Exposure to psychological trauma (for example, childhood/early life adversity, exposure to violence or assault, combat exposure, accidents or natural disasters) is known to increase one’s risk of developing certain chronic medical conditions. Clinical and population studies provide evidence of systemic inflammatory activity in trauma survivors with various psychiatric and nonpsychiatric conditions. This transdiagnostic meta-analysis quantitatively integrates the literature on the relationship of inflammatory biomarkers to trauma exposure and related symptomatology. We conducted random effects meta-analyses relating trauma exposure to log-transformed inflammatory biomarker concentrations, using meta-regression models to test the effects of study quality and psychiatric symptomatology on the inflammatory outcomes. Across k=36 independent samples and n=14 991 participants, trauma exposure was positively associated with C-reactive protein (CRP), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α (mean rs =0.2455, 0.3067, 0.2890, and 0.2998, respectively). No significant relationships were noted with fibrinogen, IL-2, IL-4, IL-8, or IL-10. In meta-regression models, the presence of psychiatric symptoms was a significant predictor of increased effect sizes for IL-1β and IL-6 (β=1.0175 and 0.3568, respectively), whereas study quality assessment scores were associated with increased effect sizes for IL-6 (β=0.3812). Positive correlations between inflammation and trauma exposure across a range of sample types and diagnoses were found. Although reviewed studies spanned an array of populations, research on any one specific psychiatric diagnosis was generally limited to one or two studies. The results suggest that chronic inflammation likely represents one potential mechanism underlying risk of health problems in trauma survivors.

Traumatic brain injury (TBI) elicits intense sympathetic nervous system (SNS) activation with profuse catecholamine secretion. The resultant hyperadrenergic state is linked to immunomodulation both within the brain and systemically. Dysregulated inflammation post-TBI exacerbates secondary brain injury and contributes to unfavorable patient outcomes including death. The aim of this study was to characterize the early dynamic profile of circulating inflammatory cytokines/chemokines in patients admitted for moderate-to-severe TBI, to examine interrelationships between these mediators and catecholamines, as well as clinical indices of injury severity and neurological outcome. Blood was sampled from 166 isolated TBI patients (aged 45 ± 20.3 years; 74.7 % male) on admission, 6-, 12-, and 24-h post-injury and from healthy controls (N = 21). Plasma cytokine [interleukin (IL)-1β, -2, -4, -5, -10, -12p70, -13, tumor necrosis factor (TNF)-α, interferon (IFN)-γ] and chemokine [IL-8, eotaxin, eotaxin-3, IFN-γ-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, -4, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1β, thymus activation regulated chemokine (TARC)] concentrations were analyzed using high-sensitivity electrochemiluminescence multiplex immunoassays. Plasma catecholamines [epinephrine (Epi), norepinephrine (NE)] were measured by immunoassay. Neurological outcome at 6 months was assessed using the extended Glasgow outcome scale (GOSE) dichotomized as good (>4) or poor (≤4) outcomes. Patients showed altered levels of IL-10 and all chemokines assayed relative to controls. Significant differences in a number of markers were evident between moderate and severe TBI cohorts. Elevated IL-8, IL-10, and TNF-α, as well as alterations in 8 of 9 chemokines, were associated with poor outcome at 6 months. Notably, a positive association was found between Epi and IL-1β, IL-10, Eotaxin, IL-8, and MCP-1. NE was positively associated with IL-1β, IL-10, TNF-α, eotaxin, IL-8, IP-10, and MCP-1. Our results provide further evidence that exaggerated SNS activation acutely after isolated TBI in humans may contribute to harmful peripheral inflammatory cytokine/chemokine dysregulation. These findings are consistent with a potentially beneficial role for therapies aimed at modulating the inflammatory response and hyperadrenergic state acutely post-injury.

To investigate the potential immunologic and anti-inflammatory effects of hypertonic saline plus dextran (HSD) in hemorrhagic trauma patients. Unbalanced inflammation triggered by shock has been linked to multiorgan dysfunction (MOD) and death. In animal and cellular models, HSD alters the inflammatory response to shock, attenuating MOD and improving outcome. It remains untested whether HSD has similar effects in humans. A single 250-mL dose of either HSD (7.5% NaCl, 6% dextran-70) or placebo (0.9% NaCl) was administered to adult blunt trauma patients in hemorrhagic shock. The primary outcome was to measure changes in immune/inflammatory markers, including neutrophil activation, monocyte subset redistribution, cytokine production, and neuroendocrine changes. Patient demographics, fluid requirements, organ dysfunction, infection, and death were recorded. A total of 27 patients were enrolled (13 HSD) with no significant differences in clinical measurements. Hyperosmolarity was modest and transient, whereas the immunologic/anti-inflammatory effects persisted for 24 hours. HSD blunted neutrophil activation by abolishing shock-induced CD11b up-regulation and causing CD62L shedding. HSD altered the shock-induced monocyte redistribution pattern by reducing the drop in “classic” CD14++ and the expansion of the “pro-inflammatory” CD14+CD16+ subsets. In parallel, HSD significantly reduced pro-inflammatory tumor necrosis factor (TNF)-α production while increasing anti-inflammatory IL-1ra and IL-10. HSD prevented shock-induced norepinephrine surge with no effect on adrenal steroids. This first human trial evaluating the immunologic/anti-inflammatory effects of hypertonic resuscitation in trauma patients demonstrates that HSD promotes a more balanced inflammatory response to hemorrhagic shock, raising the possibility that similar to experimental models, HSD might also attenuate post-trauma MOD.

