Thromboembolic events in burn patients: An analysis of risk factors and different anticoagulants.

BACKGROUND: Burn patients are in a state of activated coagulation, putting them at risk for thromboembolic events. Additionally, certain patient-related factors are associated with an increased risk of thrombus formation. This study aimed to evaluate the incidence of thromboembolic events and identify potential risk factors, including patient characteristics, surgical treatment, anticoagulation strategies, and laboratory parameters. METHODS: A single-centre retrospective cohort study was conducted on all patients with burns treated between 2002 and 2020. Medical reports of patients with and without thromboembolic events were descriptively analysed. The association of time to thromboembolic events with total body surface area (TBSA) was assessed by cause-specific Cox models adjusted for different covariates. The association of time to thromboembolic events with type and dosage of anticoagulants was assessed using a cause-specific Cox proportional hazards model with time-dependent covariates, applied to a matched subset of patients. RESULTS: The incidence of thromboembolic events was 8.1% in a cohort of 642 patients. We found a statistically significant increase in the hazard for thromboembolic events by a factor of 1.02 (95% CI 1.00 to 1.03; P ≤ 0.05) per percent increase in TBSA. We identified former alcohol abuse (HR=2.54, CI 1.33 to 4.84, P = 0.005) and higher body mass index (HR=1.06, 95% CI 1.00 to 1.12, P = 0.046) as potential risk factors for the development of thromboembolic events. We further noted inadequate median anti-Factor-X activity levels and elevated C-reactive protein and procalcitonin levels at the time of the event. CONCLUSION: Our results showed a moderate risk of thromboembolic events among burn patients, underlining the importance of close monitoring with regard to thrombus formation. In particular, patients with higher TBSA, alcohol abuse and BMI may be evaluated more regularly for thromboembolic events. Anti-Factor-X activity levels should be determined regularly and therapy should be adjusted if necessary.

Human amniotic membranes as an allogenic biological dressing for the treatment of burn wounds: Protocol for a randomized-controlled study.

Background: Burn wounds pose significant challenges in medical treatment due to their devastating nature and resource-intensive requirements. Temporary coverage of burn wounds using synthetic or biological dressings allows for reepithelization before definitive skin grafting. Allogenic skin grafts have been widely used but come with drawbacks such as rejection and disease transmission. The use of amniotic membranes (AMs) offers a promising alternative for temporary coverage, as they possess biological properties that promote faster healing and improved scar quality. The various components of the amniotic membrane, including pluripotent stem cells, extracellular matrix proteins, and regenerative factors, contribute to cell growth, migration, and differentiation, as well as preservation of the original epithelial phenotype. Objective: Reliable information on the treatment of burn wounds with AM is needed. The knowledge gained in this project may help to include this advantageous modern concept of biological dressings in clinical practice. The purpose of this study is to use human amniotic membranes from our in hospital laboratory, as an allogenic biological dressing after enzymatic debridement in superficial partial thickness, deep partial thickness or full thickness burn wounds. Methods: We will include 30 patients in a randomized-controlled trial with each patient receiving the study intervention and the control intervention. Two 7 × 7 cm burn wound areas will be compared regarding percentage of skin graft take, healing time, healing percentage value and total healing time. Human amniotic membranes will be compared to allogenic skin grafts.

Enzymatic debridement for circumferential deep burns: the role of surgical escharotomy.

