The role of biological sex in severely traumatized patients on outcomes: a matched-pair analysis.

OBJECTIVE: Analyze sex differences in TraumaRegister DGU (TR-DGU). BACKGROUND: Sex differences are considered to influence trauma outcomes. However, clinical study results are controversial. METHODS: Of 29,353 prospectively recorded cases of TR-DGU, we included primary trauma room admissions with Injury Severity Score of 9 or more into the analysis. Pairs (n = 3887) were formed from 1 male and 1 female according to age, mechanism, injury severity by Abbreviated Injury Scale (for head, thorax, abdomen, extremities), and occurrence of prehospital shock. Biochemical markers, treatment modalities, length of stay, and outcome (multiple organ failure, sepsis, mortality rates) were assessed. Statistical significance was accepted at P < 0.05. Odds ratios (ORs) are given with 95% confidence interval (CI). RESULTS: Females had less multiple organ failure [OR: 1.18 (95% CI, 1.05-1.33); P = 0.007], particularly in age group of 16 to 44 years; sepsis [OR: 1.45 (95% CI, 1.21-1.74); P < 0.001]), particularly at age more than 45 years; and mortality [OR: 1.14 (95% CI, 1.01-1.28); P = 0.037]. Prehospital chest tube insertions (214 vs 158) and surgical procedures before intensive care unit admission were more often performed in males (79.7% vs 76.4%). Females had lower mean hemoglobin levels [10.7 ± 2.6 vs 11.9 ± 2.8 (mg/dL)]. There were no sex differences in fluid resuscitation, shock index, coagulation, and base excess. CONCLUSIONS: Males are more susceptible to multiple organ failure, sepsis, and mortality after trauma. Differences were not exclusively related to reproductive age and thus cannot be attributed to sex hormones alone. Females aged 16 to 44 years seem to tolerate shock better. Higher susceptibility to sepsis might be explained by male immune function or increased systemic burden from higher rates of surgical interventions.

The Prognostic Value of Presepsin for Sepsis in Abdominal Surgery: A Prospective Study.

INTRODUCTION: Rapid diagnosis accompanied by appropriate treatment is essential in the therapy of sepsis. However, there is no blood marker available, which reliably predicts sepsis and associated mortality. Therefore, the aim of the present study was to evaluate presepsin and endotoxin in comparison with established blood markers in patients undergoing emergency visceral surgery for abdominal infection. PATIENTS AND METHODS: This prospective study included 31 patients with abdominal infection undergoing emergency surgery between March and August 2014. The Sepsis-2 and Sepsis-3 definitions of sepsis were used. Blood markers (presepsin, endotoxin, C-reactive protein, procalcitonin (PCT), interleukin 6 (IL-6), white blood count) were analyzed preoperatively and correlated with the clinical course and mortality. Additionally, a combination of the three markers, which performed best, was tested. RESULTS: Twenty patients (64.5%) in the analyzed cohort developed sepsis from an abdominal focus according to the latest sepsis definition. Out of the analyzed blood markers, presepsin exhibited the highest area under the curve, sensitivity, and specificity for the prediction of the development of sepsis. Moreover, presepsin had the highest predictive value for mortality as opposed to both endotoxin and previously established blood markers (i.e., PCT, IL-6). The multimarker approach, which included PCT, IL-6, and presepsin, showed no additional predictive value over presepsin alone. CONCLUSION: The present study suggests that presepsin is a novel predictor of sepsis and mortality from sepsis in patients undergoing surgery for intra-abdominal infections. The findings of the present study should be validated in a larger cohort.

Early down-regulation of the pro-inflammatory potential of monocytes is correlated to organ dysfunction in patients after severe multiple injury: a cohort study.

