlled hemorrhagic shock as no ongoing bleeding is observed, which is in contrast to the clinical setting with uncontrolled sources of bleeding at the time of resuscitation. Furthermore, the long-term coagulopathic effects of hemodilution or hypothermia may complicate the management of uncontrolled bleeding from sources such as the liver (37–39). Accordingly, Skarda et al. (34) recommended to perform studies in uncontrolled hemorrhage models before the results of resuscitation strategies obtained in controlled hemorrhage studies can be implemented in the clinical setting.

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Although volume- and pressure-controlled models of hemorrhagic shock offer a controlled induction of blood loss, the model of uncontrolled hemorrhage has been suggested to closely mimic the clinical situation of traumatized patients, particularly in regard to therapeutic options. Furthermore, the possible combination with a soft-tissue trauma seems to be a major advantage of uncontrolled hemorrhage models, as the absence of solid organ or tissue injuries has been identified as a major limitation for clinical relevance of a study (38, 39).

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Models of uncontrolled hemorrhage

Numerous methods have been used to induce uncontrolled hemorrhage, such as injuries to the liver, spleen, aortic lesions, or other vessel injuries (Table 2). To generate uncontrolled hemorrhage as reproducible as possible, the authors aimed to standardize their traumatic insults. In this context, Grottke et al. (9) developed a model that allows for the induction of reproducible liver injuries with different degrees of severity resulting in comparable parenchymal damage. A standardized spleen injury used by Avaro et al. (40) has been shown to induce uncontrolled hemorrhage with severe hypovolemic shock (Table 2).

In uncontrolled models of hemorrhage, a focus has been put on the timing, volume, and nature of resuscitation fluid given after shock (41–43). Furthermore, the effectiveness of different inotropic substances has been compared with each other or with isolated fluid resuscitation (44, 45). In these studies, the time period until resuscitation was between 30 and 60 min (mortality up to 100%) (Table 2). Uncontrolled hemorrhage models are also frequently used for the effectiveness of locally applied hemostatic dressings. In most of these studies, severe hepatic injuries were induced, and the observation time was between 1 and 3 h (34). The mortality rate (0%–100%) was significantly influenced by the type of the applied dressing (46–50). Further studies of uncontrolled hemorrhage focused on the effects either of different coagulation factors or of induced hypothermia on blood loss, resuscitation requirements, and outcome (9, 38, 51, 52).

Achieving a state of coagulopathy in pigs is known to be rather difficult and is therefore not reflecting the clinical situation in humans (13, 53). Therefore, some studies performed some hemodilution before the induction of injury to induce and standardize coagulopathy, which does not fully reflect the clinical situation (9, 13, 51, 54).

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Comparison of the different hemorrhage models

However, despite the frequent use of uncontrolled hemorrhage, these models are also believed to exert some clear disadvantages in terms of standardization and reproducibility, as they introduce a degree of physiologic variability in addition to the biological variability.

Taken together, it seems to be important to establish a balance between clinical relevance and the need to optimize experimental standardization and reliability. As animal models are used to investigate either pathogenetic mechanisms or preclinical assessment of therapies, Majde et al. (17) proposed that studies have to focus on standardization and reproducibility in case of pathophysiologic questions. Therefore, pressure- and volume-controlled models should be preferred to uncontrolled hemorrhage. Furthermore, it is probably important to allow the animals to fully recover in pathogenesis models (17). In preclinical models assessing therapeutic strategies, the use of uncontrolled hemorrhage seems to be of major importance.

However, a model of hemorrhage without significant additional tissue trauma is unlikely to predict the response to therapy in any clinical setting, as tissue injury alters the response to hemorrhage. Therefore, combined trauma models might be most valuable to the clinical setting of traumatized patients.

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The implementation of a combined trauma model in large animals is challenging. On the one hand, the severity of different insults has to be adapted, as an extensive burden of trauma is too severe. On the other hand, the severity of the single insult as well as of the combined trauma has to be severe enough to measure any potential benefit of therapeutic approaches. In this context, Davis and Kaups (55) failed to detect a therapeutic benefit in a pulmonary contusion model if the inciting injury is not severe enough.

