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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.

Introduction Clinical decision support tools capable of predicting which patients are at highest risk for venous thromboembolism (VTE) can assist in guiding surveillance and prophylaxis decisions. The Trauma Embolic Scoring System (TESS) has been shown to model VTE risk in civilian trauma patients. No such support tools have yet been described in combat casualties, who have a high incidence of VTE. The purpose of this study was to evaluate the utility of TESS in predicting VTE in military trauma patients.Methods A retrospective cohort study of 549 combat casualties from October 2010 to November 2012 admitted to a military treatment facility in the USA was performed. TESS scores were calculated through data obtained from the Department of Defense Trauma Registry and chart reviews. Univariate analysis and multivariate logistic regression were performed to evaluate risk factors for VTE. Receiver operating characteristic (ROC) curve analysis of TESS in military trauma patients was also performed.Results The incidence of VTE was 21.7% (119/549). The median TESS for patients without VTE was 8 (IQR 4–9), and the median TESS for those with VTE was 10 (IQR 9–11). On multivariate analysis, Injury Severity Score (ISS) (OR 1.03, p=0.007), ventilator days (OR 1.05, p=0.02), and administration of tranexamic acid (TXA) (OR 1.89, p=0.03) were found to be independent risk factors for development of VTE. On ROC analysis, an optimal high-risk cut-off value for TESS was ≥7 with a sensitivity of 0.92 and a specificity of 0.53 (area under the curve 0.76, 95% CI 0.72 to 0.80, p

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.

Abstract Background Tranexamic acid (TXA) may be a useful adjunct for military patients with severe traumatic brain injury (TBI). These patients are often treated in austere settings without immediate access to neurosurgical intervention. The purpose of this study was to evaluate any association between TXA use and progression of intracranial hemorrhage (ICH), neurologic outcomes, and venous thromboembolism (VTE) in TBI. Methods This was a retrospective cohort study of military casualties from October 2010 to December 2015 who were transferred to a military treatment facility (MTF) in the United States. Data collected included: demographics, types of injuries, initial and interval head computerized tomography (CT) scans, Glasgow Coma Scores (GCS), and six-month Glasgow Outcome Scores (GOS). Results were stratified based on TXA administration, progression of ICH, and VTE. Results Of the 687 active duty service members reviewed, 71 patients had ICH (10.3%). Most casualties were injured in a blast (80.3%), with 36 patients (50.7%) sustaining a penetrating TBI. Mean ISS was 28.2 ± 12.3. Nine patients (12.7%) received a massive transfusion within 24 h of injury, and TXA was administered to 14 (19.7%) casualties. Patients that received TXA had lower initial reported GCS (9.2 ± 4.4 vs. 12.5 ± 3.4, p = 0.003), similar discharge GCS (13.3 ± 4.0 vs. 13.8 ± 3.2, p = 0.58), and a larger improvement between initial and discharge GCS (3.7 ± 3.9 vs. 1.3 ± 3.1, p = 0.02). However, there was no difference in mortality (7.1% vs. 7.0%, p = 1.00), progression of ICH (45.5% vs. 14.7%, p = 0.09), frequency of cranial decompression (50.0% vs. 42.1%, p = 0.76), or mean GOS (3.5 ± 0.9 vs. 3.8 ± 1.0, p = 0.13). Patients administered TXA had a higher rate of VTE (35.7% vs. 7.0%, p = 0.01). On multivariate analysis, however, TXA was not independently associated with VTE. Conclusions Patients that received TXA were associated with an improvement in GCS but not in progression of ICH or GOS. TXA was not independently associated with VTE, although this may be related to a paucity of patients receiving TXA. Decisions about TXA administration in military casualties with ICH should be considered in the context of the availability of neurosurgical intervention as well as severity of extracranial injuries and need for massive transfusion.

