Abstract
BackgroundEstablished 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.MethodsMauritian 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.ResultsNHPs 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 < 0.00), and IL-10 (13,411 pg/mL ± 5598 pg/mL vs. 617 pg/mL ± 252 pg/mL, p = 0.03).ConclusionThis comparative analysis provides a unique longitudinal perspective on the post-injury inflammatory response in two clinically relevant models, and demonstrates that the addition of septic stimuli to solid organ injury increases both the hemorrhagic insult and inflammatory response.
Highlights
Established animal trauma models are limited in recapitulating the pathophysiology of human traumatic injury
As part of a preclinical immunomodulation study, we have developed two preclinical non-human primate (NHP) traumatic injury models including a closed abdomen, laparoscopic liver trauma and hemorrhage model (THM) with a fixed resuscitation protocol [14], as well as a closed abdomen polytrauma hemorrhage model (PHM) involving combined laparoscopic liver and bowel injury, uncontrolled hemorrhage as well as an open full-thickness cutaneous flank wound with subsequent goal directed resuscitation
The leukocyte data presented in this study reveals the expected post-injury changes associated with severe trauma including leukocytosis, neutrophilia, and relative lymphocytopenia in both the THM and PHM [58,59,60,61,62,63,64,65,66,67]
Summary
Established animal trauma models are limited in recapitulating the pathophysiology of human traumatic injury. The recent military conflicts in Iraq and Afghanistan have seen an unprecedented increase in survival of combat casualties despite increasing injury severity scores (ISS) and complex injury patterns [1, 2]. Attempts to mitigate the morbidity of this immune response through known pathways including blocking individual cytokines, co-stimulatory molecules, endothelial products, and complement cascade have yielded disappointing clinical outcomes in the face of promising preclinical results. This is in part due to the significant complexity and redundancy of the immune response to severe injury, which to date has not been adequately modeled in the preclinical setting by falling short on the model animal’s genetic similarity, degree of injury, goal directed critical care post-injury, and longitudinal evaluation of outcomes [10, 13]. Advances in preclinical modeling are required in order to better characterize and comprehensively differentiate the inflammatory response after various injury patterns, as well as to provide a better understanding for future interventions and clinical studies
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