INTRODUCTION: Circumferential deep burns carry a high risk for a burn induced compartment syndrome. It was recently shown that an enzymatic bromelain-based debridement with Nexobrid® is a safe and efficient procedure to release pressure in deep circumferential extremity burns reducing the need for surgical escharotomy. We therefore herein aimed to analyze the conceptual relation between Nexobrid® and surgical escharotomy. PATIENTS AND METHODS: We conducted a retrospective study on all patients with circumferential deep partial-thickness or full-thickness burns requiring immediate escharotomy that was either performed by surgical incision or Nexobrid®. Medical records of 792 patients that were treated at the burn center of the University Hospital Zurich between 2016 and 2021 were analyzed. RESULTS: Overall, 62 patients with circumferential deep partial-thickness or full-thickness burns who received preventive decompression either by Nexobrid® (N = 29) or surgical escharotomy (N = 33), were included. Whilst distribution of age, sex, BMI and type of injury showed no difference between the groups, the ABSI score, TBSA, percentage of third degree burns and mortality were significantly higher in patients who received a surgical escharotomy. CONCLUSION: While the use of Nexobrid® to prevent burn induced compartment syndrome has steadily increased, surgical escharotomies were predominantly performed in severely burned patients with a high degree of full-thickness burns. Thus, higher mortality in this patient group needs to be considered with caution and is mainly attributed to the higher TBSA. Although evidence is lacking for the use of Nexobrid® for larger body areas exceeding 15%, escharotomy is also the more reliable and faster approach in such critically burned patients.

Incidence and Time Point of Sepsis Detection as Related to Different Sepsis Definitions in Severely Burned Patients and Their Accompanying Time Course of Pro-Inflammatory Biomarkers.

BACKGROUND: Diagnosis of sepsis in burn patients remains difficult for various reasons. One major problem is the definition of sepsis itself. Therefore, previous and current sepsis definitions are a matter of ongoing validation, but a well-defined consensus on which clinical and laboratory parameters to incorporate in such a definition is lacking. The aim of the present study was to compare the incidence and time-related occurrence of septic events according to different definitions as well as their accompanying time course of pro-inflammatory biomarkers. METHODS: Across the first 14 days after admission, the incidence and time point of sepsis according to three different definitions (Sepsis-3, Sepsis American Burns Association [ABA] 2007, Sepsis Zurich Burn Center) were assessed on a daily basis in adult burn patients with total body surface area (TBSA) ≥15% admitted to the Zurich Burn Center between May 2015 and October 2018. In order to investigate how well daily drawn proinflammatory biomarkers (white blood cells (WBCs), C-reactive protein (CRP), procalcitonin (PCT), and novel pancreatic stone protein (PSP)) reflect the progression of sepsis depending on its type of definition, a longitudinal mixed model analysis was performed across the first 14 days for septic and non-septic patients. Additionally, the relative increase of biomarker levels 24, 48, and 72 h prior to a septic event was analyzed for each definition used. RESULTS: In our cohort of 90 severely burned patients, Sepsis-3 identified 46 patients (51.1%) as septic, while ABA 2007 and the Zurich Burn Center definition counted 33 patients (36.7%) and 24 patients (26.6%), respectively. Sepsis-3 detected sepsis about 1 day earlier than Sepsis ABA 2007 (p < 0.001) and about 0.5 days earlier than Sepsis Zurich Burn Center (p = 0.04). The course of pro-inflammatory biomarkers was largely unaffected by the type of sepsis definition. Irrespective of the sepsis definition, PSP was the only marker to demonstrate a highly significant interaction between time and group (sepsis versus no sepsis) (p < 0.001) with a 3.3-5.5-fold increase within 72 h before the event of sepsis, whereas CRP, PCT, and WBC showed only mild undulations. CONCLUSIONS: Despite the ongoing dilemma of how to define sepsis in burn patients, a continually calculated SOFA score as used in Sepsis-3 is advantageous to early identify a patient's detrimental progression to sepsis. Inclusion of biomarkers, such as PSP, may help support the burn specialist's diagnosis of sepsis and could improve the diagnostic performance of current and future definitions in burn patients.

Pancreatic Stone Protein Predicts Sepsis in Severely Burned Patients Irrespective of Trauma Severity: A Monocentric Observational Study.