Abstract Background The Joint Trauma System has demonstrated improved outcomes through coordinated research and process improvement programs. With fewer combat trauma patients, our military American College of Surgeons level 2 trauma center’s ability to maintain a strong trauma Process Improvement (PI) program has become difficult. As emergency general surgery (EGS) patients are similar to trauma patients, our Trauma and Acute Care Surgery (TACS) service developed an EGS PI program analogous to what is done in trauma. We describe the implementation of our novel EGS PI program and its effect on institutional PI proficiency. Methods An EGS registry was developed in 2013. Inclusion criteria were based on AAST published literature. In 2015, EGS registrar and PI coordinator positions were developed and filled with existing trauma staff. A formal EGS PI program began January 1, 2016. Pre- and post-program data was compared to determine the effect including EGS PI events had on increasing yield into our trauma PI program. Results In 2016, TACS saw 1001 EGS consults. Four hundred forty-four met criteria for registry inclusion. Eighty-two patients had 131 PI events; re-admission within 30 days, unplanned therapeutic intervention, and unplanned ICU admission were the most common events. Capture of EGS PI events yielded a 49% increase compared with 2015. Conclusion Overall patient volume and PI events post EGS PI program initiation exceeded those prior to implementation. These data suggest that extending trauma PI principles to EGS may be beneficial in maintaining inter-war military and/or lower volume trauma center readiness.

Abstract Background Established animal trauma models are limited in recapitulating the pathophysiology of human traumatic injury. Herein, we characterize the physiologic insult and inflammatory response in two clinically relevant non-human primate (NHP) trauma models. Methods Mauritian Cynomolgus Macaques underwent either a laparoscopic closed abdomen liver injury (laparoscopic 60% left-lobe hepatectomy) in an established uncontrolled severe hemorrhage model (THM), or a polytrauma hemorrhage model (PHM) involving combined liver and bowel injury, uncontrolled severe hemorrhage as well as an open full-thickness cutaneous flank wound. Fixed volume resuscitation strategies were employed in the THM and goal directed resuscitation was used in the PHM. Complete peripheral blood and critical clinical chemistry parameters, serum biomarkers of systemic inflammation, tissue perfusion parameters, as well as survival, were compared between the models throughout the 2-week study period. Results NHPs in both the THM (n = 7) and the PHM (n = 21) demonstrated tissue hypoperfusion (peak lactate 6.3 ± 0.71 mmol/L) with end organ injury (peak creatinine 3.08 ± 0.69 mg/dL) from a similar liver injury (60% left hemi-hepatectomy), though the PHM NHPs had a significantly higher blood loss (68.1% ± 12.7% vs. 34.3% ± 2.3%, p = 0.02), lower platelet counts (59 ± 25 vs. 205 ± 46 K/uL, p = 0.03) and a trend towards higher mortality (90.5% vs. 33.3%, p = 0.09). The inflammatory response was robust in both models with peak cytokine (IL-6 > 6000-fold above baseline) and peak leukocyte values (WBC 27 K/uL) typically occurring around t = 240 min from the time of hepatic injury. A more robust systemic inflammatory response was appreciated in the PHM resulting in marked elevations in peak serum IL-6 (7887 ± 2521 pg/mL vs.1076 ± 4833 pg/mL, p = 0.02), IL-1ra (34,499 ± 5987 pg/mL vs. 2511 ± 1228 pg/mL, p

Abstract Background Multi-organ failure (MOF) following trauma remains a significant cause of morbidity and mortality related to a poorly understood abnormal inflammatory response. We characterized the inflammatory response in a non-human primate soft tissue injury and closed abdomen hemorrhage and sepsis model developed to assess realistic injury patterns and induce MOF. Methods Adult male Mauritan Cynomolgus Macaques underwent laparoscopy to create a cecal perforation and non-anatomic liver resection along with a full-thickness flank soft tissue injury. Treatment consisted of a pre-hospital phase followed by a hospital phase after 120 minutes. Blood counts, chemistries, and cytokines/chemokines were measured throughout the study. Lung tissue inflammation/apoptosis was confirmed by mRNA quantitative real-time PCR (qPCR), H&E, myeloperoxidase (MPO) and TUNEL staining was performed comparing age-matched uninjured controls to experimental animals. Results Twenty-one animals underwent the protocol. Mean percent hepatectomy was 64.4 ± 5.6; percent blood loss was 69.0 ± 12.1. Clinical evidence of end-organ damage was reflected by a significant elevation in creatinine (1.1 ± 0.03 vs. 1.9 ± 0.4, p=0.026). Significant increases in systemic levels of IL-10, IL-1ra, IL-6, G-CSF, and MCP-1 occurred (11-2986-fold) by 240 minutes. Excessive pulmonary inflammation was evidenced by alveolar edema, congestion, and wall thickening (H&E staining). Concordantly, amplified accumulation of MPO leukocytes and significant pulmonary inflammation and pneumocyte apoptosis (TUNEL) was confirmed using qRT-PCR. Conclusion We created a clinically relevant large animal multi-trauma model using laparoscopy that resulted in a significant systemic inflammatory response and MOF. With this model, we anticipate studying systemic inflammation and testing innovative therapeutic options.