This study examined endotoxin-mediated cytokinemia during exertional heat stress (EHS). Subjects were divided into trained [TR; n = 12, peak aerobic power (V̇o_2peak) = 70 ± 2 ml·kg lean body mass⁻¹·min⁻¹] and untrained (UT; n = 11, V̇o_2peak= 50 ± 1 ml·kg lean body mass⁻¹·min⁻¹) groups before walking at 4.5 km/h with 2% elevation in a climatic chamber (40°C, 30% relative humidity) wearing protective clothing until exhaustion (Exh). Venous blood samples at baseline and 0.5°C rectal temperature increments (38.0, 38.5, 39.0, 39.5, and 40.0°C/Exh) were analyzed for endotoxin, lipopolysaccharide binding protein, circulating cytokines, and intranuclear NF-κB translocation. Baseline and Exh samples were also stimulated with LPS (100 ng/ml) and cultured in vitro in a 37°C water bath for 30 min. Phenotypic determination of natural killer cell frequency was also determined. Enhanced blood (104 ± 6 vs. 84 ± 3 ml/kg) and plasma volumes (64 ± 4 vs. 51 ± 2 ml/kg) were observed in TR compared with UT subjects. EHS produced an increased concentration of circulating endotoxin in both TR (8 ± 2 pg/ml) and UT subjects (15 ± 3 pg/ml) (range: not detected to 32 pg/ml), corresponding with NF-κB translocation and cytokine increases in both groups. In addition, circulating levels of tumor necrosis factor-α and IL-6 were also elevated combined with concomitant increases in IL-1 receptor antagonist in both groups and IL-10 in TR subjects only. Findings suggest that the threshold for endotoxin leakage and inflammatory activation during EHS occurs at a lower temperature in UT compared with TR subjects and support the endotoxin translocation hypothesis of exertional heat stroke, linking endotoxin tolerance and heat tolerance.

Intracranial hemorrhage (ICH) is common in traumatic brain injury (TBI) and a major determinant of death and disability. ICH commonly increases in size and coagulopathy has been implicated in such progression. We investigated the association between coagulopathy diagnosed by routine laboratory tests and ICH progression. Subgroup post hoc analysis from a randomized controlled trial including adult patients with blunt severe TBI (Glasgow Coma Scale score ≤8) and repeat computerized tomography scans in 48 hours. Coagulopathy was defined as international normalized ratio ≥1.3, activated partial thromboplastin time ≥35, or platelet count (PLT) ≤100 × 109/L any time in the first 24 hours. Progression was any size increase or new ICH. TBI-associated coagulopathy was investigated measuring soluble tissue factor (TF) and d-dimer. The ICH progressed in 37 of 72 patients (51%), in 80% if any abnormal laboratory test (coagulopathic patients) versus 36% in noncoagulopathic (p = 0.0004). Abnormal international normalized ratio (odds ratio [OR] = 4.09; 95% confidence interval [CI] = 1.29–12.95; p = 0.017), PLT (OR = 12.59; 95% CI = 1.52–108.57; p = 0.019), head Abbreviated Injury Scale (AIS) (OR = 1.82; 95% CI = 1.15–2.88; p = 0.011) were significantly associated with progression (univariate analysis). In a multiple logistic regression, only head AIS (OR = 1.81; 95% CI 1.10–2.98; p = 0.0198) and PLT (OR = 11.8; 95% CI = 1.38–101.23; p = 0.024) correlated with progression. All patients with abnormal partial thromboplastin time experienced progression. ICH progression carried a 5-fold higher odds of death; 32% with progression died versus 8.6% without. Age, head AIS, Injury Severity Score, and d-dimer were also associated with mortality. Tissue factor was not associated with progression or mortality. This study demonstrates an association between coagulopathy, diagnosed by routine laboratorial tests in the first 24 hours, with ICH progression; and ICH progression with mortality in patients with severe TBI. The causal relationship between coagulopathy and ICH progression will require further studies.

Elevated catecholamine levels might be associated with unfavorable outcome after traumatic brain injury (TBI). We investigated the association between catecholamine levels in the first 24 h post-trauma and functional outcome in patients with isolated moderate-to-severe TBI. A cohort of 174 patients who sustained isolated blunt TBI was prospectively enrolled from three Level-1 Trauma Centers. Epinephrine (Epi) and norepinephrine (NE) concentrations were measured at admission (baseline), 6, 12 and 24 h post-injury. Outcome was assessed at 6 months by the extended Glasgow Outcome Scale (GOSE) score. Fractional polynomial plots and logistic regression models (fixed and random effects) were used to study the association between catecholamine levels and outcome. Effect size was reported as the odds ratio (OR) associated with one logarithmic change in catecholamine level. At 6 months, 109 patients (62.6%) had an unfavorable outcome (GOSE 5–8 vs. 1–4), including 51 deaths (29.3%). Higher admission levels of Epi were associated with a higher risk of unfavorable outcome (OR, 2.04, 95% CI: 1.31–3.18, p = 0.002) and mortality (OR, 2.86, 95% CI: 1.62–5.01, p = 0.001). Higher admission levels of NE were associated with higher risk of unfavorable outcome (OR, 1.59, 95% CI: 1.07–2.35, p = 0.022) but not mortality (OR, 1.45, 95% CI: 0.98–2.17, p = 0.07). There was no relationship between the changes in Epi levels over time and mortality or unfavorable outcome. Changes in NE levels with time were statistically associated with a higher risk of mortality, but the changes had no relation to unfavorable outcome. Elevated circulating catecholamines, especially Epi levels on hospital admission, are independently associated with functional outcome and mortality after isolated moderate-to-severe TBI.