OBJECTIVE: The burn victim's inherent state of hyperinflammation frequently camouflages septic events delaying the initiation of targeted intensive care therapy. Accurate biomarkers are urgently needed to support sepsis detection before patients' clinical deterioration. SUMMARY OF BACKGROUND DATA: Evidence on the usefulness of pancreatic stone protein (PSP) as a powerful diagnostic and prognostic marker in critically ill patients has recently accumulated. METHODS: Analysis of biomarker kinetics (PSP, routine markers) was performed on 90 patients admitted to the Zurich Burn Center between May 2015 and October 2018 with burns ≥15% total body surface area with regard to infection and sepsis (Sepsis-3) over a 14-day time course. RESULTS: PSP differentiated between sepsis, infection and sterile inflammation from day 3 onward with an area under the curve of up to 0.89 (P < 0.001), therefore, competing with procalcitonin (area under the curve = 0.86, P < 0.001). Compared to routine inflammatory biomarkers, only PSP demonstrated a significant interaction between time and presence of sepsis - signifying a steeper increase in PSP levels in septic patients as opposed to those exhibiting a nonseptic course (interaction P < 0.001). Event-related analysis demonstrated tripled PSP serum levels within 72 hours and doubled levels within 48 hours before a clinically apparent sepsis. CONCLUSION: PSP is able to differentiate between septic and nonseptic patients during acute burn care. Its steep rise up to 72 hours before clinically overt deterioration has the potential for physicians to timely initiate treatment with reduced mortality and costs.

Response of routine inflammatory biomarkers and novel Pancreatic Stone Protein to inhalation injury and its interference with sepsis detection in severely burned patients.

BACKGROUND: Inhalation of thermal and chemical products of combustion evokes an immune response measurable at a systemic level. Inhalation injury related kinetics of currently available inflammatory biomarkers and novel Pancreatic Stone Protein (PSP) as well as their interference with septic events has not been addressed to literature yet. METHODS: Analysis of the influence of inhalation injury and ARDS on biomarker kinetics (PSP, procalcitonin (PCT), C-reactive Protein (CRP), white blood cells (WBC)) in 90 patients admitted to Zurich Burn Center between May 2015 and October 2018 with burns ≥15% total body surface area (TBSA) over 14 days. RESULTS: Twenty-five (27%) of 90 included patients presented with inhalation injury (median age 52 years [IQR 27], median TBSA 31.5% [IQR 21], mean ABSI-Score 7±3). At admission, only WBC demonstrated significantly higher values in the inhalation injury group (p=0.011). Acute respiratory distress syndrome (ARDS) was present in 32% without association to the severity of inhalation injury (p=0.11). WBC, CRP and PCT failed to delineate inhalation injury related inflammation from septic progression at most time points. PSP was the strongest marker to identify septic patients both by its higher values and steeper increase over time (p<0.001). CONCLUSION: Inhalation injury leads to an inflammatory response at a systemic level with alterations of biomarkers. While routine inflammatory markers demonstrated strong interferences between inhalation injury with its associated ARDS and evolving sepsis, PSP reliably identified septic patients in a setting of inflammatory turbulences secondary to inhalation injury.

Expression of Pancreatic Stone Protein is Unaffected by Trauma and Subsequent Surgery in Burn Patients.

BACKGROUND: Altered levels of pro-inflammatory markers secondary to trauma or surgery present a major problem to physicians in being prone to interfere with the clinical identification of infectious events. METHODS: Patients admitted to Zurich Burn Center between May 2015 and October 2018 with burns ≥10% total body surface area (TBSA) and without infection. Longitudinal analysis of the time course of PSP and routine inflammatory biomarkers [procalcitonin (PCT), C-reactive protein (CRP) and white blood cells (WBC)] over two days after (a) trauma with initial debridement and (b) subsequent burn surgeries was performed. The influence of TBSA, abbreviated burn severity index (ABSI), age and length of operation was investigated using a linear mixed effect regression model. RESULTS: Sixty-six patients (15 female) were included with a mean age of 45.5 ± 18.3 years, median TBSA of 22% (IQR 17) and mean ABSI score 6.8 ± 2.7. PSP was the only biomarker that showed no association with any of the baseline characteristics. Additionally, PSP serum levels did not change over time neither after the burn trauma (p = 0.832) nor after secondary procedures (p = 0.113), while PCT levels increased significantly after the trauma (p < 0.001). Similarly, CRP serum levels were elevated significantly after both trauma and surgery (p < 0.001), whereas WBC values demonstrated a significant decline after the trauma (p < 0.001). CONCLUSION: Established biomarkers (WBC, CRP and PCT) demonstrate decisive alterations after tissue destruction caused by burn injuries and subsequent surgical interventions. The robustness of PSP serum levels toward these inflammatory insults is a quality criterion for an upcoming sepsis biomarker.

