A putative "chemokine switch" that regulates systemic acute inflammation in humans.

Systemic inflammation is complex and likely drives clinical outcomes in critical illness such as that which ensues following severe injury. We obtained time course data on multiple inflammatory mediators in the blood of blunt trauma patients. Using dynamic network analyses, we inferred a novel control architecture for systemic inflammation: a three-way switch comprising the chemokines MCP-1/CCL2, MIG/CXCL9, and IP-10/CXCL10. To test this hypothesis, we created a logical model comprising this putative architecture. This model predicted key qualitative features of systemic inflammation in patient sub-groups, as well as the different patterns of hospital discharge of moderately vs. severely injured patients. Thus, a rational transition from data to data-driven models to mechanistic models suggests a novel, chemokine-based mechanism for control of acute inflammation in humans and points to the potential utility of this workflow in defining novel features in other complex diseases.

Diurnal Variation in Systemic Acute Inflammation and Clinical Outcomes Following Severe Blunt Trauma.

Animal studies suggest that the time of day is a determinant of the immunological response to both injury and infection. We hypothesized that due to this diurnal variation, time of injury could affect the systemic inflammatory response and outcomes post-trauma and tested this hypothesis by examining the dynamics of circulating inflammatory mediators in blunt trauma patients injured during daytime vs. nighttime. From a cohort of 472 blunt trauma survivors, two stringently matched sub-cohorts of moderately/severely injured patients [injury severity score (ISS) >20] were identified. Fifteen propensity-matched, daytime-inured ("mDay") patients (age 43.6 ± 5.2, M/F 11/4, ISS 22.9 ± 0.7) presented during the shortest local annual period (8:00 am-5:00 pm), and 15 propensity-matched "mNight" patients (age 43 ± 4.3, M/F 11/4, ISS 24.5 ± 2.5) presented during the shortest night period (10:00 pm-5:00 am). Serial blood samples were obtained (3 samples within the first 24 h and daily from days 1-7) from all patients. Thirty-two plasma inflammatory mediators were assayed. Two-way Analysis of Variance (ANOVA) was used to compare groups. Dynamic Network Analysis (DyNA) and Dynamic Bayesian Network (DyBN) inference were utilized to infer dynamic interrelationships among inflammatory mediators. Both total hospital and intensive care unit length of stay were significantly prolonged in the mNight group. Circulating IL-17A was elevated significantly in the mNight group from 24 h to 7 days post-injury. Circulating MIP-1α, IL-7, IL-15, GM-CSF, and sST2 were elevated in the mDay group. DyNA demonstrated elevated network complexity in the mNight vs. the mDay group. DyBN suggested that cortisol and sST2 were central nodes upstream of TGF-ß1, chemokines, and Th17/protective mediators in both groups, with IL-6 being an additional downstream node in the mNight group only. Our results suggest that time of injury affects clinical outcomes in severely injured patients in a manner associated with an altered systemic inflammation program, possibly implying a role for diurnal or circadian variation in the response to traumatic injury.

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

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.

Don't call me crazy! Delirium occurs outside of the intensive care unit.

INTRODUCTION: Delirium has been well studied among patients in the intensive care unit (ICU); however, data beyond the ICU is limited. The purpose of this study is to prospectively evaluate the incidence and associated risk factors for delirium in noncritical care areas (NCCA). METHODS: After institutional review board approval, a prospective cohort study was conducted at our urban Level I Trauma Center from December 2015 to February 2016. All patients admitted to the designated study area by a trauma surgeon were included. The Confusion Assessment Method (CAM) was administered every 12 hours until discharge. Delirious patients (CAM+) were administered the CAM-S to quantify the severity of delirium. Demographics, laboratory data, and inpatient medication lists were analyzed. RESULTS: Of 148 participants, 12 (8%) were CAM+ and 136 (92%) were CAM-. The average CAM-S of CAM+ patients was 7 ± 3. Included patients were aged 52 ± 20 years and 45% were men. Of patients 65 years or older, 9 (21%) were CAM+. Medications associated with delirium were: albuterol (p = 0.01), atorvastatin (p = 0.01), duloxetine (p = 0.04), sertraline (p = 0.04), folic acid (p = 0.01), thiamine (p = 0.01), vitamin D (p < 0.001), haloperidol (p = 0.04), metoprolol (p = 0.02), and vancomycin (p = 0.02). Abnormal laboratory values associated with delirium included: Albumin (p = 0.03; odds ratio [OR], 7.94, 95% confidence interval [CI], 1.1-63.20), Calcium (p = 0.01; OR, 4.95; 95% CI, 1.5-16.7), Sodium (p = 0.04; OR, 3.91; 95% CI, 1.13-13.5), hematocrit (p = 0.04), and mean corpuscular hemoglobin concentration (p < 0.05; OR, 5.29; 95% CI, 1.19-23.46). CONCLUSIONS: Our study demonstrated an 8% incidence of delirium overall in NCCA, increasing to 21% in patients 65 years or older. Many risk factors identified among NCCA patients are consistent with the ICU literature; however, our CAM+ patients had additional risk factors which have not been previously associated with the development of delirium. Screening of NCCA patients for delirium should be considered. LEVEL OF EVIDENCE: Prognostic and Epidemological, level IV.