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Models with hemorrhage combined with brain, chest, or abdominal trauma

Indeed, a variety of large animal models combine different aspects of severe trauma. Because of the high clinical incidence and impact of chest trauma as well as the role of the lungs as a crucial shock organ, diverse studies have combined a blunt chest trauma with controlled hemorrhage (21, 37, 56–60). In these models, blunt chest trauma was combined with either pressure-controlled hemorrhage (with a MAP between 20 and 30 mmHg) (23, 37, 56) or a volume-controlled hemorrhage (with blood withdrawals between 10 and 45 mL/kg body weight [BW]) (57–61) (Table 3). The duration of the shock period was between 30 and 90 min. Depending on these variables and the therapeutic approach, a mortality rate between 0% and 65% was observed. It can be assumed that a significant tissue trauma is included, and the induction of controlled hemorrhage results in a high extent of standardization in these models.

Comparable to chest trauma, also TBI has been combined with controlled and/or uncontrolled hemorrhage (15, 62–68). In these studies, TBI was induced by either a fluid percussion or a cryogenic impact (Table 4). The severity (pressure-controlled models with MAP between 20 and 50 mmHg; volume-controlled models with 30%–45% of total blood volume) and the duration of shock (period, 15–120 min) differed among the studies according to the study aim. Overall, a mortality rate between 0% and 100% was observed.

However, the absence of solid organ injuries in the previously mentioned studies represents a potential limitation, as posttraumatic coagulopathy has the potential to complicate bleeding control from nonvascular sources such as the liver. In a study by Feinstein et al. (37), chest trauma was combined with an abdominal trauma with hepatic injury for induction of uncontrolled hemorrhagic shock. This injury is also prone to bleeding in the further study period. This setup might closely reflect the clinical situation of traumatized patients and incorporate the high clinical coincidence of abdominal and chest trauma (37) (Table 3). However, in terms of standardization and reproducibility, there seem to be some weaknesses. This is of special importance as it is assumed that a combined trauma model itself is more difficult to reproduce because of the variances of each separate entity (9).

Because of these weaknesses, other studies have added a controlled hemorrhage as an additional insult to an abdominal trauma or to a combined chest/abdominal trauma. This might result in an improved reproducibility in combined trauma models. In general, a MAP between 35 and 50 mmHg was targeted. The duration of the shock period was between 30 and 90 min with a mortality rate between 0% and 30%, depending on the chosen variables and the therapeutic approaches (21, 23, 69, 70) (Table 3). In summary, abdominal trauma with hepatic injury can serve as a source of uncontrolled bleeding and as an indicator for potential coagulation disorders with secondary bleeding in these multisystem injury models. However, the induced insults have to be analyzed carefully in the combined trauma models. In a recently published pig model, a combination of a single rib fracture with abdominal trauma and hemorrhagic shock has been established (70). However, the rib fracture was mainly used to create a soft-tissue trauma in absence of a hypoxia period and not to induce a significant chest trauma. Therefore, this model can only partly be regarded as a combined chest and abdominal trauma model.

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Combined models with fractures

Because of the high incidence of fractures of the extremities in multiple-trauma patients (>60%), some combined trauma models also include a long-bone fracture (tibia or femur) (16, 70–74) (Table 3). Because of the significance of an additional tissue injury for a clinically relevant response to a combined traumatic insult, the implementation of fractures seems to be reasonable. Furthermore, these models might be used for the evaluation of individualized treatment strategies (e.g., timing of definitive fracture stabilization).

In conclusion, combined trauma models are clinically relevant to investigate pathophysiologic changes of organ and immune function after multiple traumas. However, the insults themselves as well as their severity have to be thoroughly selected to create a valid and reliable model. Furthermore, possible limitations have to be considered before transferring results from these models to the clinical setting.

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Translating the results of experimental studies to the clinical application has been challenging, indicating the need for a better understanding of the models being used and their potential limitations. In general, the source of the animals, the availability and experience of personnel, the environmental parameters of the laboratory (e.g., humidity, temperature, light intensity), the conduct of experiments (sample size), and the variability in equipment and laboratory testing have been identified as potential reasons for variability in developing animal models (13, 16, 51, 75, 76). Furthermore, specific animal differences, such as sex and age, have to be considered as significant influencing factors for the results of experimental studies. Age has been shown to have a significant impact on the posttraumatic response after different types of injuries. Sheehy et al. (77) were able to show that juvenile pigs demonstrated a significantly different immunological response compared with older animals. Furthermore, TBI resulted in an increased cerebral blood flow in young animals, whereas it was decreased in older pigs (78). In further studies, female sex was associated with protective effects on the posttraumatic course after diverse traumatic impacts (79, 80). In addition, also 17β-estradiol exerted beneficial effects after severe trauma, such as hemorrhage and lung injury, in diverse experimental models (81–84).