INTRODUCTION: Severe tissue trauma results in a general inflammatory immune response (SIRS) representing an overall inflammatory reaction of the immune system. However, there is little known about the functional alterations of monocytes in the early posttraumatic phase, characterized by the battle of the individual with the initial trauma. METHODS: Thirteen patients with severe multiple injury; injury severity score (ISS) >16 points (17 to 57) were included. The cytokine synthesis profiles of monocytes were characterized on admission, and followed up 6, 12, 24, 48, and 72 hours after severe multiple injury using flow cytometry. Whole blood was challenged with lipopolysaccharide (LPS) and subsequently analyzed for intracellular monocyte-related TNF-alpha, IL-1beta, IL-6, and IL-8. The degree of organ dysfunction was assessed using the multiple organ dysfunction syndrome (MODS)-score of Marshall on admission, 24 hours and 72 hours after injury. RESULTS: Our data clearly show that the capacity of circulating monocytes to produce these mediators de novo was significantly diminished very early reaching a nadir 24 hours after severe injury followed by a rapid and nearly complete recovery another 48 hours later compared with admission and controls, respectively. In contrast to the initial injury severity, there was a significant correlation detectable between the clinical signs of multiple organ dysfunction and the ex vivo cytokine response. CONCLUSIONS: As our data derived from very narrow intervals of measurements, they might contribute to a more detailed understanding of the early immune alterations recognized after severe trauma. It can be concluded that indeed as previously postulated an immediate hyperactivation of circulating monocytes is rapidly followed by a substantial paralysis of cell function. Moreover, our findings clearly demonstrate that the restricted capacity of monocytes to produce proinflammatory cytokines after severe injury is not only an in vitro phenomenon but also undistinguishable associated with the onset of organ dysfunction in the clinical scenario.

Monocytic HLA-DR Expression for Prediction of Anastomotic Leak after Colorectal Surgery.

BACKGROUND: Earlier detection of anastomotic leakage (AL) after colorectal procedures could minimize the detrimental clinical impact of AL and thereby reduce morbidity and mortality. STUDY DESIGN: We conducted a prospective study with assessment of the diagnostic accuracy of monocytic HLA-DR (mHLA-DR) expression compared with WBCs, C-reactive protein (CRP), and procalcitonin (PCT) in predicting AL in patients undergoing elective colorectal operation with anastomosis. RESULTS: Comparison of the blood marker values on postoperative day (POD) 4 revealed significant differences for all markers, but the difference for mHLA-DR was highly significant (15% expression of monocytes in AL patients vs 34% in patients without AL; p = 0.001). Together with WBC (p = 0.026), mHLA-DR expression was the only test to show significance on day 3 (14% vs 31%; p < 0.001). Receiver operating characteristic analysis revealed that mHLA-DR expression had superior diagnostic accuracy compared with all other diagnostic markers both on POD 3 (mHLA-DR area under the curve [AUC] 0.928; WBC AUC 0.734; CRP AUC 0.707; PCT AUC 0.672) and POD 4 (mHLA-DR AUC 0.887; WBC AUC 0.738; CRP AUC 0.709; PCT AUC 0.696). Monocytic HLA-DR had a negative predictive value of at least 94% on PODs 3 and 4, as well as specificity and positive predictive values of 100% at a threshold of 23% on POD 3 and 24% on POD 4, respectively. CONCLUSIONS: Expression of mHLA-DR appears to be a more accurate predictor for AL after colorectal operation compared with WBC, CRP, and PCT. It represents a promising test to precisely monitor the perioperative course of high-risk patients and contribute to safer discharge.

Systemic ubiquitin release after blunt trauma and burns: association with injury severity, posttraumatic complications, and survival.

BACKGROUND: Recent data suggest that ubiquitin (Ub) is systemically released after trauma, has pleiotropic effects on host defense mechanisms, and that Ub administration reduces fluid shifts into tissues during inflammation. Ub release after burns (B) has not been studied and its association with injury severity and outcome after blunt trauma (T) is unknown. Thus, we evaluated Ubs association with injury severity and outcomes after B and T. METHODS: Injury severity was assessed with the Injury Severity Score (ISS) in T and burn size (% total body surface area, %TBSA) in B. A total of 129 T (ISS: 26 +/- 13) and 55 B (46% +/- 18% TBSA) were observed for sepsis/multiple organ failure (MOF) and survival. In B, sequential organ failure assessment scores were documented daily. Fifty volunteers served as controls (C) Ub serum levels were measured on day 0 (admission), 1, 3, 5, and 7 by enzyme-linked immunosorbent assay. Data were analyzed using bivariate or partial correlation analyses, t test, and analysis of variance with Tukey post-hoc test for multiple comparisons (two-tailed p < 0.05). RESULTS: Ub was significantly elevated in patients. Peak levels (ng/mL) were detectable on day 0 (C: 118 +/- 76; T: 359 +/- 205; B: 573 +/- 331) and increased with increased ISS, %TBSA, and presence of inhalation injury. In T, Ub normalized by day 3, but remained elevated in B. In B, Ub correlated significantly negative with sequential organ failure assessment scores (r: -0.143; p = 0.0147), sepsis/MOF development (r: -0.363; p = 0.001), and survival (r: -0.231; p = 0.009). Compared with B who recovered uneventfully, Ub levels were significantly lower on days 1 to 7 and on days 5/7 in B who developed sepsis/MOF or died, respectively. CONCLUSION: Ub concentrations reflect the extent of tissue damage. Along with Ubs previously described anti- inflammatory properties, this study suggests that its systemic release is protective, that burn patients who develop sepsis/MOF have a relative Ub deficiency and that Ub could play an important role during the physiologic response to burn injury.