Objective. Ischemia-reperfusion injury (IRI) produces systemic inflammation with the potential for causing organ failure in tissues peripheral to the initial site of injury. We speculate that treatment strategies that dampen inflammation may be therapeutically beneficial to either the initial site of injury or peripheral organs. To test this, we evaluated the impact of FTY720-induced sequestration of circulating mature lymphocytes on renal IRI and secondary organ injury. Methods. A microvascular clamp was surgically placed around the left renal pedicle of anesthetized male Sprague-Dawley rats with either vehicle or FTY720 treatment (0.3 mg/kg) intravenously injected after 15 min of ischemia. Blood flow was restored after 60 min. Cohorts of anesthetized rats were euthanized at 6, 24, or 72 hrs with tissue samples collected for analysis. Results. FTY720 treatment resulted in profound T lymphocyte reduction in peripheral blood. Histopathologic examination, clinical chemistries, and gene transcript expression measurements revealed that FTY720 treatment reduced hepatocellular degeneration, reduced serum markers of liver injury (ALT/AST), and reduced the expression of gene targets associated with IRI. Conclusion. These findings support an anti-inflammatory effect of FTY720 in the liver where the expression of genes associated with apoptosis, chemotaxis, and the AP-1 transcription factor was reduced. Findings presented here provide the basis for future studies evaluating FTY720 as a potential therapeutic agent to treat complications resulting from renal IRI.

Acute ischemia-reperfusion injury (IRI) of the extremities leads to local and systemic inflammatory changes which can hinder limb function and can be life threatening. This study examined whether the administration of the T-cell sequestration agent, FTY720, following hind limb tourniquet-induced skeletal muscle IRI in a rat model would attenuate systemic inflammation and multiple end organ injury. Sprague-Dawley rats were subjected to 1 hr of ischemia via application of a rubber band tourniquet. Animals were randomized to receive an intravenous bolus of either vehicle control or FTY720 15 min after band placement. Rats (n=10/time point) were euthanized at 6, 24, and 72 hr post-IRI. Peripheral blood as well as lung, liver, kidney, and ischemic muscle tissue was analyzed and compared between groups. FTY720 treatment markedly decreased the number of peripheral blood T cells (p

Iron-based CO2 catalysts have shown promise as a viable route to the production of olefins from CO2 and H2 gas. However, these catalysts can suffer from low conversion and high methane selectivity, as well as being particularly vulnerable to water produced during the reaction. In an effort to improve both the activity and durability of iron-based catalysts on an alumina support, copper (10–30%) has been added to the catalyst matrix. In this paper, the effects of copper addition on the catalyst activity and morphology are examined. The addition of 10% copper significantly increases the CO2 conversion, and decreases methane and carbon monoxide selectivity, without significantly altering the crystallinity and structure of the catalyst itself. The FeCu/K catalysts form an inverse spinel crystal phase that is independent of copper content and a metallic phase that increases in abundance with copper loading (>10% Cu). At higher loadings, copper separates from the iron oxide phase and produces metallic copper as shown by SEM-EDS. An addition of copper appears to increase the rate of the Fischer–Tropsch reaction step, as shown by modeling of the chemical kinetics and the inter- and intra-particle transport of mass and energy.