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Differences between the models and the clinical situation

Furthermore, the complexity of experimental models, although providing clinical reality, adds many variables that might significantly influence the results. Despite the similarities between humans and pigs in the response to hemorrhagic shock, the species-specific differences and impairments due to experimental necessities need further attention. Among these are coagulation, responses to vasopressors, and immunologic differences. Coagulation disorders in multiple-trauma patients are part of the lethal triad and therefore are investigated by many researchers. However, it is well known that it is difficult to achieve a state of coagulopathy in pigs. Therefore, data about posttraumatic coagulation disorders and the transferability to the human situation have to be interpreted carefully (13, 26, 53, 74, 85). Some studies therefore induced hemodilution before the injury to generate a standardized coagulopathy, which clearly neither mimics the clinical situation (9). In addition, different vasopressin receptors exist in pigs and humans that may result in a different hemodynamic response to exogenously administered vasopressin (37, 44). Porcine granulocytes should not be considered representative for the human setting because of differences of elastase release and activity. Furthermore, the reticuloendothelial system in swine is located in the pulmonary region, which is in contrast to the situation in humans. This might have significant effects, e.g., on the pulmonary artery pressure in specific situations (86).

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Differences because of experimental setup

Besides the differences between pigs and humans, there are also necessities due to the experimental setup that need further attention. The use of anesthesia and mechanical ventilation before, during, and immediately after the insults due to ethical reasons as well as the performance of laparotomy before the splenic or hepatic injury are different from the clinical situation. Anesthesia can mask many features of the stress responses to hemorrhage and resuscitation by its effects on sensorimotor and cardiovascular function and metabolic demands (9, 54, 56). Early mechanical ventilation with administration of positive pressure ventilation might ameliorate the progression of pulmonary failure especially in models with experimental chest trauma. Furthermore, adjustment of the ventilation parameters to maintain normocapnea to mimic the intensive care unit (ICU) situation might complicate the interpretation of oxygenation, work of breathing, and peak inspiratory pressure. Pastore et al. (20) were able to show that the nonphysiologic supine position results in a significant formation of lung edema, which has clearly been related to an increase in pulmonary arterial pressure. Furthermore, an impaired oxygenation has been described because of increased ventilation/perfusion heterogeneity. In this context, impaired ventilation and increased perfusion of dorsal regions have been described (18, 19). Another potential flaw in the design of experimental studies might be obtaining of multiple bronchoalveolar lavages with a repetitive disconnection from the ventilator. In this context, frequent saline lavage has been reported to induce lung injury (55). The application of diverse drugs and infusions might have the potential to modulate cellular injury and influence survival. Anesthetic and analgesic drugs are of course required because of the nature of the invasive procedures; however, they might exert significant depressive effects on cardiovascular function (87). In addition, interactions of these substances with the inflammatory response have been demonstrated (88). Ketamine has been shown to reduce the inflammatory response with decreased systemic levels of proinflammatory cytokines (89–95). Locally, it interferes with the determinants of primary immunity preventing the exacerbation and extension of local inflammation (88).

Other confounders might be the use of heparin, which influences blood viscosity, the release of vasoactive agents, the synthesis of cytokines, endothelial cell interactions, the coagulation as well as the complement cascade, and the transfusion need of autologous blood (24). Clinically, the effects of donated blood that has been separated into packed red blood cells and then stored for a prolonged period have been demonstrated to alter significantly the posttraumatic response (96).