Temporary Intra-Operative Portocaval Shunts, Post-Operative Infections, and Mid-Term Survival after Cava-Sparing Liver Transplantation.

BACKGROUND: Temporary intra-operative portocaval shunts (TPCS) are believed to improve outcomes after cava-sparing liver transplantation. We hypothesize that decompression of the portal venous system via a TPCS reduces gut congestion, thereby decreasing bacterial translocation. Thus, we sought to clarify whether transplantation with a TPCS alters rates of post-operative infections and survival. PATIENTS AND METHODS: Patients undergoing liver transplantation (n = 189) were stratified by usage of a TPCS and the type of intra-operative antibiotic prophylaxis. Rates of post-operative infections were analyzed using the χ2 test. The log-rank test was used to compare 120-d survival. RESULTS: The analysis of patients transplanted with a TPCS and meropenem revealed increased infection rates with gut-specific pathogens (Escherichia coli, Escherichia faecalis, Escherichia faecium; p = 0.04) and equal 120-d survival in comparison with patients transplanted without a TPCS. When vancomycin was added to meropenem infection rates did not differ and patients transplanted with a TPCS had better survival in comparison with patients transplanted without a TPCS (p = 0.02). Within the TPCS group, the administration of meropenem and vancomycin was associated with improved survival in comparison with meropenem only (p = 0.03). CONCLUSION: Survival of patients may be improved by usage of a TPCS when gut-specific pathogens are covered by intra-operative antibiotic prophylaxis.

Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome.

OBJECTIVES: Complex regional pain syndrome type 1 (CRPS 1) is a disorder that can affect an extremity after minor trauma or surgery. The pathogenesis of this syndrome is unclear. It has clinical signs of severe local inflammation as a result of an exaggerated inflammatory response, but neurogenic dysregulation also may contribute to it. METHODS: For further insights into the pathogenesis of CRPS 1, the authors investigated inflammatory and neurogenic mediators-C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), soluble tumor necrosis factor receptor I/II (sTNFR I/II), sE-selectin, sL-selectin, sP-selectin, substance P, neuropeptide Y, and calcitonin gene-related peptide-in venous blood from both the healthy arm and the arm with acute CRPS I from 25 patients and from 30 healthy volunteers. RESULTS: Levels of IL-8 and sTNFR I/II were significantly elevated in patients, whereas all soluble forms of selectins were significantly suppressed. There was no significant difference in white blood cell count (WBC), CRP, and IL-6. Substance P was significantly elevated in patients. The other two neuropeptides were unchanged. None of the parameters studied showed any differences between the CRPS I-affected arm and the normal arm. CONCLUSIONS: Elevated IL-8 and sTNFR I/II levels indicate an association between CRPS I and an inflammatory process. Normal WBC, CRP, and IL-6 give evidence for localized inflammation. The hypothesis of neurogenic-induced inflammation mediated by neuropeptides is supported by elevated substance P levels.

Major surgical trauma differentially affects T-cells and APC.

