Combined Hemorrhage/Trauma Models in Pigs—Current State and Future Perspectives
Hildebrand, Frank*; Andruszkow, Hagen*; Huber-Lang, Markus†; Pape, Hans-Christoph*; van Griensven, Martijn‡
*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: email@example.com.
The authors have no conflicts of interest to declare.
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.
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).
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).
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).
CONTROLLED HEMORRHAGE (VOLUME OR PRESSURE CONTROLLED)
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).
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.
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.
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.
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).
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).
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.
COMBINED TRAUMA MODELS
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.
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.
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.
LIMITATIONS OF EXISTING TRAUMA MODELS
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).
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).
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).
NEED FOR LONG-TERM TRAUMA MODELS
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).
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.
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.
1. Boulanger L, Joshi AV, Tortella BJ, Menzin J, Caloyeras JP, Russell MW: Excess mortality, length of stay, and costs associated with serious hemorrhage among trauma patients: findings from the National Trauma Data Bank. Am Surg 73 (12): 1269–1274, 2007.
2. Wutzler S, Wafaisade A, Maegele M, Laurer H, Geiger EV, Walcher F, Barker J, Lefering R, Marzi I: Lung Organ Failure Score (LOFS): probability of severe pulmonary organ failure after multiple injuries including chest trauma. Injury 43 (9): 1507–1512, 2012.
3. Lindner T, Bail HJ, Manegold S, Stockle U, Haas NP: Shock trauma room diagnosis: initial diagnosis after blunt abdominal trauma. A review of the literature [in German]. Der Unfallchirurg 107 (10): 892–902, 2004.
4. Waydhas C: Thoracic trauma [in German]. Der Unfallchirurg 103 (10): 871–889, 2000; quiz 890, 910.
5. Mommsen P, Barkhausen T, Frink M, Zeckey C, Probst C, Krettek C, Hildebrand F: Productive capacity of alveolar macrophages and pulmonary organ damage after femoral fracture and hemorrhage in IL-6 knockout mice. Cytokine 53 (1): 60–65, 2011.
6. Waydhas C, Gorlinger K: Coagulation management in multiple trauma [in German]. Der Unfallchirurg 112 (11): 942–950, 2009.
7. Huber-Wagner S, Qvick M, Mussack T, Euler E, Kay MV, Mutschler W, Kanz KG: Massive blood transfusion and outcome in 1062 polytrauma patients: a prospective study based on the Trauma Registry of the German Trauma Society. Vox Sang 92 (1): 69–78, 2007.
8. Dewar DC, Tarrant SM, King KL, Balogh ZJ: Changes in the epidemiology and prediction of multiple-organ failure after injury. J Trauma Acute Care Surg 74 (3): 774–779, 2013.
9. Grottke O, Braunschweig T, Philippen B, Gatzweiler KH, Gronloh N, Staat M, Rossaint R, Tolba R: A new model for blunt liver injuries in the swine. Eur Surg Res 44 (2): 65–73, 2010.
10. Takasu A, Norio H, Gotoh Y, Sakamoto T, Okada Y: Effect of induced-hypothermia on short-term survival after volume-controlled hemorrhage in pigs. Resuscitation 56 (3): 319–328, 2003.
11. Hauser CJ: Preclinical models of traumatic, hemorrhagic shock. Shock 24 (Suppl 1): 24–32, 2005.
12. Burns JW, Baer LA, Darlington DN, Dubick MA, Wade CE: Screening of potential small volume resuscitation products using a severe hemorrhage sedated swine model. Int J Burns Trauma 2 (1): 59–67, 2012.
13. Frith D, Cohen MJ, Brohi K: Animal models of trauma-induced coagulopathy. Thromb Res 129 (5): 551–556, 2012.
14. Tsukamoto T, Pape HC: Animal models for trauma research: what are the options? Shock 31 (1): 3–10, 2009.
15. Zink BJ, Stern SA, McBeth BD, Wang X, Mertz M: Effects of ethanol on limited resuscitation in a model of traumatic brain injury and hemorrhagic shock. J Neurosurg 105 (6): 884–893, 2006.
16. Cho SD, Holcomb JB, Tieu BH, Englehart MS, Morris MS, Karahan ZA, Underwood SA, Muller PJ, Prince MD, Medina L, et al.: Reproducibility of an animal model simulating complex combat-related injury in a multiple-institution format. Shock 31 (1): 87–96, 2009.
