Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock

Abstract

IntroductionWe wished to characterize the relationship of advanced age to clinical outcomes and to transcriptomic responses after severe blunt traumatic injury with hemorrhagic shock.MethodsWe performed epidemiological, cytokine, and transcriptomic analyses on a prospective, multi-center cohort of 1,928 severely injured patients.ResultsWe found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts. However, aged patients had more comorbidities. Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities. Additionally, advanced age was an independent predictor of a complicated recovery and 28-day mortality. Acutely after trauma, blood neutrophil genome-wide expression analysis revealed an attenuated transcriptomic response as compared to the young; this attenuated response was supported by the patients’ plasma cytokine and chemokine concentrations. Later, these patients demonstrated gene expression changes consistent with simultaneous, persistent pro-inflammatory and immunosuppressive states.ConclusionsWe concluded that advanced age is one of the strongest non-injury related risk factors for poor outcomes after severe trauma with hemorrhagic shock and is associated with an altered and unique peripheral leukocyte genomic response. As the general population’s age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

Contemporary Patterns of Multiple Organ Dysfunction in Trauma

“…These studies define complicated MODS using ''Time To Recovery,'' which incorporates all deaths into the ''complicated'' MODS category and may explain the propensity toward higher overall injury severity. Other studies identify advanced age as a potential driver of complicated MODS in non-TBI injured patients (14). Our study supports this, and we also show PRMODS to be associated with higher admission base deficit and transfusion requirements, both of which are implicated in immunosuppressive responses after trauma (8).…”

Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis

“…Thus, return to homeostasis is a key objective for future immunomodulation therapy of elderly trauma and sepsis patients (33,34,41). However, it is clear that juveniles do not return to baseline genomic expression patterns after severe trauma within 3 days in this study.…”

“…We have previously demonstrated that, in response to injury, the elderly do not have an exaggerated inflammatory response nor greater suppression of adaptive immunity genes but, rather, a delayed return to baseline (33,34,41). Thus, return to homeostasis is a key objective for future immunomodulation therapy of elderly trauma and sepsis patients (33,34,41).…”

The future of murine sepsis and trauma research models

“…This "storm" (whether cytokine or genomic [27]) that occurs with severe infection or injury affects every aspect of mammalian biologymultiple molecules, genes, cells, tissues, compartments, and Mortality is increased significantly in the elderly in sepsis and trauma, and the incidence is increased in the former as well. Typical murine studies use animals that are the age equivalent of an adolescent human and thus, cannot reflect the majority of sepsis patients nor those at the greatest risk for poor outcomes after trauma [32][33][34]. Total circulating leukocyte comparisons…”