Risky business? Investigating outcomes of patients undergoing urgent laparoscopic appendectomy on antithrombotic therapy.

INTRODUCTION: The literature regarding outcomes in patients on irreversible antithrombotic therapy (IAT) undergoing urgent laparoscopic appendectomy is limited. The aim of this multicenter retrospective study was to examine the impact of prehospital IAT on outcomes in this population. METHODS: From 2010 to 2014, seven institutions from the Southwest Surgical Multicenter Trials (SWSC MCT) group conducted a retrospective study to evaluate the clinical course of all patients on IAT who underwent urgent/emergent laparoscopic appendectomy. The IAT+ group was subdivided into IAT+ (Aspirin only) and IAT+ (Aspirin-Plavix). These groups were matched 1:1 to controls. The primary outcomes were estimated blood loss (EBL) and transfusion requirement. Secondary outcomes included infections (SSI - Surgical Site Infection, DSI - Deep Space Infection, and OSI - Organ Space Infection), hospital length of stay (HLOS), complications, 30-day readmissions, and mortality. RESULTS: Out of the 2903 patients included in the study, 287 IAT+ patients were identified and matched in a 1:1 ratio to 287 IAT-patients. In the IAT+ vs IAT-analysis, no significant differences in EBL (p = 1.0), transfusion requirement during the preoperative (p = 0.5), intraoperative (p = 0.3) or postoperative periods (p = 0.5), infectious complications (SSI; p = 1.0, DSI; p = 1.0, and OSI; p = 0.1), overall complications (p = 0.3), HLOS (p = 0.7), 30-day readmission (p = 0.3), or mortality (p = 0.1) were noted. Similarly, outcomes in the IAT+ (Aspirin only) and IAT+ (Aspirin-Plavix) subgroups failed to demonstrate any significant differences when compared to controls. CONCLUSIONS: Our analysis suggests that IAT is not associated with worse outcomes in urgent/emergent laparoscopic appendectomy. Prehospital use of IAT should not be used to delay laparoscopic appendectomy.

Elevated Admission Base Deficit Is Associated with a Complex Dynamic Network of Systemic Inflammation Which Drives Clinical Trajectories in Blunt Trauma Patients.

We hypothesized that elevated base deficit (BD) ≥ 4 mEq/L upon admission could be associated with an altered inflammatory response, which in turn may impact differential clinical trajectories. Using clinical and biobank data from 472 blunt trauma survivors, 154 patients were identified after excluding patients who received prehospital IV fluids or had alcohol intoxication. From this subcohort, 84 patients had a BD ≥ 4 mEq/L and 70 patients with BD < 4 mEq/L. Three samples within the first 24 h were obtained from all patients and then daily up to day 7 after injury. Twenty-two cytokines and chemokines were assayed using Luminex™ and were analyzed using two-way ANOVA and dynamic network analysis (DyNA). Multiple mediators of the innate and lymphoid immune responses in the BD ≥ 4 group were elevated differentially upon admission and up to 16 h after injury. DyNA revealed a higher, sustained degree of interconnectivity of the inflammatory response in the BD ≥ 4 patients during the initial 16 h after injury. These results suggest that elevated admission BD is associated with differential immune/inflammatory pathways, which subsequently could predispose patients to follow a complicated clinical course.

