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