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.
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
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.