17. Majde JA: Animal models for hemorrhage and resuscitation research. J Trauma 54 (Suppl 5): S100–S105, 2003.
18. Mure M, Domino KB, Lindahl SG, Hlastala MP, Altemeier WA, Glenny RW: Regional ventilation-perfusion distribution is more uniform in the prone position. J Appl Physiol 88 (3): 1076–1083, 2000.
19. Mure M, Glenny RW, Domino KB, Hlastala MP: Pulmonary gas exchange improves in the prone position with abdominal distension. Am J Respir Crit Care Med 157 (6 Pt 1): 1785–1790, 1998.
20. Pastore CV, Pirrone F, Mazzola S, Rizzi M, Viola M, Sironi G, Albertini M: Mechanical ventilation and volutrauma: study in vivo of a healthy pig model. Biol Res 44 (3): 219–227, 2011.
21. Mulier KE, Greenberg JG, Beilman GJ: Hypercoagulability in porcine hemorrhagic shock is present early after trauma and resuscitation. J Surg Res 174 (1): e31–e35, 2012.
22. Scribner DM, Witowski NE, Mulier KE, Lusczek ER, Wasiluk KR, Beilman GJ: Liver metabolomic changes identify biochemical pathways in hemorrhagic shock. J Surg Res 164 (1): e131–e139, 2010.
23. Hildebrand F, Weuster M, Mommsen P, Mohr J, Frohlich M, Witte I, Keibl C, Ruchholtz S, Seekamp A, Pape HC, et al.: A combined trauma model of chest and abdominal trauma with hemorrhagic shock—description of a new porcine model. Shock 38 (6): 664–670, 2012.
24. Lomas-Niera JL, Perl M, Chung CS, Ayala A: Shock and hemorrhage: an overview of animal models. Shock 24 (Suppl 1): 33–39, 2005.
25. Noritomi DT, Pereira AJ, Bugano DD, Rehder PS, Silva E: Impact of Plasma-Lyte pH 7.4 on acid-base status and hemodynamics in a model of controlled hemorrhagic shock. Clinics 66 (11): 1969–1974, 2011.
26. Martini WZ, Cortez DS, Dubick MA, Park MS, Holcomb JB: Thrombelastography is better than PT, aPTT, and activated clotting time in detecting clinically relevant clotting abnormalities after hypothermia, hemorrhagic shock and resuscitation in pigs. J Trauma 65 (3): 535–543, 2008.
27. Doucet JJ, Hoyt DB, Coimbra R, Schmid-Schonbein GW, Junger WG, Paul LW, Loomis WH, Hugli TE: Inhibition of enteral enzymes by enteroclysis with nafamostat mesilate reduces neutrophil activation and transfusion requirements after hemorrhagic shock. J Trauma 56 (3): 501–510, 2004; discussion 510–511.
28. Martini WZ, Chung KK, Dubick MA, Blackbourne LH: Daily profiles of fibrinogen metabolism for 5 days following hemorrhage and lactated ringer’s resuscitation in pigs. Shock 37 (6): 605–610, 2012.
29. Takasu A, Ishihara S, Anada H, Sakamoto T, Okada Y: Surface cooling, which fails to reduce the core temperature rapidly, hastens death during severe hemorrhagic shock in pigs. J Trauma 48 (5): 942–947, 2000.
30. Kurita T, Uraoka M, Morita K, Suzuki M, Morishima Y, Sato S: Influence of haemorrhage on the pseudo-steady-state remifentanil concentration in a swine model: a comparison with propofol and the effect of haemorrhagic shock stage. Br J Anaesth 107 (5): 719–725, 2011.
31. Rhee P, Burris D, Kaufmann C, Pikoulis M, Austin B, Ling G, Harviel D, Waxman K: Lactated Ringer’s solution resuscitation causes neutrophil activation after hemorrhagic shock. J Trauma 44 (2): 313–319, 1998.
32. Wladis A, Hjelmqvist H, Brismar B, Kjellstrom BT: Acute metabolic and endocrine effects of induced hypothermia in hemorrhagic shock: an experimental study in the pig. J Trauma 45 (3): 527–533, 1998.
33. Gomez H, Mesquida J, Hermus L, Polanco P, Kim HK, Zenker S, Torres A, Namas R, Vodovotz Y, Clermont G, et al.: Physiologic responses to severe hemorrhagic shock and the genesis of cardiovascular collapse: can irreversibility be anticipated? J Surg Res 178 (1): 358–369, 2012.
34. Skarda DE, Mulier KE, George ME, Bellman GJ: Eight hours of hypotensive versus normotensive resuscitation in a porcine model of controlled hemorrhagic shock. Acad Emerg Med 15 (9): 845–852, 2008.