Trends in intubation rates and durations in ventilated severely injured trauma patients: an analysis from the TraumaRegister DGU®.

BACKGROUND: Endotracheal intubation in severely injured patients is known to be a risk factor for systemic complications. We aimed to examine the changes in intubation rates and durations in severely injured trauma patients, and rates of the systemic complications associated with ventilation changes by using a large trauma registry over the period of 13 years. METHODS: Patient demographics, Injury Severity Score (ISS), ventilation days, ventilation free days (VFD), and prevalence of systemic complications (sepsis and multiple organ failure (MOF)) were obtained from the TraumaRegister DGU® and were compared over the study period. RESULTS: During the study period (2002 - 2014), 35,232 patients were recorded in TraumaRegister DGU®. 72.7 % of patients (n = 25,629) were intubated, and 27.3 % (n = 9603) of patients did not require mechanical ventilation throughout their hospital stay. The mean age was 48 ± 21 years, mean ISS was 27.9 ± 11.5, mean length of ICU stay was 11.7 ± 13.8 days, mean time on mechanical ventilator was 7.1 ± 11.3 days, and mean ventilation free days (spontaneous respiration) was 19.5 ± 11.9 days. We observed a reduction in the intubation rates (87.5 % in 2002 versus 63.6 % in 2014), and early extubation (10 ventilation days in 2002, and 5.9 days in 2014) over time. CONCLUSION: Our study reveals a reduction in intubation rates and ventilation duration during the observation period. Moreover, we were able to observe decreased incidence of systemic complications such as sepsis over the 13 year study period, while no changes in incidence of MOF were registered. The exact relationship can not be proven in our study. This needs to be addressed in further analysis.

Computational Analysis Supports an Early, Type 17 Cell-Associated Divergence of Blunt Trauma Survival and Mortality.

OBJECTIVE: Blunt trauma patients may present with similar demographics and injury severity yet differ with regard to survival. We hypothesized that this divergence was due to different trajectories of systemic inflammation and utilized computational analyses to define these differences. DESIGN: Retrospective clinical study and experimental study in mice. SETTING: Level 1 trauma center and experimental laboratory. PATIENTS: From a cohort of 493 victims of blunt trauma, we conducted a pairwise, retrospective, case-control study of patients who survived over 24 hours but ultimately died (nonsurvivors; n = 19) and patients who, after ICU admission, went on to be discharged(survivors; n = 19). INTERVENTIONS: None in patients. Neutralizing anti-interleukin-17A antibody in mice. MEASUREMENTS AND MAIN RESULTS: Data on systemic inflammatory mediators assessed within the first 24 hours and over 7 days were analyzed with computational modeling to infer dynamic networks of inflammation. Network density among inflammatory mediators in nonsurvivors increased in parallel with organ dysfunction scores over 7 days, suggesting the presence of early, self-sustaining, pathologic inflammation involving high-mobility group protein B1, interleukin-23, and the Th17 pathway. Survivors demonstrated a pattern commensurate with a self-resolving, predominantly lymphoid response, including higher levels of the reparative cytokine interleukin-22. Mice subjected to trauma/hemorrhage exhibited reduced organ damage when treated with anti-interleukin-17A. CONCLUSIONS: Variable type 17 immune responses are hallmarks of organ damage, survival, and mortality after blunt trauma and suggest a lymphoid cell-based switch from self-resolving to self-sustaining inflammation.

Individual-specific principal component analysis of circulating inflammatory mediators predicts early organ dysfunction in trauma patients.

PURPOSE: We hypothesized that early inflammation can drive, or impact, later multiple organ dysfunction syndrome (MODS), that patient-specific principal component analysis (PCA) of circulating inflammatory mediators could reveal conserved dynamic responses which would not be apparent from the unprocessed data, and that this computational approach could segregate trauma patients with regard to subsequent MODS. METHODS: From a cohort of 472 blunt trauma survivors, 2 separate subcohorts of moderately/severely injured patients were studied. Multiple inflammatory mediators were assessed in serial blood samples in the first 24 hours postinjury. PCA of these time course data was used to derive patient-specific "inflammation barcodes," followed by hierarchical clustering to define patient subgroups. To define the generalizability of this approach, 2 different but overlapping Luminex kits were used. RESULTS: PCA/hierarchical clustering of 24-hour Luminex data segregated the patients into 2 groups that differed significantly in their Marshall multiple organ dysfunction score on subsequent days, independently of the specific set of inflammatory mediators analyzed. Multiple inflammatory mediators and their dynamic networks were significantly different in the 2 groups in both patient cohorts, demonstrating that the groups were defined based on "core" early responses exhibit truly different dynamic inflammatory trajectories. CONCLUSION: Identification of patient-specific "core responses" can lead to early segregation of diverse trauma patients with regard to later MODS. Hence, we suggest that a focus on dynamic inflammatory networks rather than individual biomarkers is warranted.