Macrophages have been reported to initiate immunosuppression following trauma and hemorrhage, and recent experimental studies suggest a pivotal role of T-cells in maintaining immunosuppression. The aim of the present study was to investigate the interaction of APC and T-cells in humans following major surgery. First, APC and T-cells from 14 surgical patients were isolated, counted and characterized by their specific surface marker profile 2 and 24 h postoperatively. Then, these cells were co-incubated with cells of the other type, which had been isolated pre-operatively. Chemokine secretion from pre-operative cells as measured by enzyme immunoassay served as a bioassay for the function of the stimulating postoperative cells. CD3(+) T-cells and surface marker CD28 were markedly suppressed postoperatively, while CD3(+)CD25(+)CD127(-)Tregs were not suppressed. CD14(+)APC counts were increased with the most significant increase observed in CD14(+)HLA-DR(-) myeloid-derived suppressor cells. In co-cultures, APC showed increased postoperative secretion of TNF-α and IL-6 independently of whether they had been co-incubated with pre- or postoperative T-cells. T-cells incubated with CD14(+) cells 2 h postoperatively secreted diminished amounts of IFN-γ. The results of the study suggest that T-cells play a pivotal role in mediating immunosuppression after major abdominal surgery.

A consensus statement on empiric therapy for suspected gram-positive infections in surgical patients.

BACKGROUND: Multidrug resistance among gram-positive pathogens in tertiary and other care centers is common. A systematic decision pathway to help select empiric antibiotic therapy for suspected gram-positive postsurgical infections is presented. DATA SOURCES: A Medline search with regard to empiric antibiotic therapy was performed and assessed by the 15-member expert panel. Two separate panel meetings were convened and followed by a writing, editorial, and review process. CONCLUSIONS: The main goal of empiric treatment in postsurgical patients with suspected gram-positive infections is to improve clinical status. Empiric therapy should be initiated at the earliest sign of infection in all critically ill patients. The choice of therapy should flow from beta-lactams to vancomycin to parenteral linezolid or quinupristin-dalfopristin. In patients likely to be discharged, oral linezolid is an option. Antibiotic resistance is an important issue, and in developing treatment algorithms for reduction of resistance, the utility of these new antibiotics may be extended and reduce morbidity and mortality.

Alarmins MRP8 and MRP14 induce stress tolerance in phagocytes under sterile inflammatory conditions.

Hyporesponsiveness by phagocytes is a well-known phenomenon in sepsis that is frequently induced by low-dose endotoxin stimulation of Toll-like receptor 4 (TLR4) but can also be found under sterile inflammatory conditions. We now demonstrate that the endogenous alarmins MRP8 and MRP14 induce phagocyte hyporesponsiveness via chromatin modifications in a TLR4-dependent manner that results in enhanced survival to septic shock in mice. During sterile inflammation, polytrauma and burn trauma patients initially present with high serum concentrations of myeloid-related proteins (MRPs). Human neonatal phagocytes are primed for hyporesponsiveness by increased peripartal MRP concentrations, which was confirmed in murine neonatal endotoxinemia in wild-type and MRP14(-/-) mice. Our data therefore indicate that alarmin-triggered phagocyte tolerance represents a regulatory mechanism for the susceptibility of neonates during systemic infections and sterile inflammation.

Functional characterization of cultured keratinocytes after acute cutaneous burn injury.

BACKGROUND: In addition to forming the epithelial barrier against the outside environment keratinocytes are immunologically active cells. In the treatment of severely burned skin, cryoconserved keratinocyte allografts gain in importance. It has been proposed that these allografts accelerate wound healing also due to the expression of a favourable--keratinocyte-derived--cytokine and growth factor milieu. METHODS: In this study the morphology and cytokine expression profile of keratinocytes from skin after acute burn injury was compared to non-burned skin. Skin samples were obtained from patients after severe burn injury and healthy controls. Cells were cultured and secretion of selected inflammatory mediators was quantified using Bioplex Immunoassays. Immunohistochemistry was performed to analyse further functional and morphologic parameters. RESULTS: Histology revealed increased terminal differentiation of keratinocytes (CK10, CK11) in allografts from non-burned skin compared to a higher portion of proliferative cells (CK5, vimentin) in acute burn injury. Increased levels of IL-1α, IL-2, IL-4, IL-10, IFN-γ and TNFα could be detected in culture media of burn injury skin cultures. Both culture groups contained large amounts of IL-1RA. IL-6 and GM-CSF were increased during the first 15 days of culture of burned skin compared to control skin. Levels of VEGF, FGF-basic, TGF-ß und G-CSF were high in both but not significantly different. Cryoconservation led to a diminished mediator synthesis except for higher levels of intracellular IL-1α and IL-1ß. CONCLUSION: Skin allografts from non-burned skin show a different secretion pattern of keratinocyte-derived cytokines and inflammatory mediators compared to keratinocytes after burn injury. As these secreted molecules exert auto- and paracrine effects and subsequently contribute to healing and barrier restoration after acute burn injury therapies affecting this specific cytokine/growth factor micromilieu could be beneficial in burned patients.