35. Dalle Lucca JJ, Li Y, Simovic MO, Slack JL, Cap A, Falabella MJ, Dubick M, Lebeda F, Tsokos GC: Decay-accelerating factor limits hemorrhage-instigated tissue injury and improves resuscitation clinical parameters. J Surg Res 179 (1): 153–167, 2013.
36. Roch A, Woloch C, Blayac D, Solas C, Quaranta S, Mardelle V, Castanier M, Papazian L, Sampol-Manos E: Effect of fluid loading during hypovolaemic shock on caspofungin pharmacokinetic parameters in pig. Crit Care 15 (5): R219, 2011.
37. Feinstein AJ, Cohn SM, King DR, Sanui M, Proctor KG: Early vasopressin improves short-term survival after pulmonary contusion. J Trauma 59 (4): 876–882, 2005; discussion 882–883.
38. Alam HB, Chen Z, Honma K, Koustova E, Querol RI, Jaskille A, Inocencio R, Ariaban N, Toruno K, Nadel A, et al.: The rate of induction of hypothermic arrest determines the outcome in a Swine model of lethal hemorrhage. J Trauma 57 (5): 961–969, 2004.
39. Garraway N, Brown DR, Nash D, Kirkpatrick A, Schneidereit NP, Van Heest R, Hwang H, Simons R: Active internal re-warming using a centrifugal pump and heat exchanger following haemorrhagic shock, surgical trauma and hypothermia in a porcine model. Injury 38 (9): 1039–1046, 2007.
40. Avaro JP, Mardelle V, Roch A, Gil C, de Biasi C, Oliver M, Fusai T, Thomas P: Forty-minute endovascular aortic occlusion increases survival in an experimental model of uncontrolled hemorrhagic shock caused by abdominal trauma. J Trauma 71 (3): 720–725, 2011; discussion 725–726.
41. Riha GM, Kunio NR, Van PY, Hamilton GJ, Anderson R, Differding JA, Schreiber MA: Hextend and 7.5% hypertonic saline with dextran are equivalent to lactated Ringer’s in a swine model of initial resuscitation of uncontrolled hemorrhagic shock. J Trauma 71 (6): 1755–1760, 2011.
42. Kiraly LN, Differding JA, Enomoto TM, Sawai RS, Muller PJ, Diggs B, Tieu BH, Englehart MS, Underwood S, Wiesberg TT, et al.: Resuscitation with normal saline (NS) vs. lactated Ringers (LR) modulates hypercoagulability and leads to increased blood loss in an uncontrolled hemorrhagic shock swine model. J Trauma 61 (1): 57–64, 2006; discussion 64–65.
43. Watters JM, Brundage SI, Todd SR, Zautke NA, Stefater JA, Lam JC, Muller PJ, Malinoski D, Schreiber MA: Resuscitation with lactated ringer’s does not increase inflammatory response in a swine model of uncontrolled hemorrhagic shock. Shock 22 (3): 283–287, 2004.
44. Stadlbauer KH, Wagner-Berger HG, Raedler C, Voelckel WG, Wenzel V, Krismer AC, Klima G, Rheinberger K, Nussbaumer W, Pressmar D, et al.: Vasopressin, but not fluid resuscitation, enhances survival in a liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs. Anesthesiology 98 (3): 699–704, 2003.
45. Voelckel WG, Raedler C, Wenzel V, Lindner KH, Krismer AC, Schmittinger CA, Herff H, Rheinberger K, Konigsrainer A: Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs. Crit Care Med 31 (4): 1160–1165, 2003.
46. De Castro GP, MacPhee MJ, Driscoll IR, Beall D, Hsu J, Zhu S, Hess JR, Scalea TM, Bochicchio GV: New hemostatic dressing (FAST dressing) reduces blood loss and improves survival in a grade V liver injury model in noncoagulopathic swine. J Trauma 70 (6): 1408–1412, 2011.
47. Holcomb JB, Pusateri AE, Harris RA, Reid TJ, Beall LD, Hess JR, MacPhee MJ: Dry fibrin sealant dressings reduce blood loss, resuscitation volume, and improve survival in hypothermic coagulopathic swine with grade V liver injuries. J Trauma 47 (2): 233–240, 1999; discussion 240–242.
48. De Castro GP, Dowling MB, Kilbourne M, Keledjian K, Driscoll IR, Raghavan SR, Hess JR, Scalea TM, Bochicchio GV: Determination of efficacy of novel modified chitosan sponge dressing in a lethal arterial injury model in swine. J Trauma Acute Care Surg 72 (4): 899–907, 2012.