Temporal Patterns of Circulating Inflammation Biomarker Networks Differentiate Susceptibility to Nosocomial Infection Following Blunt Trauma in Humans.

BACKGROUND: Severe traumatic injury can lead to immune dysfunction that renders trauma patients susceptible to nosocomial infections (NI) and prolonged intensive care unit (ICU) stays. We hypothesized that early circulating biomarker patterns following trauma would correlate with sustained immune dysregulation associated with NI and remote organ failure. METHODS: In a cohort of 472 blunt trauma survivors studied over an 8-year period, 127 patients (27%) were diagnosed with NI versus 345 trauma patients without NI. To perform a pairwise, case-control study with 1:1 matching, 44 of the NI patients were compared with 44 no-NI trauma patients selected by matching patient demographics and injury characteristics. Plasma obtained upon admission and over time were assayed for 26 inflammatory mediators and analyzed for the presence of dynamic networks. RESULTS: Significant differences in ICU length of stay (LOS), hospital LOS, and days on mechanical ventilation were observed in the NI patients versus no-NI patients. Although NI was not detected until day 7, multiple mediators were significantly elevated within the first 24 hours in patients who developed NI. Circulating inflammation biomarkers exhibited 4 distinct dynamic patterns, of which 2 clearly distinguish patients destined to develop NI from those who did not. Mediator network connectivity analysis revealed a higher, coordinated degree of activation of both innate and lymphoid pathways in the NI patients over the initial 24 hours. CONCLUSIONS: These studies implicate unique dynamic immune responses, reflected in circulating biomarkers that differentiate patients prone to persistent critical illness and infections following injury, independent of mechanism of injury, injury severity, age, or sex.

Insights into the Role of Chemokines, Damage-Associated Molecular Patterns, and Lymphocyte-Derived Mediators from Computational Models of Trauma-Induced Inflammation.

SIGNIFICANCE: Traumatic injury elicits a complex, dynamic, multidimensional inflammatory response that is intertwined with complications such as multiple organ dysfunction and nosocomial infection. The complex interplay between inflammation and physiology in critical illness remains a challenge for translational research, including the extrapolation to human disease from animal models. RECENT ADVANCES: Over the past decade, we and others have attempted to decipher the biocomplexity of inflammation in these settings of acute illness, using computational models to improve clinical translation. In silico modeling has been suggested as a computationally based framework for integrating data derived from basic biology experiments as well as preclinical and clinical studies. CRITICAL ISSUES: Extensive studies in cells, mice, and human blunt trauma patients have led us to suggest (i) that while an adequate level of inflammation is required for healing post-trauma, inflammation can be harmful when it becomes self-sustaining via a damage-associated molecular pattern/Toll-like receptor-driven feed-forward circuit; (ii) that chemokines play a central regulatory role in driving either self-resolving or self-maintaining inflammation that drives the early activation of both classical innate and more recently recognized lymphoid pathways; and (iii) the presence of multiple thresholds and feedback loops, which could significantly affect the propagation of inflammation across multiple body compartments. FUTURE DIRECTIONS: These insights from data-driven models into the primary drivers and interconnected networks of inflammation have been used to generate mechanistic computational models. Together, these models may be used to gain basic insights as well as serving to help define novel biomarkers and therapeutic targets.

Impact of Injury Severity on Dynamic Inflammation Networks Following Blunt Trauma.