Hypothermia for prediction of death in severely injured blunt trauma patients.

Hypothermia is considered an independent predictor of death after trauma. The aim of this study was to assess these premises based on data from the TraumaRegistry DGU® (TR-DGU) using its outcome predication tool, the Revised Injury Severity Classification (RISC) score, in comparison with three previously published regression models by Shafi, Martin, and Wang. We hypothesized that body temperature on admission would improve accuracy of the RISC score. Data of 5,197 patients with documented body temperature on admission (T) and complete data for RISC score prognosis were selected from TR-DGU. Hypothermia was defined as T of 35°C or less. Patients were divided into hypothermia and normothermia group. Differences were assessed using Mann-Whitney U and chi-squared tests. Statistical significance was accepted at P < 0.01(*). Moreover, we performed multivariate logistic regression analyses using TR-DGU data on the four models (including RISC) with hospital mortality as dependant variable. Results are given as mean or odds ratio (OR) with 95% confidence intervals (95% CIs). Hypothermic patients were more severely injured (Injury Severity Score, 35.0 vs. 29.2 points*) and had higher rates of shock (38.3 vs. 16.8%*), organ failure (71.8 vs. 46%*), and sepsis (17.5 vs. 10.6%*). Survival was worse (29.2 vs. 13.7%*). Comparison of the above models revealed hypothermia as an independent risk factor (Martin: OR, 1.43 [95% CI, 2.21-1.42*]; and Wang: OR, 1.77 [95% CI, 2.21-1.42*]) only, although it would drop out from the model (RISC: OR, 1.12 [95% CI, 1.41-0.89; P = 0.33] and Shafi: OR, 1,.21 [95% CI, 1.60-0.92; P = 0.17]) as long as parameters to indicate hemorrhage and/or coagulopathy were included in sufficient number, a finding confirmed by a subsequent sensitivity analysis. We conclude that hypothermia is a result of injury severity and therefore unlikely to be an independent predictor of mortality. Our data suggest that hypothermia belongs closely to the hemorrhage/coagulopathy group of predictors.

Prevention of abdominal wound infection (PROUD trial, DRKS00000390): study protocol for a randomized controlled trial.

BACKGROUND: Wound infection affects a considerable portion of patients after abdominal operations, increasing health care costs and postoperative morbidity and affecting quality of life. Antibacterial coating has been suggested as an effective measure to decrease postoperative wound infections after laparotomies. The INLINE metaanalysis has recently shown the superiority of a slowly absorbable continuous suture for abdominal closure; with PDS plus® such a suture has now been made available with triclosan antibacterial coating. METHODS/DESIGN: The PROUD trial is designed as a randomised, controlled, observer, surgeon and patient blinded multicenter superiority trial with two parallel groups and a primary endpoint of wound infection during 30 days after surgery. The intervention group will receive triclosan coated polydioxanone sutures, whereas the control group will receive the standard polydioxanone sutures; abdominal closure will otherwise be standardized in both groups. Statistical analysis is based on intention-to-treat population via binary logistic regression analysis, the total sample size of n=750 is sufficient to ensure alpha=5% and power=80%, an interim analysis will be carried out after data of 375 patients are available. DISCUSSION: The PROUD trial will yield robust data to determine the effectiveness of antibacterial coating in one of the standard sutures for abdominal closure and potentially lead to amendment of current guidelines. The exploration of clinically objective parameters as well as quality of life holds immediate relevance for clinical management and the pragmatic trial design ensures high external validity. TRIAL REGISTRATION: The trial protocol has been registered with the German Clinical Trials Register (DRKS00000390).

Neutrophil-derived circulating free DNA (cf-DNA/NETs), a potential prognostic marker for mortality in patients with severe burn injury.

