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

ABSTRACT: 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.Retrospective clinical study and experimental study in mice.Level 1 trauma center and experimental laboratory.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).None in patients. Neutralizing anti-interleukin-17A antibody in mice.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.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.

SUBMITTER: Abboud A

PROVIDER: S-EPMC5201164 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Abboud Andrew A Namas Rami A RA Ramadan Mostafa M Mi Qi Q Almahmoud Khalid K Abdul-Malak Othman O Azhar Nabil N Zaaqoq Akram A Namas Rajaie R Barclay Derek A DA Yin Jinling J Sperry Jason J Peitzman Andrew A Zamora Ruben R Simmons Richard L RL Billiar Timothy R TR Vodovotz Yoram Y

Critical care medicine 20161101 11

<h4>Objective</h4>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.<h4>Design</h4>Retrospective clinical study and experimental study in mice.<h4>Setting</h4>Level 1 trauma center and experimental laboratory.<h4>Patients</h4>From a cohort of 493 victims of blunt trauma, we ...[more]

PMID: 27513538

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Project description:ImportanceHemorrhagic shock is a common cause of preventable death after injury. Vasopressor administration for patients with blunt trauma and hemorrhagic shock is often discouraged.ObjectiveTo evaluate the association of early norepinephrine administration with 24-hour mortality among patients with blunt trauma and hemorrhagic shock.Design, setting, and participantsThis retrospective, multicenter, observational cohort study used data from 3 registries in the US and France on all consecutive patients with blunt trauma from January 1, 2013, to December 31, 2018. Patients were alive on admission with hemorrhagic shock, defined by prehospital or admission systolic blood pressure less than 100 mm Hg and evidence of hemorrhage (ie, prehospital or resuscitation room transfusion of packed red blood cells, receipt of emergency treatment for hemorrhage control, transfusion of >10 units of packed red blood cells in the first 24 hours, or death from hemorrhage). Blunt trauma was defined as any exposure to nonpenetrating kinetic energy, collision, or deceleration. Statistical analysis was performed from January 15, 2021, to February 22, 2022.ExposureContinuous administration of norepinephrine in the prehospital environment or resuscitation room prior to hemorrhage control, according to European guidelines.Main outcomes and measuresThe primary outcome was 24-hour mortality, and the secondary outcome was in-hospital mortality. The average treatment effect (ATE) of early norepinephrine administration on 24-hour mortality was estimated according to the Rubin causal model. Inverse propensity score weighting and the doubly robust approach with 5 distinct analytical strategies were used to determine the ATE.ResultsA total of 52 568 patients were screened for inclusion, and 2164 patients (1508 men [70%]; mean [SD] age, 46 [19] years; median Injury Severity Score, 29 [IQR, 17-36]) presented with acute hemorrhage and were included. A total of 1497 patients (69.1%) required emergency hemorrhage control, 128 (5.9%) received a prehospital transfusion of packed red blood cells, and 543 (25.0%) received a massive transfusion. Norepinephrine was administered to 1498 patients (69.2%). The 24-hour mortality rate was 17.8% (385 of 2164), and the in-hospital mortality rate was 35.6% (770 of 2164). None of the 5 analytical strategies suggested any statistically significant association between norepinephrine administration and 24-hour mortality, with ATEs ranging from -4.6 (95% CI, -11.9 to 2.7) to 2.1 (95% CI, -2.1 to 6.3), or between norepinephrine administration and in-hospital mortality, with ATEs ranging from -1.3 (95% CI, -9.5 to 6.9) to 5.3 (95% CI, -2.1 to 12.8).Conclusions and relevanceThe findings of this study suggest that early norepinephrine infusion was not associated with 24-hour or in-hospital mortality among patients with blunt trauma and hemorrhagic shock. Randomized clinical trials that study the effect of early norepinephrine administration among patients with trauma and hypotension are warranted to further assess whether norepinephrine is safe for patients with hemorrhagic shock.