INTRODUCTION: Clinical outcomes following trauma depend on the extent of injury and the host's response to injury, along with medical care. We hypothesized that dynamic networks of systemic inflammation manifest differently as a function of injury severity in human blunt trauma. STUDY DESIGN: From a cohort of 472 blunt trauma survivors studied following institutional review board approval, three Injury Severity Score (ISS) subcohorts were derived after matching for age and sex: mild ISS (49 patients [33 males and 16 females, aged 42 ± 1.9 years; ISS 9.5 ± 0.4]); moderate ISS (49 patients [33 males and 16 females, aged 42 ± 1.9; ISS 19.9 ± 0.4]), and severe ISS (49 patients [33 males and 16 females, aged 42 ± 2.5 years; ISS 33 ± 1.1]). Multiple inflammatory mediators were assessed in serial blood samples. Dynamic Bayesian Network inference was utilized to infer causal relationships based on probabilistic measures. RESULTS: Intensive care unit length of stay, total length of stay, days on mechanical ventilation, Marshall Multiple Organ Dysfunction score, prevalence of prehospital hypotension and nosocomial infection, and admission lactate and base deficit were elevated as a function of ISS. Multiple circulating inflammatory mediators were significantly elevated in severe ISS versus moderate or mild ISS over both the first 24 h and out to 7 days after injury. Dynamic Bayesian Network suggested that interleukin 6 production in severe ISS was affected by monocyte chemotactic protein 1/CCL2, monokine inducible by interferon γ (MIG)/CXCL9, and IP-10/CXCL10; by monocyte chemotactic protein 1/CCL2 and MIG/CXCL9 in moderate ISS; and by MIG/CXCL9 alone in mild ISS over 7 days after injury. CONCLUSIONS: Injury Severity Score correlates linearly with morbidity, prevalence of infection, and early systemic inflammatory connectivity of chemokines to interleukin 6.

Trauma in silico: Individual-specific mathematical models and virtual clinical populations.

Trauma-induced critical illness is driven by acute inflammation, and elevated systemic interleukin-6 (IL-6) after trauma is a biomarker of adverse outcomes. We constructed a multicompartment, ordinary differential equation model that represents a virtual trauma patient. Individual-specific variants of this model reproduced both systemic inflammation and outcomes of 33 blunt trauma survivors, from which a cohort of 10,000 virtual trauma patients was generated. Model-predicted length of stay in the intensive care unit, degree of multiple organ dysfunction, and IL-6 area under the curve as a function of injury severity were in concordance with the results from a validation cohort of 147 blunt trauma patients. In a subcohort of 98 trauma patients, those with high-IL-6 single-nucleotide polymorphisms (SNPs) exhibited higher plasma IL-6 levels than those with low IL-6 SNPs, matching model predictions. Although IL-6 could drive mortality in individual virtual patients, simulated outcomes in the overall cohort were independent of the propensity to produce IL-6, a prediction verified in the 98-patient subcohort. In silico randomized clinical trials suggested a small survival benefit of IL-6 inhibition, little benefit of IL-1ß inhibition, and worse survival after tumor necrosis factor-α inhibition. This study demonstrates the limitations of extrapolating from reductionist mechanisms to outcomes in individuals and populations and demonstrates the use of mechanistic simulation in complex diseases.

Prehospital Hypotension Is Associated With Altered Inflammation Dynamics and Worse Outcomes Following Blunt Trauma in Humans.