The predictive value of circulating free DNA/neutrophil extracellular traps (cf-DNA/NETs) has recently been shown in patients with major trauma for sepsis, multiple organ failure, and mortality. Here we report on the predictive potential of cf-DNA/NETs for mortality in patients with severe burn injury. In a prospective study 32 patients with severe burn injury were included. Blood samples were sequentially obtained on day 1, 3, 5, and 7 after admission. cf-DNA/NETs was directly quantified from plasma by means of rapid fluorescence assay. Time kinetics of cf-DNA/NETs were correlated with clinical data, C-reactive protein (CRP), procalcitonin (PCT), and interleukin (IL)-6. Furthermore sensitivity, specificity, and positive and negative predictive value, as well as receiver operation characteristic (ROC) curves were calculated. Seven patients died within the first month after burn injury. cf-DNA/NETs values from these patients were significantly increased already on day 1 and 3 after admission compared with patients who survived (p < 0.01). In contrast, PCT levels of nonsurvivors were significantly elevated on day 3 and 5 (p < 0.01), while CRP and IL-6 did not show any significant difference between survivors and nonsurvivors. At a cutoff of 255 ng/ml, cf-DNA/NETs had sensitivity of 0.8 and specificity of 0.74. ROC revealed largest areas under the curve (AUC) for cf-DNA/NETs on day 1 (0.851) and 3 (0.883) after admission. For all values between day 1 and 7, AUC was 0.815. cf-DNA/NETs seems to be a rapid, valuable marker for prediction of mortality in burn patients. A larger confirmation trial ought to be carried out.

Circulating proteasomes after burn injury.

The objective of the study is to test whether circulating proteasomes are increased in burn patients and to assess whether possible alterations are associated with severity of injury, organ failure, and/or clinically relevant outcomes. In this study, plasma was obtained from burn patients on days 0 (admission, n = 50), 1 (n = 36), 3 (n = 35), 5 (n = 28), 7 (n=34), and 30 (n = 10) (controls: 40 volunteers). The 20S/26S proteasome levels were measured by enzyme-linked immunosorbent assay. Proteasome peptidase activity was assessed using a chymotryptic-like peptide substrate in combination with epoxomicin (specific proteasome inhibitor). Percentage of TBSA burned, presence of inhalation injury, development of sepsis/multiple organ failure, and sequential organ failure assessment scores were documented. On admission, plasma proteasome activity was higher in patients than in controls (P = .011). 26S proteasomes were not detectable. The 20S proteasome concentrations (median [25th/75th percentile]) peaked on day 0 (673 [399/1566] ng/mL; control: 195 [149/249] ng/mL, P < .001), gradually declined within 7 days, and fully returned to baseline at day 30 (116.5 [78/196] ng/mL). Elevated 20S proteasomes were associated with the presence of inhalation injury and correlated linearly with %TBSA in patients without inhalation injury. Initial 20S proteasome concentrations discriminated the presence of inhalation injury in patients with (sensitivity 0.88 and specificity 0.71) and without (sensitivity 0.83 and specificity 0.97) cutaneous burns but did not discriminate sepsis/multiple organ failure development or survival. Circulating 20S proteasome is a biomarker of tissue damage. The 20S proteasome plasma concentrations in patients with burns and/or inhalation injury are unlikely to predict outcomes but may be useful for the diagnosis of inhalation injury.

The potential role of T-cells and their interaction with antigen-presenting cells in mediating immunosuppression following trauma-hemorrhage.

OBJECTIVE: Trauma-hemorrhage results in depressed immune responses of antigen-presenting cells (APCs) and T-cells. Recent studies suggest a key role of depressed T-cell derived interferon (IFN)-g in this complex immune cell interaction. The aim of this study was to elucidate further the underlying mechanisms responsible for dysfunctional T-cells and their interaction with APCs following trauma-hemorrhage. DESIGN: Adult C3H/HeN male mice were subjected to trauma-hemorrhage (3-cm midline laparotomy) followed by hemorrhage (blood pressure of 35 +/- 5 mmHg for 90 min and resuscitation) or sham operation. At 24 h thereafter, spleens were harvested and T-cells (by Microbeads) and APCs (via adherence) were Isolated. Co-cultures of T-cells and APCs were established for 48 h and stimulated with concanavalin A and lipopolysaccharide. T-Cell specific cytokines known to affect APC function (i.e. interleukin(IL)-2, IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF)) were measured in culture supernatants by Multiplex assay. The expression of MHC class II as well as co-stimulatory surface molecules on T-cells and APCs was determined by flow cytometry. RESULTS: The release of IL-4 and GM-CSF by T-cells was suppressed following trauma-hemorrhage, irrespective of whether sham or trauma-hemorrhage APCs were present. Antigen-presenting cells from animals subjected to trauma-hemorrhage did not affect T-cell derived cytokine release by sham T-cells. In contrast, T-cells from trauma-hemorrhage animals depressed MHC class II expression of CD11c(+) cells, irrespective of whether APCs underwent sham or trauma-hemorrhage procedure. Surprisingly, co-stimulatory molecules on APCs (CD80, CD86) were not affected by trauma-hemorrhage. CONCLUSIONS: These results suggest that beside IFN-g other T-cell derived cytokines contribute to immunosuppression following trauma-hemorrhage causing diminished MHC II expression on APCs. Thus, T-cells appear to play an important role in this interaction at the time-point examined. Therapeutic approaches should aim at maintenance of T-cell function and their interaction with APCs to prevent extended immunosuppression following trauma-hemorrhage.