Project description:ImportanceAlthough several studies have demonstrated an improvement in mortality for injured adults who receive whole-body computed tomography (WBCT), it is unclear whether children experience the same benefit.ObjectiveTo determine whether emergent WBCT is associated with lower mortality among children with blunt trauma compared with a selective CT approach.Design, setting, and participantsA retrospective, multicenter cohort study was conducted from January 1, 2010, to December 31, 2014, using data from the National Trauma Data Bank on children aged 6 months to 14 years with blunt trauma who received an emergent CT scan in the first 2 hours after emergency department arrival. Data analysis was conducted from February 2 to December 29, 2017.ExposuresPatients were classified as having WBCT if they received CT head, CT chest, and CT abdomen/pelvis scans in the first 2 hours and as having a selective CT if they did not receive all 3 scans.Main outcomes and measuresThe primary outcome was in-hospital mortality in the 7 days after ED arrival. To adjust for potential confounding, propensity score weighting was used. Subgroup analyses were performed for those with the highest mortality risk (ie, occupants and pedestrians involved in motor vehicle crashes, children with a Glasgow Coma Scale score lower than 9, children with hypotension, and those admitted to the intensive care unit).ResultsOf the 42?912 children included in the study (median age [interquartile range], 9 [5-12] years; 27?861 [64.9%] boys), 8757 (20.4%) received a WBCT. Overall, 405 (0.9%) children died within 7 days. After adjusting for the propensity score, children who received WBCT had no significant difference in mortality compared with those who received selective CT (absolute risk difference, -0.2%; 95% CI, -0.6% to 0.1%). All subgroup analyses similarly showed no significant association between WBCT and mortality.Conclusions and relevanceAmong children with blunt trauma, WBCT, compared with a selective CT approach, was not associated with lower mortality. These findings do not support the routine use of WBCT for children with blunt trauma.

Project description:Trauma/hemorrhagic shock followed by resuscitation (T/HS-R) results in multi-system inflammation and organ dysfunction, in part driven by binding of damage-associated molecular pattern molecules to Toll-like Receptor 4 (TLR4). We carried out experimental T/HS-R (pseudo-fracture plus 2 h of shock followed by 0-22 h of resuscitation) in C57BL/6 (wild type [WT]) and TLR4-null (TLR4-/-) mice, and then defined the dynamics of 20 protein-level inflammatory mediators in the heart, gut, lung, liver, spleen, kidney, and systemic circulation. Cross-correlation and Principal Component Analysis (PCA) on data from the 7 tissues sampled suggested that TLR4-/- samples express multiple inflammatory mediators in a small subset of tissue compartments as compared to the WT samples, in which many inflammatory mediators were localized non-specifically to nearly all compartments. We and others have previously defined a central role for type 17 immune cells in human trauma. Accordingly, correlations between IL-17A and GM-CSF (indicative of pathogenic Th17 cells); between IL-17A and IL-10 (indicative of non-pathogenic Th17 cells); and IL-17A and TNF (indicative of memory/effector T cells) were assessed across all tissues studied. In both WT and TLR4-/- mice, positive correlations were observed between IL-17A and GM-CSF, IL-10, and TNF in the kidney and gut. In contrast, the variable and dynamic presence of both pathogenic and non-pathogenic Th17 cells was inferred in the systemic circulation of TLR4-/- mice over time, suggesting a role for TLR4 in efflux of these cells into peripheral tissues. Hypergraph analysis - used to define dynamic, cross compartment networks - in concert with PCA-suggested that IL-17A was present persistently in all tissues at all sampled time points except for its absence in the plasma at 0.5h in the WT group, supporting the hypothesis that T/HS-R induces efflux of Th17 cells from the circulation and into specific tissues. These analyses suggest a complex, context-specific role for TLR4 and type 17 immunity following T/HS-R.

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

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

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