Hemorrhagic shock drives glycocalyx, barrier and organ dysfunction early after polytrauma.

Polytrauma (PT) is frequently associated with hemorrhagic shock (HS), which increases morbidity and mortality. Although various aspects of HS have been addressed in PT patients, the impact of an additional HS is largely unknown regarding the development of multiple organ dysfunction associated with disturbed glycocalyx and barrier function early after trauma. A prospective, longitudinal, mono-centered, observational study enrolling severely injured patients (Injury Severity Score, ISS=38.1±2.6) served for an in-depth analysis of blood (drawn on days 0, 1, 2, 3 and 5) and clinical data (up to 21days) of 30 patients who were then stratified into PT with and without HS. HS significantly enhanced signs of acute organ injury, assessed by increased serum concentrations of novel damage markers. Moreover, indicators of glycocalyx and tight-junction dysfunction were found in PT patients all of which were significantly enhanced in co-presence of HS. These markers revealed multiple significant correlations with specific barrier, fluid-balance, coagulation, inflammation, and clinical-outcome parameters. Strikingly, mucosa fragments, which affected clotting, could be detected in serum after PT/HS. The results point to HS as a main driver for glycocalyx and barrier breakdown and suggest novel tools for the monitoring of organ dysfunction in the early course after PT.

Reconstruction of the Heel, Middle Foot Sole, and Plantar Forefoot with the Medial Plantar Artery Perforator Flap: Clinical Experience with 28 Cases.

BACKGROUND: Defects in the weight-bearing region of the foot sole can represent a substantial restriction in quality of life and pose a challenge for reconstructive plastic surgery. The purpose of this article is to report the authors' experience with the use of the medial plantar artery perforator flap for reconstruction of defects of the foot sole in three different regions: heel, middle foot sole, and plantar forefoot. METHODS: From January of 2003 to May of 2016, 28 patients (13 male and 15 female patients) with an average age of 54 years (range, 12 to 84 years) underwent reconstruction with 28 medial plantar artery perforator flaps. Twenty-six flaps were harvested as pedicle perforator flaps and two as free perforator flaps. All flaps were raised from the ipsilateral instep area. The defect locations included the heel (20 cases), middle foot sole (four cases), and forefoot (four cases). The causes of reconstruction were tumors in 18 patients, decubitus in eight patients, and trauma in two patients. RESULTS: The flap sizes varied from 2.5 × 2.5 cm to 5.5 × 9.5 cm. All of the flaps survived completely after surgery, apart from one. The donor sites were all covered with a split-thickness skin graft. Follow-up observations were conducted for 4 to 12 months, and all patients had good functional recovery with satisfactory cosmetic results. CONCLUSION: The medial plantar artery perforator flap can be considered an optimal method of foot sole reconstruction not only for covering the weight-bearing area of the heel but also for the middle and forefoot plantar region. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects.

During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pHi), we propose a direct mechanistic link between complement activation and neutrophil pHi In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pHi of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pHi These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pHi balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.

An Integrated Clinico-transcriptomic Approach Identifies a Central Role of the Heme Degradation Pathway for Septic Complications after Trauma.