The impact of endogenous triggers on trauma-associated inflammation.

PURPOSE OF REVIEW: Inflammation immediately starting after trauma is a consequence of an efficient host defense system that is not only capable of sensing exogenous and pathogen-derived danger signals, but also endogenous, multifunctional alarm signals, which both can initiate an inflammatory response. RECENT FINDINGS: Even in the absence of infection, Toll-like receptors play an important role in inflammation via recognition of host-derived, endogenous 'damage signals' like heat shock proteins and 'alarmins' such as the nuclear protein high-mobility group box protein 1, which are presented as a result of tissue trauma. In addition to the Toll-like receptors, a number of other receptors are involved in the host inflammatory response, including the new family of nucleotide oligomerization domain-like receptors capable of sensing the presence of danger signals in the cytoplasm. Important links occur between the Toll-like receptors as key inducers of the pro-forms of interleukin-1beta and interleukin-18 and the activation of certain nucleotide oligomerization domain-like receptors, resulting in inflammasome formation--an essential process leading to the secretion of these proinflammatory cytokines. SUMMARY: In addition to improved insights into the regulation of traumatic inflammation and the etiology of the systemic inflammatory response syndrome, some endogenous immune triggers seem to have the potential to serve as novel biomarkers in predicting post-traumatic complications.

Dehydroepiandrosterone restores depressed peripheral blood mononuclear cell function following major abdominal surgery via the estrogen receptors.

OBJECTIVE: Peripheral blood mononuclear cell (PBMC) dysfunction occurs following major abdominal surgery and correlates with an increased rate of septic complications. Studies have shown that dehydroepiandrosterone (DHEA) restores cell-mediated immune responses after trauma-hemorrhage in mice. Nonetheless, it remains unknown whether DHEA has any salutary effects on depressed PBMC function in surgical patients. DESIGN: Laboratory experiment. SETTING: University laboratory. PATIENTS: Fifteen patients undergoing major abdominal surgery. INTERVENTIONS: Blood samples were obtained preoperatively and 2 hrs postoperatively. MEASUREMENTS AND MAIN RESULTS: PBMCs were cultured with 33% plasma in the presence or absence of DHEA (10(-10) M, 10(-8) M physiologic concentration, 10(-6) M, 10(-5) M). In an additional set of samples, the estrogen receptor antagonist tamoxifen (10(-6) M) was added. The release of proinflammatory cytokines (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha) was measured in the supernatants by enzyme-linked immunosorbent assay. Abdominal surgery resulted in depressed interleukin-1beta and tumor necrosis factor-alpha release by PBMC. Addition of DHEA to the culture medium, however, significantly improved the release of interleukin-1beta and tumor necrosis factor-alpha and stimulated the interleukin-6 release capacity of PBMC. This effect was most pronounced for a concentration of 10(-5)M DHEA. The immunomodulatory effect of DHEA on PBMC cytokine release was completely blocked by tamoxifen. In contrast, the modulatory effect of DHEA was enhanced by the addition of postoperative plasma. CONCLUSIONS: DHEA stimulates proinflammatory cytokine release capacities of human PBMCs following major abdominal surgery. The estrogen receptor appears to be involved in mediating the immunomodulatory effect of DHEA. Thus, DHEA might be a useful adjunct for preventing immunosuppression in surgical patients.