Reproducibility of an Animal Model Simulating Complex Combat-Related Injury in a Multiple-Institution Format

Abstract

We developed a complex combat-relevant model of abdominal and extremity trauma, hemorrhagic shock, hypothermia, and acidosis. We then simulated injury, preoperative, and operative phases. We hypothesized that this model is reproducible and useful for randomized multicenter preclinical trials. Yorkshire swine were anesthetized, intubated, and instrumented. They then underwent femur fracture, 60% total blood volume hemorrhage, a 30-min shock period, induced hypothermia to 33 degrees C, and hemorrhage volume replacement with 3:1 isotonic sodium chloride solution (NS) at each of three centers. Hemodynamic parameters were measured continuously. Thromboelastography, arterial blood gas, and laboratory values were collected at baseline, after the shock period, and after NS replacement. Thirty-seven animals were used for model development. Eight (21%) died before completion of the study period. Twenty-nine survivors were included in the analysis. MAP (+/-SEM) after the shock period was 32 +/- 2 mmHg and was similar between centers (P = 0.4). Mean pH, base deficit, and lactate levels were 7.29 +/- 0.02, 8.20 +/- 0.65 mmol/L, and 5.29 +/- 0.44 mmol/L, respectively, after NS replacement. These were similar between centers (P > 0.05). Prothrombin time values increased significantly over time at all centers, reflecting a progressive coagulopathy (P < 0.02). Thromboelastography maximum amplitude values were similar among centers (P > 0.05) and demonstrated progressively weakened platelet interaction over time (P < 0.03). Hematocrit was similar after controlled hemorrhage (P = 0.15) and dilution (P = 0.9). The pH, lactate, base deficit, and coagulation tests reflect a severely injured state. A complex porcine model of polytrauma and shock can be used for multi-institutional study with excellent reproducibility. A consistent severe injury profile was achieved, after which experimental interventions can be applied. This is the first report of a reproducible multicenter trauma and resuscitation-related animal model.

Validation of acute traumatic coagulopathy in an ovine model of trauma and haemorrhage

“…Existing animal models of trauma and hemorrhage demonstrate considerable variation in the degree of injury severity and target pressure or volume of hemorrhage (29, 40,51,65,67,177,[200][201][202][203]. This contributes to inter-model variations in coagulation function response and limits the reproducibility and comparability of these existing models.…”

“…However pigs have demonstrated significant variability in coagulation function response to trauma and hemorrhage (51,67,177,(200)(201)(202)(203). Both viscoelastic and plasma based assays of coagulation function have shown pigs to be relatively hypercoaguable compared to humans and to have protein C levels that are only 36% of human values (58,60).…”

“…The majority of these models have provided information on the presence and time course of coagulopathy in response to trauma and hemorrhage (29,65,67,177,200,201).…”

“…A second porcine model demonstrated altered platelet function and prolonged PT that was exacerbated by fluid resuscitation but unaltered by induced hypothermia, although the initial prolongation in PT failed to attain the current clinical definition of ATC (177). Nonsignificant changes in PT or INR were evident in the remaining 5 porcine models (51,(200)(201)(202)(203), although a significant reduction in ROTEM mean clot firmness was evident in one study (203) and significant changes developed following fluid resuscitation and/or the induction of hypothermia and acidosis in the remaining three studies (51,201,202).…”

“…porcine models with varying effects on coagulation function observed (29, 40,51,65,67,177,[200][201][202][203]. All rodent models demonstrated a minimum 20% prolongation in PT, aPTT or PT ratio (PTr) (29, 40, 65) which was attenuated by monoclonal antibodies to aPC in one study (40).…”