Early Immunologic Response in Multiply Injured Patients With Orthopaedic Injuries Is Associated With Organ Dysfunction

Abstract

Objectives: To quantify the acute immunologic biomarker response in multiply injured patients with axial and lower extremity fractures and to explore associations with adverse short-term outcomes including organ dysfunction and nosocomial infection (NI). Design: Prospective cohort study. Setting: Level 1 academic trauma center. Patients: Consecutive multiply injured patients, 18–55 years of age, with major pelvic and lower extremity orthopaedic injuries (all pelvic/acetabular fractures, operative femur and tibia fractures) that presented as a trauma activation and admitted to the intensive care unit from April 2015 through October 2016. Sixty-one patients met inclusion criteria. Intervention: Blood was collected upon presentation to the hospital and at the following time points: 8, 24, 48 hours, and daily during intensive care unit admission. Blood was processed by centrifugation, separation into 1.0-mL plasma aliquots, and cryopreserved within 2 hours of collection. Main Outcome Measurements: Plasma analyses of protein levels of cytokines/chemokines were performed using a Luminex panel Bioassay of 20 immunologic mediators. Organ dysfunction was measured by the Marshall Multiple Organ Dysfunction score (MODScore) and nosocomial infection (NI) was recorded. Patients were stratified into low (MODS ≤ 4; n = 34) and high (MODS > 4; n = 27) organ dysfunction groups. Results: The MODS >4 group had higher circulating levels of interleukin (IL)-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), IL-1 receptor antagonist (IL-1RA), and monokine induced by interferon gamma (MIG) compared with the MODS ≤4 group at nearly all time points. MODS >4 exhibited lower levels of IL-21 and IL-22 compared with MODS ≤4. Patients who developed NI (n = 24) had higher circulating concentrations of IL-10, MIG, and high mobility group box 1 (HMGB1) compared with patients who did not develop NI (n = 37). Conclusions: Temporal quantification of immune mediators identified 8 biomarkers associated with greater levels of organ dysfunction in polytrauma patients with major orthopaedic injuries. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

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

“…We have also demonstrated previously that two of these chemokines (MCP-1 and IP-10) are biomarkers of adverse outcomes in trauma [48, 51]. Circulating levels of the cytokine IL-6 were statistically significantly different between groups by AUC analysis, again in line with a previous study in a separate cohort of extremity fracture patients [57]. The role of IL-6 in this setting may be quite central, since recent studies have reported improved fracture healing in an animal model of bone fracture following administration of neutralizing antibodies directed against the IL-6 receptor [58].…”

“…This network phenotype was associated with significantly elevated levels of several chemokines and cytokines. These included the chemokines IL-8, MIG, IP-10, and MCP-1; we have reported elevations of these mediators in a separate study of extremity fracture patients [57]. We have also demonstrated previously that two of these chemokines (MCP-1 and IP-10) are biomarkers of adverse outcomes in trauma [48, 51].…”

Early systemic immune biomarkers predict bone regeneration after trauma

“…Additional work is needed to validate the predictive power of these computational models, and reproducibility in experiments with human clinical samples remains to be determined. Of note, recent clinical studies have taken a similar approach by analyzing serum/ plasma from trauma patients and finding that levels of certain cytokines were associated with greater immune dysregulation and multiple organ dysfunction (54,55). In that same vein, the results from this study can motivate further investigation into systemic immune profiles as a potentially powerful tool for early prediction of trauma healing outcomes.…”

Different experimental multiple trauma models induce comparable inflammation and organ injury

“…This was demonstrated by increased release of organ-specific transaminases as specific indicators of injury, as well as by enhanced activity loss and mortality 27,30,52 . Furthermore, IL-6 is enhanced in polytraumatized patients and predictive for the clinical outcome 53,54 . Thus, the data from the underlying study showing the highest systemic and local inflammatory changes with enhanced proinflammatory cytokines and infiltrates with inflammatory cells concurrent with organ damage in the hemorrhagic shock model, as well as in all models of multiple trauma including shock, are supporting the clinical and previous experimental reports.…”