OBJECTIVE: The present study was aimed to identify mechanisms linked to complicated courses and adverse events after severe trauma by a systems biology approach. SUMMARY BACKGROUND DATA: In severe trauma, overwhelming systemic inflammation can result in additional damage and the development of complications, including sepsis. METHODS: In a prospective, longitudinal single-center study, RNA samples from circulating leukocytes from patients with multiple injury (injury severity score ≥17 points; n = 81) were analyzed for dynamic changes in gene expression over a period of 21 days by whole-genome screening (discovery set; n = 10 patients; 90 samples) and quantitative RT-PCR (validation set; n = 71 patients, 517 samples). Multivariate correlational analysis of transcripts and clinical parameters was used to identify mechanisms related to sepsis. RESULTS: Transcriptome profiling of the discovery set revealed the strongest changes between patients with either systemic inflammation or sepsis in gene expression of the heme degradation pathway. Using quantitative RT-PCR analyses (validation set), the key components haptoglobin (HP), cluster of differentiation (CD) 163, heme oxygenase-1 (HMOX1), and biliverdin reductase A (BLVRA) showed robust changes following trauma. Upregulation of HP was associated with the severity of systemic inflammation and the development of sepsis. Patients who received allogeneic blood transfusions had a higher incidence of nosocomial infections and sepsis, and the amount of blood transfusion as source of free heme correlated with the expression pattern of HP. CONCLUSIONS: These findings indicate that the heme degradation pathway is associated with increased susceptibility to septic complications after trauma, which is indicated by HP expression in particular.

Direct transplantation of native pericytes from adipose tissue: A new perspective to stimulate healing in critical size bone defects.

BACKGROUND AIMS: Fractures with a critical size bone defect (e.g., open fracture with segmental bone loss) are associated with high rates of delayed union and non-union. The prevention and treatment of these complications remain a serious issue in trauma and orthopaedic surgery. Autologous cancellous bone grafting is a well-established and widely used technique. However, it has drawbacks related to availability, increased morbidity and insufficient efficacy. Mesenchymal stromal cells can potentially be used to improve fracture healing. In particular, human fat tissue has been identified as a good source of multilineage adipose-derived stem cells, which can be differentiated into osteoblasts. The main issue is that mesenchymal stromal cells are a heterogeneous population of progenitors and lineage-committed cells harboring a broad range of regenerative properties. This heterogeneity is also mirrored in the differentiation potential of these cells. In the present study, we sought to test the possibility to enrich defined subpopulations of stem/progenitor cells for direct therapeutic application without requiring an in vitro expansion. METHODS: We enriched a CD146+NG2+CD45- population of pericytes from freshly isolated stromal vascular fraction from mouse fat tissue and tested their osteogenic differentiation capacity in vitro and in vivo in a mouse model for critical size bone injury. RESULTS: Our results confirm the ability of enriched CD146+NG2+CD45- cells to efficiently generate osteoblasts in vitro, to colonize cancellous bone scaffolds and to successfully contribute to regeneration of large bone defects in vivo. CONCLUSIONS: This study represents proof of principle for the direct use of enriched populations of cells with stem/progenitor identity for therapeutic applications.

Improvement of prognostic performance in severely injured patients by integrated clinico-transcriptomics: a translational approach.