49. Arnaud F, Okada T, Solomon D, Haque A, Carroll EE, Sagini E, McCarron R: Initial evaluation of a nano-engineered hemostatic agent in a severe vascular and organ hemorrhage swine model. J Trauma Acute Care Surg 73 (5): 1180–1187, 2012.
50. Mueller GR, Pineda TJ, Xie HX, Teach JS, Barofsky AD, Schmid JR, Gregory KW: A novel sponge-based wound stasis dressing to treat lethal noncompressible hemorrhage. J Trauma Acute Care Surg 73 (2 Suppl 1): S134–139, 2012.
51. Martinowitz U, Holcomb JB, Pusateri AE, Stein M, Onaca N, Freidman M, Macaitis JM, Castel D, Hedner U, Hess JR: Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries. J Trauma 50 (4): 721–729, 2001.
52. Alam HB, Rhee P, Honma K, Chen H, Ayuste EC, Lin T, Toruno K, Mehrani T, Engel C, Chen Z: Does the rate of rewarming from profound hypothermic arrest influence the outcome in a swine model of lethal hemorrhage? J Trauma 60 (1): 134–146, 2006.
53. Inaba K, Rhee P, Teixeira PG, Barmparas G, Putty B, Branco BC, Cohn S, Demetriades D: Intracorporeal use of advanced local hemostatics in a damage control swine model of grade IV liver injury. J Trauma 71 (5): 1312–1318, 2011.
54. Grottke O, Braunschweig T, Henzler D, Coburn M, Tolba R, Rossaint R: Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury. Crit Care 14 (2): R62, 2010.
55. Davis JW, Kaups KL: Base deficit in the elderly: a marker of severe injury and death. J Trauma 45 (5): 873–877, 1998.
56. Desselle WJ, Greenhaw JJ, Trenthem LL, Fabian TC, Proctor KG: Macrophage cyclooxygenase expression, immunosuppression, and cardiopulmonary dysfunction after blunt chest trauma. J Trauma 51 (2): 239–251, 2001; discussion 251–252.
57. Isbell CL, Batchinsky AI, Hetz KM, Baker WL, Cancio LC: Correlation between capnography and arterial carbon dioxide before, during, and after severe chest injury in swine. Shock 37 (1): 103–109, 2012.
58. Batchinsky AI, Weiss WB, Jordan BS, Dick EJ Jr, Cancelada DA, Cancio LC: Ventilation-perfusion relationships following experimental pulmonary contusion. J Appl Physiol 103 (3): 895–902, 2007.
59. Cohn SM, Zieg PM: Experimental pulmonary contusion: review of the literature and description of a new porcine model. J Trauma 41 (3): 565–571, 1996.
60. Kelly ME, Miller PR, Greenhaw JJ, Fabian TC, Proctor KG: Novel resuscitation strategy for pulmonary contusion after severe chest trauma. J Trauma 55 (1): 94–105, 2003.
61. Maxwell RA, Gibson JB, Slade JB, Fabian TC, Proctor KG: Noninvasive cardiac output by partial CO2 rebreathing after severe chest trauma. J Trauma 51 (5): 849–853, 2001.
62. Gibson JB, Maxwell RA, Schweitzer JB, Fabian TC, Proctor KG: Resuscitation from severe hemorrhagic shock after traumatic brain injury using saline, shed blood, or a blood substitute. Shock 17 (3): 234–244, 2002.
63. Glass TF, Fabian MJ, Schweitzer JB, Weinberg JA, Proctor KG: Secondary neurologic injury resulting from nonhypotensive hemorrhage combined with mild traumatic brain injury. J Neurotrauma 16 (9): 771–782, 1999.
64. Glass TF, Fabian MJ, Schweitzer JB, Weinberg JA, Proctor KG: The impact of hypercarbia on the evolution of brain injury in a porcine model of traumatic brain injury and systemic hemorrhage. J Neurotrauma 18 (1): 57–71, 2001.
65. Hariri RJ, Firlick AD, Shepard SR, Cohen DS, Barie PS, Emery JM 3rd, Ghajar JB: Traumatic brain injury, hemorrhagic shock, and fluid resuscitation: effects on intracranial pressure and brain compliance. J Neurosurg 79 (3): 421–427, 1993.
66. Patel MB, Feinstein AJ, Saenz AD, Majetschak M, Proctor KG: Prehospital HBOC-201 after traumatic brain injury and hemorrhagic shock in swine. J Trauma 61 (1): 46–56, 2006.
67. Stern SA, Zink BJ, Mertz M, Wang X, Dronen SC: Effect of initially limited resuscitation in a combined model of fluid-percussion brain injury and severe uncontrolled hemorrhagic shock. J Neurosurg 93 (2): 305–314, 2000.
