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

Khalid Almahmoud,Jason Sperry,Timothy R Billiar,Michael S Truitt,Rami A Namas,Andrew Abboud,Todd O Mckinley,Yoram Vodovotz,Greg E Gaski,Andrew B Peitzman,Ruben Zamora

doi:10.1371/journal.pone.0217577

Abstract

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.

Highlights

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]
Our results suggest that severe extremity/soft tissue injury can drive a differential inflammation program associated with self-sustaining inflammation and worse clinical outcomes, as compared to mild/moderate soft tissue injury which is instead associated with a core network of lymphoid inflammatory mediators and self-resolving inflammation
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

Summary

Introduction

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]. Several studies have shown that early stabilization of fractures and appropriate management of soft tissue injury decreases short-term complications, improves long-term function, and decreases overall mortality rate [20, 21] These studies are contrasted by other studies in which early aggressive fracture interventions in vulnerable patients (moderate/severe chest injury, acidosis, and hemodynamic instability) worsened acute outcomes and led to some cases of death resulting from an exaggerated immunologic response [22, 23] [24]. Taken together, these disparate clinical courses in patients with fractures highlight both the complexity and potency of the immune response to bone injury. Understanding how fractures incite, propagate, and perturb the trauma inflammatory response is critical to optimize trauma patient care

Methods

Results

Conclusion