INTRODUCTION: Severe trauma triggers a systemic inflammatory response that contributes to secondary complications, such as nosocomial infections, sepsis or multi-organ failure. The present study was aimed to identify markers predicting complications and an adverse outcome of severely injured patients by an integrated clinico-transcriptomic approach. METHODS: In a prospective study, RNA samples from circulating leukocytes from severely injured patients (injury severity score ≥ 17 points; n = 104) admitted to a Level I Trauma Center were analyzed for dynamic changes in gene expression over a period of 21 days by quantitative RT-PCR. Transcriptomic candidates were selected based on whole genome screening of a representative discovery set (n = 10 patients) or known mechanisms of the immune response, including mediators of inflammation (IL-8, IL-10, TNF-α, MIF, C5, CD59, SPHK1), danger signaling (HMGB1, TLR2, CD14, IL-33, IL-1RL1), and components of the heme degradation pathway (HP, CD163, HMOX1, BLVRA, BLVRB). Clinical markers comprised standard physiological and laboratory parameters and scoring systems routinely determined in trauma patients. RESULTS: Leukocytes, thrombocytes and the expression of sphingosine kinase-1 (SPHK1), complement C5, and haptoglobin (HP) have been identified as markers with the best performance. Leukocytes showed a biphasic course with peaks on day 0 and day 11 after trauma, and patients with sepsis exhibited significantly higher leukocyte levels. Thrombocyte numbers showed a typical profile with initial thrombopenia and robust thrombocytosis in week 3 after trauma, ranging 2- to 3-fold above the upper normal value. 'Relative thrombocytopenia' was associated with multi-organ dysfunction, the development of sepsis, and mortality, the latter of which could be predicted within 3 days prior to the time point of death. SPHK1 expression at the day of admission indicated mortality with excellent performance. C5-expression on day 1 after trauma correlated with an increased risk for the development of nosocomial infections during the later course, while HP was found to be a marker for the development of sepsis. CONCLUSIONS: The combination of clinical and transcriptomic markers improves the prognostic performance and may represent a useful tool for individual risk stratification in trauma patients.

Impact of plasma histones in human sepsis and their contribution to cellular injury and inflammation.

INTRODUCTION: Circulating histones have been identified as mediators of damage in animal models of sepsis and in patients with trauma-associated lung injury. Despite existing controversies on actual histone concentrations, clinical implications and mechanism of action in various disease conditions, histone levels in human sepsis, association with disease progression and mediated effects on endothelial and immune cells remain unreported. This study aimed to determine histone levels and its clinical implication in septic patients and to elucidate histone-mediated effects ex-vivo. METHODS: Histone levels, endogenous activated protein C (APC) levels and clinical data from two independent cohorts of septic patients were obtained. Histone levels were compared with various control groups including healthy individuals, intensive care unit (ICU) patients without sepsis, ICU patients with multiple organ failure and patients with minor or multiple trauma, all without infection. Endothelial and monocytic cells were stimulated with histones. Cellular integrity and sepsis prototypical cytokines were evaluated. The mechanism of action of histones via Toll-like receptor 4 (TLR4) was evaluated using a function blocking antibody. Histone degradation in plasma was studied by immunoblotting. RESULTS: Histone H4 levels were significantly elevated in patients with sepsis (cohort I; n = 15 and cohort II; n = 19) versus ICU controls (n = 12), patients with multiple organ failure (n = 12) or minor trauma (n = 7), associated with need for renal replacement therapy and decrease in platelet count during disease progression, and remarkably were significantly associated with increased mortality rates in septic patients (ICU-, 28 day- and 90 day mortality rates). There was an inverse correlation between plasma histones and endogenous APC levels. Histone stimulation induced the release of sepsis prototypic cytokines and decreased cell integrity indicated by a significant increase of lactate dehydrogenase (LDH) and propidium iodide (PI) staining. Blocking of TLR4 decreased cellular cytotoxicity on endothelial cells. The calculated half-life of histones in spiked plasma was 4.6 minutes. CONCLUSIONS: Histone levels in septic patients are significantly increased and might mediate disease aggravation by cellular injury and inflammation via TLR4 signaling, which potentially results in multiple organ failure and fatal outcome.

Zonulin as prehaptoglobin2 regulates lung permeability and activates the complement system.