68. White NJ, Wang X, Bradbury N, Moon-Massat PF, Freilich D, Auker C, McCarron R, Scultetus A, Stern SA: Fluid resuscitation of uncontrolled hemorrhage using a hemoglobin-based oxygen carrier: effect of traumatic brain injury. Shock 39 (2): 210–219, 2013.
69. Lexcen DR, Lusczek ER, Witowski NE, Mulier KE, Beilman GJ: Metabolomics classifies phase of care and identifies risk for mortality in a porcine model of multiple injuries and hemorrhagic shock. J Trauma Acute Care Surg 73 (2 Suppl 1): S147–S155, 2012.
70. Alam HB, Hamwi KB, Duggan M, Fikry K, Lu J, Fukudome EY, Chong W, Bramos A, Kim K, Velmahos G: Hemostatic and pharmacologic resuscitation: results of a long-term survival study in a swine polytrauma model. J Trauma 70 (3): 636–645, 2011.
71. Majetschak M, Cohn SM, Obertacke U, Proctor KG: Therapeutic potential of exogenous ubiquitin during resuscitation from severe trauma. J Trauma 56 (5): 991–999, 2004; discussion 999–1000.
72. Howes DW, Stratford A, Stirling M, Ferri CC, Bardell T: Administration of recombinant factor VIIa decreases blood loss after blunt trauma in noncoagulopathic pigs. J Trauma 62 (2): 311–315, 2007; discussion 314–315.
73. Wu D, Qi J: Mechanisms of the beneficial effect of NHE1 inhibitor in traumatic hemorrhage: inhibition of inflammatory pathways. Resuscitation 83 (6): 774–781, 2012.
74. Spoerke N, Zink K, Cho SD, Differding J, Muller P, Karahan A, Sondeen J, Holcomb JB, Schreiber M: Lyophilized plasma for resuscitation in a swine model of severe injury. Arch Surg 144 (9): 829–834, 2009.
75. Sailhamer EA, Chen Z, Ahuja N, Velmahos GC, de Moya M, Rhee P, Shults C, Alam HB: Profound hypothermic cardiopulmonary bypass facilitates survival without a high complication rate in a swine model of complex vascular, splenic, and colon injuries. J Am Coll Surg 204 (4): 642–653, 2007.
76. Savage SA, Fitzpatrick CM, Kashyap VS, Clouse WD, Kerby JD: Endothelial dysfunction after lactated Ringer’s solution resuscitation for hemorrhagic shock. J Trauma 59 (2): 284–290, 2005.
77. Sheehy A, Hsu S, Sinn I, Tai J, Kolodgie FD, Nakazawa G, Yazdani SK, Quee SC, Virmani R, Polyakov I: Vascular response to coronary artery stenting in mature and juvenile swine. Cardiovasc Revasc Med 12 (6): 375–384, 2011.
78. Durham SR, Raghupathi R, Helfaer MA, Marwaha S, Duhaime AC: Age-related differences in acute physiologic response to focal traumatic brain injury in piglets. Pediatr Neurosurg 33 (2): 76–82, 2000.
79. Armstead WM, Riley J, Vavilala MS: TBI sex dependently upregulates ET-1 to impair autoregulation, which is aggravated by phenylephrine in males but is abrogated in females. J Neurotrauma 29 (7): 1483–1490, 2012.
80. Semenas E, Nozari A, Wiklund L: Sex differences in cardiac injury after severe haemorrhage and ventricular fibrillation in pigs. Resuscitation 81 (12): 1718–1722, 2010.
81. Semenas E, Sharma HS, Nozari A, Basu S, Wiklund L: Neuroprotective effects of 17beta-estradiol after hypovolemic cardiac arrest in immature piglets: the role of nitric oxide and peroxidation. Shock 36 (1): 30–37, 2011.
82. Hamidi SA, Dickman KG, Berisha H, Said SI: 17beta-Estradiol protects the lung against acute injury: possible mediation by vasoactive intestinal polypeptide. Endocrinology 152 (12): 4729–4737, 2011.
83. Kawasaki T, Chaudry IH: The effects of estrogen on various organs: therapeutic approach for sepsis, trauma, and reperfusion injury. Part 2: liver, intestine, spleen, and kidney. J Anesth 26 (6): 892–899, 2012.
84. Kawasaki T, Chaudry IH: The effects of estrogen on various organs: therapeutic approach for sepsis, trauma, and reperfusion injury. Part 1: central nervous system, lung, and heart. J Anesth 26 (6): 883–891, 2012.