OBJECTIVE: To define the impact of prehospital hypotension on the dynamic, systemic acute inflammatory response to blunt trauma. DESIGN: Retrospective study. SETTINGS: Tertiary care institution. PATIENTS: Twenty-two hypotensive blunt trauma patients matched with 28 normotensive blunt trauma patients. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: From a cohort of 472 blunt trauma survivors studied following institutional review board approval, two stringently matched subcohorts were derived. Twenty-two patients who sustained prehospital hypotension following blunt trauma (15 males and 7 females; age, 45 ± 3.8; Injury Severity Score, 20.7 ± 1.8) were matched with 28 normotensive trauma patients (20 males and 8 females; age, 46.1 ± 2.5; Injury Severity Score, 20.8 ± 1.3). Serial blood samples (three samples within the first 24 hr and then from days 1 to 7 postinjury) were assessed for 24 inflammatory mediators using Luminex, and No2-/No3- was measured using the nitrate reductase/Griess assay. Two-way analysis of variance was used to compare groups. Dynamic Bayesian Network inference was used to infer causal relationships based on probabilistic measures. Statistically significant differences were observed in ICU length of stay, total length of stay, days on mechanical ventilator, and Marshall Multiple Organ Dysfunction score between hypotensive and normotensive patients. Shock markers (shock index, pH, lactate, and base deficit) were significantly altered in hypotensive patients. Plasma levels of chemokines (monocyte chemotactic protein-1/CCL2, inducible protein-10/CXCL10, macrophage inflammatory protein-1α/CCL3, and interleukin-8/CCL8) and cytokines (interleukin-6, interleukin-10, interleukin-17, granulocyte-macrophage colony-stimulating factor, interleukin-1ß, and interleukin-7) as well as soluble interleukin-2 receptor-α were significantly elevated over the first 7 days postinjury in the hypotensive versus normotensive patients. Dynamic Bayesian Network suggested that the chemokines monocyte chemotactic protein-1/CCL2 and monokine induced by gamma interferon/CXCL9 in the hypotensive and normotensive patients, respectively, affect plasma interleukin-6 levels differentially in the initial 24 hours postinjury. CONCLUSIONS: Studies in stringently matched patient cohorts suggest that an episode of prehospital hypotension post trauma leads to early, dynamic reprogramming of systemic inflammation (including differential upstream regulation of interleukin-6), which is associated with worse outcomes.

Inhalative IL-10 treatment after bilateral femoral fractures affect pulmonary inflammation in mice.

BACKGROUND: Musculoskeletal injuries induce systemic inflammation which often impairs lung function contributing to morbidity. IL-10 has been shown to have a beneficial effect on immune dysfunction and organ damage after different traumatic insults. We sought to investigate the effect of inhalative IL-10 administration on the systemic and pulmonary inflammatory response in a small animal model of bilateral femoral fracture. MATERIALS AND METHODS: Male C57/BL6 mice (6 animals per group) were subjected to bilateral femoral fracture and intramedullary nailing followed by inhalative administration of either 50µL PBS (Fx group) or 50µg/kg recombinant mouse IL-10 dissolved in 50µL PBS (FxIL-10 group). All animals were sacrificed at 6, 24, or 72h after fracture induction. Blood samples were collected and analyzed for IL-6, IL-10, KC, and MCP-1 (CCL2) plasma concentrations by Bio-Plex Pro™ assays. Pulmonary infiltration by neutrophils was assessed by myeloperoxidase (MPO) activity (ELISA) and histological analysis of lung tissue. Pulmonary ICAM-1 expression (immunohistochemistry), and pulmonary IL-6 levels (ELISA) were determined. RESULTS: Inhalative IL-10 administration showed a decrease in the pulmonary infiltration by neutrophils. A significant decrease in the expression of the adhesion molecule ICAM-1 after local IL-10 application was observed. In contrast, local IL-10 administration did not show a significant effect on the systemic inflammatory response. CONCLUSION: Our findings suggest that inhalative IL-10 administration may beneficially modulate the pulmonary microenvironment, in which IL-10 effect on the local ICAM-1 expression seems to play a central role.

Post-traumatic thrombo-embolic complications in polytrauma patients.

INTRODUCTION: Thrombo-embolic events after trauma are considered to be life-threatening complications. Our aim was to determine the incidence of arterial and venous thrombo-embolic events (TE) in severely-injured trauma patients, and its associated risk factors by using a large trauma registry. METHODS: Patients' data from the TraumaRegister DGU® (TR-DGU) were screened for TE (DVT [symptomatic deep vein thrombosis], PE [symptomatic pulmonary embolism], MI [myocardial infarction], and stroke) through the clinical course of severely injured adult trauma patients from January 2005 to December 2012. Univariate analysis was used to compare the clinical outcomes (endpoints: mortality, ICU and hospital length of stay, ventilator days), and a multivariate regression analysis was used to assess the independent risk factors associated with each TE event. RESULTS: From a cohort of 40,846 trauma patients, 1122 (2.8%) patients developed a TE during their post-traumatic clinical course (313, 0.8% DVT; 425, 1.0% PE; 160, 0.4% MI and 231, 0.6% stroke). ICU length of stay [LOS], total LOS, days on mechanical ventilation, and incidence of multiple organ failure (MOF) and sepsis were significantly increased in patients with TE complications. Injury severity, major pelvic injury, and one or more operations were found to be independent risk factors for the development of DVT. Age ≥ 60 years, male gender, and more than one operation were risk factors for PE development. For MI age was the only significant risk factor. The occurrence of a stroke is increased in patients with an age ≥ 60 years, major head injury (AIS head ≥ 3), and more than one operation. Finally, mortality rates were significantly higher in the TE group when compared to the non-TE cohort (21.8% vs. 12.7%; p < 0.001). CONCLUSION: TE complications were associated with longer ICU and hospital stay as well as a higher mortality. Overall, age and repeated operations were the most important risk factors for the development of TE events.

