Research Article: Computational evidence for an early, amplified systemic inflammation program in polytrauma patients with severe extremity injuries

Date Published: June 4, 2019

Publisher: Public Library of Science

Author(s): Khalid Almahmoud, Andrew Abboud, Rami A. Namas, Ruben Zamora, Jason Sperry, Andrew B. Peitzman, Michael S. Truitt, Greg E. Gaski, Todd O. McKinley, Timothy R. Billiar, Yoram Vodovotz, Raghavan Raju.


Extremity and soft tissue injuries contribute significantly to inflammation and adverse in-hospital outcomes for trauma survivors; accordingly, we examined the complex association between clinical outcomes inflammatory responses in this setting using in silico tools. Two stringently propensity-matched, moderately/severely injured (Injury Severity Score > 16) patient sub-cohorts of ~30 patients each were derived retrospectively from a cohort of 472 blunt trauma survivors and segregated based on their degree of extremity injury severity (above or below 3 on the Abbreviated Injury Scale). Serial blood samples were analyzed for 31 plasma inflammatory mediators. In addition to standard statistical analyses, Dynamic Network Analysis (DyNA) and Principal Component Analysis (PCA) were used to model systemic inflammation following trauma. Patients in the severe extremity injury sub-cohort experienced longer intensive care unit length of stay (LOS), total LOS, and days on a mechanical ventilator, with higher Marshall Multiple Organ Dysfunction (MOD) Scores over the first 7 days post-injury as compared to the mild/moderate extremity injury sub-cohort. The higher severity cohort had statistically significant elevated lactate, base deficit, and creatine phosphokinase on first blood draw, along with significant changes in multiple circulating inflammatory mediators. DyNA pointed to a sustained role for type 17 immunity in both sub-cohorts, along with IFN-γ in the severe extremity injury group. DyNA network complexity increased over 7 days post-injury in the severe injury group, while generally decreasing over this same time period in the mild/moderate injury group. PCA suggested a more robust activation of multiple pathways in the severe extremity injury group as compared to the mild/moderate injury group. These studies thus point to the possibility of self-sustaining inflammation following severe extremity injury vs. resolving inflammation following less severe extremity injury.

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Trauma is the leading cause of death for adults under the age of 45 and incurs substantial disability in term of long-term morbidity, higher need for rehabilitation service, as well as greater financial costs [1, 2]. Patient outcomes following trauma are influenced by numerous factors including age [3, 4], gender [5, 6], extent of the injury [7, 8], as well as patient-to-patient variability in inflammatory and pathophysiologic responses [7, 9]. While the progression of post-trauma inflammation is complex, many consider the best predictors of outcomes to be the severity and patterns of the injury itself [7]. This core consideration has driven the development and refinement of multiple trauma scoring systems over the last few decades, among which the Injury Severity Score (ISS) remains the most commonly used [10, 11]. However, it is becoming increasingly recognized that response to injury, primarily mediated by the immune system, affects both acute and longer-term outcomes after injury [12–15].

Severe extremity trauma induces an inflammatory response that contributes to both early and delayed complications, muscle necrosis, and ischemia reperfusion injury [12]. We and others have used both data-driven and mechanistic computational modeling approaches to address this complexity and to gain both basic and translational insights into trauma, hemorrhage, and related phenomena such as sepsis [12, 56]. Our goal in the present study was to examine the association between the clinical outcomes and the early, dynamic, systemic acute inflammatory response in the setting of major bone/soft tissue injury in a manner that would allow for the least degree of ambiguity while still reflecting the reality and diversity of clinical outcomes. In addition to confirming multiple prior observations about the clinical impact of different degrees of extremity injury severity in blunt trauma patients, we correlated these outcomes with differential inflammatory trajectories and dynamic networks.




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