85. Norio H, Takasu A, Kawakami M, Saitoh D, Sakamoto T, Okada Y: Rapid body cooling by cold fluid infusion prolongs survival time during uncontrolled hemorrhagic shock in pigs. J Trauma 52 (6): 1056–1061, 2002; discussion 1061.
86. Redl H, Schlag G, Bahrami S, Yao YM: Animal models as the basis of pharmacologic intervention in trauma and sepsis patients. World J Surg 20 (4): 487–492, 1996.
87. Swindle M: Swine in the Laboratory: Surgery, Anesthesia, Imaging & Experimental Techniques. Boca Raton, FL: CRC Press, 2007.
88. De Kock M, Loix S, Lavand’homme P: Ketamine and peripheral inflammation. CNS Neurosci Ther 19 (6): 403–410, 2013.
89. Koga K, Ogata M, Takenaka I, Matsumoto T, Shigematsu A: Ketamine suppresses tumor necrosis factor-alpha activity and mortality in carrageenan-sensitized endotoxin shock model. Circ Shock 44 (3): 160–168, 1994.
90. Takenaka I, Ogata M, Koga K, Matsumoto T, Shigematsu A: Ketamine suppresses endotoxin-induced tumor necrosis factor alpha production in mice. Anesthesiology 80 (2): 402–408, 1994.
91. Shaked G, Czeiger D, Dukhno O, Levy I, Artru AA, Shapira Y, Douvdevani A: Ketamine improves survival and suppresses IL-6 and TNFalpha production in a model of gram-negative bacterial sepsis in rats. Resuscitation 62 (2): 237–242, 2004.
92. Gurfinkel R, Czeiger D, Douvdevani A, Shapira Y, Artru AA, Sufaro Y, Mazar J, Shaked G: Ketamine improves survival in burn injury followed by sepsis in rats. Anesth Analg 103 (2): 396–402, 2006.
93. Neder Meyer T, Lazaro Da Silva A: Ketamine reduces mortality of severely burnt rats, when compared to midazolam plus fentanyl. Burns 30 (5): 425–430, 2004.
94. Kawasaki C, Kawasaki T, Ogata M, Nandate K, Shigematsu A: Ketamine isomers suppress superantigen-induced proinflammatory cytokine production in human whole blood. Can J Anaesth 48 (8): 819–823, 2001.
95. Kawasaki T, Ogata M, Kawasaki C, Ogata J, Inoue Y, Shigematsu A: Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesth Analg 89 (3): 665–669, 1999.
96. Wu X, Kochanek PM, Cochran K, Nozari A, Henchir J, Stezoski SW, Wagner R, Wisniewski S, Tisherman SA: Mild hypothermia improves survival after prolonged, traumatic hemorrhagic shock in pigs. J Trauma 59 (2): 291–299, 2005; discussion 299–301.
97. Strohmaier W, Trupka A, Pfeiler C, Thurnher M, Khakpour Z, Gippner-Steppert C, Jochum M, Redl H: Bilateral lavage with diluted surfactant improves lung function after unilateral lung contusion in pigs. Crit Care Med 33 (10): 2286–2293, 2005.
98. Hawksworth JS, Graybill JC, Brown TS, Wallace SM, Davis TA, Tadaki DK, Elster EA: Lymphocyte modulation with FTY720 improves hemorrhagic shock survival in swine. PloS One 7 (4): e34224, 2012.
99. Leixnering M, Reichetseder J, Schultz A, Figl M, Wassermann E, Thurnher M, Redl H: Gelatin thrombin granules for hemostasis in a severe traumatic liver and spleen rupture model in swine. J Trauma 64 (2): 456–461, 2008.
100. Ayuste EC, Chen H, Koustova E, Rhee P, Ahuja N, Chen Z, Valeri CR, Spaniolas K, Mehrani T, Alam HB: Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer’s solution. J Trauma 60 (1): 52–63, 2006.
101. Frink M, Flohe S, van Griensven M, Mommsen P, Hildebrand F: Facts and fiction: the impact of hypothermia on molecular mechanisms following major challenge. Mediators Inflamm 2012:762840, 2012.
102. Walport MJ: Complement. First of two parts. N Engl J Med 344 (14): 1058–1066, 2001.
103. Chang ZL: Important aspects of Toll-like receptors, ligands and their signaling pathways. Inflamm Res 59 (10): 791–808, 2010.
105. Bracht H, Scheuerle A, Groger M, Hauser B, Matallo J, McCook O, Seifritz A, Wachter U, Vogt JA, Asfar P, et al.: Effects of intravenous sulfide during resuscitated porcine hemorrhagic shock. Crit Care Med
40 (7): 2157–2167, 2012.