Inducible protein-10, a potential driver of neurally controlled interleukin-10 and morbidity in human blunt trauma.

OBJECTIVE: Blunt trauma and traumatic spinal cord injury induce systemic inflammation that contributes to morbidity. Dysregulated neural control of systemic inflammation postinjury is likely exaggerated in patients with traumatic spinal cord injury. We used in silico methods to discern dynamic inflammatory networks that could distinguish systemic inflammation in traumatic spinal cord injury from blunt trauma. DESIGN: Retrospective study. SETTINGS: Tertiary care institution. PATIENTS: Twenty-one severely injured thoracocervical traumatic spinal cord injury patients and matched 21 severely injured blunt trauma patients without spinal cord injury. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were obtained from days 1 to 14 postinjury. Twenty-four plasma inflammatory mediators were quantified. Statistical significance between the two groups was determined by two-way analysis of variance. Dynamic Bayesian network inference was used to suggest dynamic connectivity and central inflammatory mediators. Circulating interleukin-10 was significantly elevated in thoracocervical traumatic spinal cord injury group versus non-spinal cord injury group, whereas interleukin-1ß, soluble interleukin-2 receptor-α, interleukin-4, interleukin-5, interleukin-7, interleukin-13, interleukin-17, macrophage inflammatory protein 1α and 1ß, granulocyte-macrophage colony-stimulating factor, and interferon-γ were significantly reduced in traumatic spinal cord injury group versus non-spinal cord injury group. Dynamic Bayesian network suggested that post-spinal cord injury interleukin-10 is driven by inducible protein-10, whereas monocyte chemotactic protein-1 was central in non-spinal cord injury dynamic networks. In a separate validation cohorts of 356 patients without spinal cord injury and 85 traumatic spinal cord injury patients, individuals with plasma inducible protein-10 levels more than or equal to 730 pg/mL had significantly prolonged hospital and ICU stay and days on mechanical ventilator versus patients with plasma inducible protein-10 level less than 730 pg/mL. CONCLUSION: This is the first study to compare the dynamic systemic inflammatory responses of traumatic spinal cord injury patients versus patients without spinal cord injury, suggesting a key role for inducible protein-10 in driving systemic interleukin-10 and morbidity and highlighting the potential utility of in silico tools to identify key inflammatory drivers.

Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies.

The translation of in vitro findings to clinical outcomes is often elusive. Trauma/hemorrhagic shock (T/HS) results in hepatic hypoxia that drives inflammation. We hypothesize that in silico methods would help bridge in vitro hepatocyte data and clinical T/HS, in which the liver is a primary site of inflammation. Primary mouse hepatocytes were cultured under hypoxia (1% O2) or normoxia (21% O2) for 1-72 h, and both the cell supernatants and protein lysates were assayed for 18 inflammatory mediators by Luminex™ technology. Statistical analysis and data-driven modeling were employed to characterize the main components of the cellular response. Statistical analyses, hierarchical and k-means clustering, Principal Component Analysis, and Dynamic Network Analysis suggested MCP-1/CCL2 and IL-1α as central coordinators of hepatocyte-mediated inflammation in C57BL/6 mouse hepatocytes. Hepatocytes from MCP-1-null mice had altered dynamic inflammatory networks. Circulating MCP-1 levels segregated human T/HS survivors from non-survivors. Furthermore, T/HS survivors with elevated early levels of plasma MCP-1 post-injury had longer total lengths of stay, longer intensive care unit lengths of stay, and prolonged requirement for mechanical ventilation vs. those with low plasma MCP-1. This study identifies MCP-1 as a main driver of the response of hepatocytes in vitro and as a biomarker for clinical outcomes in T/HS, and suggests an experimental and computational framework for discovery of novel clinical biomarkers in inflammatory diseases.