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Besides the aforementioned limitations, many authors stated that real long-term trauma models are missing that accurately simulate the natural clinical trajectory of trauma. In most experimental studies, time frames were selected that closely reflect the clinical setting resulting in a focus on the first hours after trauma (Tables 1–3). In this context, the posttraumatic observation period of multiple studies was between 2 and 6 h, whereas the hospital course of a patient who faced similar injuries regularly lasted for days and weeks (56). Accordingly, it has been shown in a pig model of pulmonary contusion that it takes more than 8 h to observe involvement of the noncontused lung (97), whereas experimental pulmonary contusion did not result in hypoxemia during a shorter experimental period of 4 h (59). It therefore has to be assumed that long-term consequences (e.g., susceptibility to pneumonia or development of adult respiratory distress syndrome of isolated or combined trauma) are missed by a majority of the published models (37).

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Studies with long-term observation

Only a very limited number of studies included an observation period of up to 24 h in intubated animals (21–23, 34, 57, 69). In some other experiments, animals were extubated after up to 24 h and then observed for several days in an awake state (21, 22, 28, 44, 47, 69, 98, 99). However, this does not really mimic the clinical situation of most of the multiply injured patients who are intubated and treated on the ICU for several days. Thus, the need of further studies with a longer observation period under intensive care conditions has been pointed out by many authors (48, 50, 71). De Castro et al. (48) stated that the survival and the success of their therapeutic approach for bleeding control in hepatic injury have to be investigated for a significantly longer period (up to 96 h). Various other studies agree and state that—due to the limited experimental and observation time—no valid and reliable assessments on kinetics of functional recovery or deterioration of endothelial or organ function, kinetics of the immune response, long-term treatment effects, or compensation mechanisms are possible (54, 76, 100). For example, posttraumatic apoptosis has been described to occur relatively late following tissue challenge, and it was shown that the process continues for up to 3 days. Hypothermia seems to affect this apoptotic process including the inhibition of activation of caspase enzymes and the preservation of mitochondrial function (101). To investigate the apoptotic cascade as a therapeutic target after multiple trauma (e.g., by modulation of the body temperature), long-term models seem to be of major importance. Furthermore, severe trauma has been associated with immune dysfunction not only in the early posttraumatic course but also in later stages. In this context, little is known about the long-term effects of the activation of the complement system. It has been described that the early excessive activation of the complement system results in a complementopathy, which is associated with an immunosuppression. However, the long-term effects of this complementopathy on organ function are also unknown (102). Toll-like receptors (TLRs) play a key role in the recognition of pathogen-associated molecular patterns and are found on diverse cells of the innate immune system (e.g., monocytes/macrophages, dendritic cells, polymorphonuclear granulocytes). Trauma and infections result in an activation of the TLRs and their coreceptor CD14, which recruit the adaptor molecule MyD88 for intracellular signal transduction with activation of transcription factors. This finally results in a humeral and cellular inflammatory response (103). Long-term effects of this early TLR activation as well as therapeutic strategies for modulation of the early posttraumatic immune response (e.g., blockade of C5a and/or CD14) are not well described.

The performance of extended experiments comprises significant challenges and possible limitations. These include logistic necessities and the associated costs. In this context, both personnel with clinical and scientific experience in intensive care medicine and trauma surgery and adequately equipped facilities are needed to ensure that the observed pathologies are not iatrogenic. It also has to be taken in account that growth might be an important issue in swine when observing long-term outcomes with observation periods of several weeks. However, this aspect might be of minor importance in models with a study period of several days.

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In conclusion, diverse combined trauma models in pigs exist indicative of high clinical relevance. The majority of these animal models have been designed to focus on the first hours after trauma. It is well known that a significant number of deaths associated with hemorrhage occur in this period. Only a very limited number of studies have a longer observation period of up to 24 h. This might be not enough to resemble the clinical situation with a mean duration of mechanical ventilation of 5.6 ± 10.4 days and a stay on the ICU of 9.7 ± 12.9 days (104). Consequently, there is a strong demand for long-term studies in combined trauma models with a high degree of validity and reliability. Despite the high costs and the significant logistic challenges of long-term experiments, sample sizes should not be compromised to detect differences between study and control groups (51, 75, 76). Only then that real effective novel therapeutics can be provided for multiply injured patients to improve organ function and clinical outcome.

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The authors thank Fritz Seidl, MA, Interpreting and Translating, for copy editing our manuscript.

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Hemorrhage; chest trauma; abdominal trauma; long-bone fracture; pigs

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