106. Martini WZ, Cortez DS, Dubick MA, Blackbourne LH: Different recovery profiles of coagulation factors, thrombin generation, and coagulation function after hemorrhagic shock in pigs. J Trauma Acute Care Surg
73 (3): 640–647, 2012.
107. George ME, Mulier KE, Beilman GJ: Hypothermia is associated with improved outcomes in a porcine model of hemorrhagic shock. J Trauma 68 (3): 662–668, 2010.
108. Dalle Lucca JJ, Simovic M, Li Y, Moratz C, Falabella M, Tsokos GC: Decay-accelerating factor mitigates controlled hemorrhage-instigated intestinal and lung tissue damage and hyperkalemia in swine. J Trauma
71 (Suppl 1): S151–S160, 2011.
109. Segal N, Rees J, Convertino VA, Metzger A, Zarama D, Voulgaropoulos L, McKnite SH, Yannopoulos D, Tang W, Vicaut E, et al.: Improving microcirculation with therapeutic intrathoracic pressure regulation in a porcine model of hemorrhage. Resuscitation
82 (Suppl 2): S16–S22, 2011.
110. Chen Z, Chen H, Rhee P, Koustova E, Ayuste EC, Honma K, Nadel A, Alam HB: Induction of profound hypothermia modulates the immune/inflammatory response in a swine model of lethal hemorrhage. Resuscitation 66 (2): 209–216, 2005.
111. Bochicchio G, Kilbourne M, Kuehn R, Keledjian K, Hess J, Scalea T: Use of a modified chitosan dressing in a hypothermic coagulopathic grade V liver injury model. Am J Surg 198 (5): 617–622, 2009.
112. Fries D, Krismer A, Klingler A, Streif W, Klima G, Wenzel V, Haas T, Innerhofer P: Effect of fibrinogen on reversal of dilutional coagulopathy: a porcine model. Br J Anaesth
95 (2): 172–177, 2005.
113. Honickel M, Rieg A, Rossaint R, Braunschweig T, Spronk HM, ten Cate H, van Oerle R, Tolba R, Grottke O: Prothrombin complex concentrate reduces blood loss and enhances thrombin generation in a pig model with blunt liver injury under severe hypothermia. Thromb Haemost 106 (4): 724–733, 2011.
114. Riddez L, Johnson L, Hahn RG: Early hemodynamic changes during uncontrolled intra-abdominal bleeding. Eur Surg Res 31 (1): 19–25, 1999.
115. Duggan MJ, Mejaddam AY, Beagle J, Demoya MA, Velmahosa GC, Alam HB, Rago A, Zugates G, Busold R, Freyman T, et al.: Development of a lethal, closed-abdomen grade V hepato-portal injury model in non-coagulopathic swine. J Surg Res
182 (1): 101–107, 2013.
116. Silbergleit R, Satz W, Lee DC, McNamara RM: Hypothermia from realistic fluid resuscitation in a model of hemorrhagic shock. Ann Emerg Med 31 (3): 339–343, 1998.
117. Iyegha UP, Greenberg JJ, Mulier KE, Chipman J, George M, Beilman GJ: Environmental hypothermia in porcine polytrauma and hemorrhagic shock is safe. Shock 38 (4): 387–394, 2012.
118. Drabek T, Kochanek PM, Stezoski J, Wu X, Bayir H, Morhard RC, Stezoski SW, Tisherman SA: Intravenous hydrogen sulfide does not induce hypothermia or improve survival from hemorrhagic shock in pigs. Shock 35 (1): 67–73, 2011.
119. Schnuriger B, Inaba K, Barmparas G, Rhee P, Putty B, Branco BC, Talving P, Demetriades D: A new survivable damage control model including hypothermia, hemodilution, and liver injury. J Surg Res 169 (1): 99–105, 2011.
120. Alam HB, Bice LM, Butt MU, Cho SD, Dubick MA, Duggan M, Englehart MS, Holcomb JB, Morris MS, Prince MD, et al.: Testing of blood products in a polytrauma model: results of a multi-institutional randomized preclinical trial. J Trauma
67 (4): 856–864, 2009.
121. Fritz HG, Walter B, Holzmayr M, Brodhun M, Patt S, Bauer R: A pig model with secondary increase of intracranial pressure after severe traumatic brain injury and temporary blood loss. J Neurotrauma 22 (7): 807–821, 2005.
