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BackgroundSystemic inflammatory response remains a poorly understood cause of morbidity and mortality after traumatic injury. Recent nonhuman primate (NHP) trauma models have been used to characterize the systemic response to trauma, but none have incorporated a critical care phase without the use of general anesthesia. We describe the development of a prolonged critical care environment with sedation and ventilation support, and also report corresponding NHP biologic and inflammatory markers.MethodsEight adult male rhesus macaques underwent ventilation with sedation for 48-96 hours in a critical care setting. Three of these NHPs underwent "sham" procedures as part of trauma control model development. Blood counts, chemistries, coagulation studies, and cytokines/chemokines were collected throughout the study, and histopathologic analysis was conducted at necropsy.ResultsEight NHPs were intentionally survived and extubated. Three NHPs were euthanized at 72-96 hours without extubation. Transaminitis occurred over the duration of ventilation, but renal function, acid-base status, and hematologic profile remained stable. Chemokine and cytokine analysis were notable for baseline fold-change for Il-6 and Il-1ra (9.7 and 42.7, respectively) that subsequently downtrended throughout the experiment unless clinical respiratory compromise was observed.ConclusionsA NHP critical care environment with ventilation support is feasible but requires robust resources. The inflammatory profile of NHPs is not profoundly altered by sedation and mechanical ventilation. NHPs are susceptible to the pulmonary effects of short-term ventilation and demonstrate a similar bioprofile response to ventilator-induced pulmonary pathology. This work has implications for further development of a prolonged care NHP model.

Beyond its anti-fibrinolytic mechanism, tranexamic acid has been suggested to have anti-inflammatory properties which may contribute to the survival benefit it provides to trauma patients. The objective of this study was to assess possible immunomodulatory effects of tranexamic acid as well as potential amelioration of end-organ injury in a rodent hemorrhagic shock model. Controlled hemorrhagic shock was induced in adult Sprague Dawley rats to a mean arterial pressure of 30 mmHg. Groups of 10 rats were administered intravenous tranexamic acid (300mg/kg) or vehicle control (normal saline) intravenously 15 minutes after the induction of shock. After 60 minutes of hemorrhagic shock, resuscitation was started. Animals were euthanized at six, 24, or 72 hours from the start of shock. Serum laboratory values to include inflammatory biomarkers were measured, and end organ histology was evaluated. Tranexamic acid treatment was associated with a significant decrease in serum IL-1β at six and 24 hours and IL-10 at 24 hours from start of shock compared to vehicle control. Histologic analysis demonstrated mild decreases in both perivascular pulmonary edema and follicular mesenteric lymph node hyperplasia in the tranexamic acid treatment group but also increased myocardial lymphocytic infiltration with necrosis and degeneration. Tranexamic acid was also associated with a small but significant increase in peripheral neutrophil count as well as a significant decrease in neutrophil aggregation in pulmonary tissue at six hours post-injury. These data thus demonstrate a mixed effect of tranexamic acid. While there was an improvement in pulmonary edema and a suppressive effect on several key inflammatory mediators, there was also increased myocardial degeneration and necrosis, which is possibly related to the pro-thrombotic effect of tranexamic acid.

Acute limb ischemia is a common cause of morbidity and mortality following trauma both in civilian centers and in combat related injuries. Rapid determination of tissue viability and surgical restoration of blood flow are desirable, but not always possible. We sought to characterize the response to increasing periods of hind limb ischemia in a porcine model such that we could define a period of critical ischemia (the point after which irreversible neuromuscular injury occurs), evaluate non-invasive methods for characterizing that ischemia, and establish a model by which we could predict whether or not the animal's locomotion would return to baselines levels post-operatively. Ischemia was induced by either application of a pneumatic tourniquet or vessel occlusion (performed by clamping the proximal iliac artery and vein at the level of the inguinal ligament). The limb was monitored for the duration of the procedure with both 3-charge coupled device (3CCD) and infrared (IR) imaging for tissue oxygenation and perfusion, respectively. The experimental arms of this model are effective at inducing histologically evident muscle injury with some evidence of expected secondary organ damage, particularly in animals with longer ischemia times. Noninvasive imaging data shows excellent correlation with post-operative functional outcomes, validating its use as a non-invasive means of viability assessment, and directly monitors post-occlusive reactive hyperemia. A classification model, based on partial-least squares discriminant analysis (PLSDA) of imaging variables only, successfully classified animals as "returned to normal locomotion" or "did not return to normal locomotion" with 87.5% sensitivity and 66.7% specificity after cross-validation. PLSDA models generated from non-imaging data were not as accurate (AUC of 0.53) compared the PLSDA model generated from only imaging data (AUC of 0.76). With some modification, this limb ischemia model could also serve as a means on which to test therapies designed to prolong the time before critical ischemia.