122. Zink BJ, Stern SA, Wang X, Chudnofsky CC: Effects of ethanol in an experimental model of combined traumatic brain injury and hemorrhagic shock. Acad Emerg Med 5 (1): 9–17, 1998.
123. Zink BJ, Schultz CH, Wang X, Mertz M, Stern SA, Betz AL: Effects of ethanol on brain lactate in experimental traumatic brain injury with hemorrhagic shock. Brain Res 837 (1–2): 1–7, 1999.
124. Zink BJ, Schultz CH, Stern SA, Mertz M, Wang X, Johnston P, Keep RF: Effects of ethanol and naltrexone in a model of traumatic brain injury with hemorrhagic shock. Alcohol Clin Exp Res 25 (6): 916–923, 2001.
125. Zink BJ, Sheinberg MA, Wang X, Mertz M, Stern SA, Betz AL: Acute ethanol intoxication in a model of traumatic brain injury with hemorrhagic shock: effects on early physiological response. J Neurosurg 89 (6): 983–990, 1998.
126. Malhotra AK, Schweitzer JB, Fox JL, Fabian TC, Proctor KG: Cerebral perfusion pressure elevation with oxygen-carrying pressor after traumatic brain injury and hypotension in Swine. J Trauma 56 (5): 1049–1057, 2004.
127. Stern S, Rice J, Philbin N, McGwin G, Arnaud F, Johnson T, Flournoy WS, Ahlers S, Pearce LB, McCarron R, et al.: Resuscitation with the hemoglobin-based oxygen carrier, HBOC-201, in a swine model of severe uncontrolled hemorrhage and traumatic brain injury. Shock
31 (1): 64–79, 2009.
128. Teranishi K, Scultetus A, Haque A, Stern S, Philbin N, Rice J, Johnson T, Auker C, McCarron R, Freilich D, et al.: Traumatic brain injury and severe uncontrolled haemorrhage with short delay pre-hospital resuscitation in a swine model. Injury
43 (5): 585–593, 2012.
129. Rice J, Philbin N, Handrigan M, Hall C, McGwin G, Ahlers S, Pearce LB, Arnaud F, McCarron R, Freilich D: Vasoactivity of bovine polymerized hemoglobin (HBOC-201) in swine with traumatic hemorrhagic shock with and without brain injury. J Trauma 61 (5): 1085–1099, 2006.
130. Rosenthal G, Morabito D, Cohen M, Roeytenberg A, Derugin N, Panter SS, Knudson MM, Manley G: Use of hemoglobin-based oxygen-carrying solution-201 to improve resuscitation parameters and prevent secondary brain injury in a swine model of traumatic brain injury and hemorrhage: laboratory investigation. J Neurosurg 108 (3): 575–587, 2008.
131. Jin G, DeMoya MA, Duggan M, Knightly T, Mejaddam AY, Hwabejire J, Lu J, Smith WM, Kasotakis G, Velmahos GC, et al.: Traumatic brain injury and hemorrhagic shock: evaluation of different resuscitation strategies in a large animal model of combined insults. Shock
38 (1): 49–56, 2012.
132. Sillesen M, Johansson PI, Rasmussen LS, Jin G, Jepsen CH, Imam AM, Hwabejire J, Lu J, Duggan M, Velmahos G, et al.: Platelet activation and dysfunction in a large-animal model of traumatic brain injury and hemorrhage. J Trauma Acute Care Surg
74 (5): 1252–1259, 2013.
133. Jin G, Duggan M, Imam A, Demoya MA, Sillesen M, Hwabejire J, Jepsen CH, Liu B, Mejaddam AY, Lu J, et al.: Pharmacologic resuscitation for hemorrhagic shock combined with traumatic brain injury. J Trauma Acute Care Surg
73 (6): 1461–1470, 2012.
134. Bourguignon PR, Shackford SR, Shiffer C, Nichols P, Nees AV: Delayed fluid resuscitation of head injury and uncontrolled hemorrhagic shock. Arch Surg 133 (4): 390–398, 1998.
135. Novak L, Shackford SR, Bourguignon P, Nichols P, Buckingham S, Osler T, Sartorelli K: Comparison of standard and alternative prehospital resuscitation in uncontrolled hemorrhagic shock and head injury. J Trauma
47 (5): 834–844, 1999.
136. Alspaugh DM, Sartorelli K, Shackford SR, Okum EJ, Buckingham S, Osler T: Prehospital resuscitation with phenylephrine in uncontrolled hemorrhagic shock and brain injury. J Trauma 48 (5): 851–863, 2000; discussion 863–864.
Hemorrhage; chest trauma; abdominal trauma; long-bone fracture; pigs
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