Zonulin is a protein involved in the regulation of tight junctions (TJ) in epithelial or endothelial cells. Zonulin is known to affect TJ in gut epithelial cells, but little is known about its influences in other organs. Prehaptoglobin2 has been identified as zonulin and is related to serine proteases (MASPs, C1qrs) that activate the complement system. The current study focused on the role of zonulin in development of acute lung injury (ALI) in C57BL/6 male mice following intrapulmonary deposition of IgG immune complexes. A zonulin antagonist (AT-1001) and a related peptide with permeability agonist activities (AT-1002) were employed and given intratracheally or intravenously. Also, zonulin was blocked in lung with a neutralizing antibody. In a dose-dependent manner, AT-1001 or zonulin neutralizing antibody attenuated the intensity of ALI (as quantitated by albumin leak, neutrophil accumulation, and proinflammatory cytokines). A similar pattern was found using the bacterial lipopolysaccharide model of ALI. Using confocal microscopy on sections of injured lungs, staining patterns for TJ proteins were discontinuous, reduced, and fragmented. As expected, the leak of blood products into the alveolar space confirmed the passage of 3 and 20 kDa dextran, and albumin. In contrast to AT-1001, application of the zonulin agonist AT-1002 intensified ALI. Zonulin both in vitro and in vivo induced generation of complement C3a and C5a. Collectively, these data suggest that zonulin facilitates development of ALI both by enhancing albumin leak and complement activation as well as increased buildup of neutrophils and cytokines during development of ALI.

Changes and regulation of the C5a receptor on neutrophils during septic shock in humans.

During experimental sepsis, excessive generation of the anaphylatoxin C5a results in reduction of the C5a receptor (C5aR) on neutrophils. These events have been shown to result in impaired innate immunity. However, the regulation and fate of C5aR on neutrophils during sepsis are largely unknown. In contrast to 30 healthy volunteers, 60 patients in septic shock presented evidence of complement activation with significantly increased serum levels of C3a, C5a, and C5b-9. In the septic shock group, the corresponding decrease in complement hemolytic activity distinguished survivors from nonsurvivors. Neutrophils from patients in septic shock exhibited decreased C5aR expression, which inversely correlated with serum concentrations of C-reactive protein (CRP) and clinical outcome. In vitro exposure of normal neutrophils to native pentameric CRP led to a dose- and time-dependent loss of C5aR expression on neutrophils, whereas the monomeric form of CRP, as well as various other inflammatory mediators, failed to significantly alter C5aR levels on neutrophils. A circulating form of C5aR (cC5aR) was detected in serum by immunoblotting and a flow-based capture assay, suggestive of an intact C5aR molecule. Levels of cC5aR were significantly enhanced during septic shock, with serum levels directly correlating with lethality. The data suggest that septic shock in humans is associated with extensive complement activation, CRP-dependent loss of C5aR on neutrophils, and appearance of cC5aR in serum, which correlated with a poor outcome. Therefore, cC5aR may represent a new sepsis marker to be considered in tailoring individualized immune-modulating therapy.

Danger signals activating the immune response after trauma.

Sterile injury can cause a systemic inflammatory response syndrome (SIRS) that resembles the host response during sepsis. The inflammatory response following trauma comprises various systems of the human body which are cross-linked with each other within a highly complex network of inflammation. Endogenous danger signals (danger-associated molecular patterns; DAMPs; alarmins) as well as exogenous pathogen-associated molecular patterns (PAMPs) play a crucial role in the initiation of the immune response. With popularization of the "danger theory," numerous DAMPs and PAMPs and their corresponding pathogen-recognition receptors have been identified. In this paper, we highlight the role of the DAMPs high-mobility group box protein 1 (HMGB1), interleukin-1α (IL-1α), and interleukin-33 (IL-33) as unique dual-function mediators as well as mitochondrial danger signals released upon cellular trauma and necrosis.

Early complementopathy after multiple injuries in humans.

After severe tissue injury, innate immunity mounts a robust systemic inflammatory response. However, little is known about the immediate impact of multiple trauma on early complement function in humans. In the present study, we hypothesized that multiple trauma results in immediate activation, consumption, and dysfunction of the complement cascade and that the resulting severe "complementopathy" may be associated with morbidity and mortality. Therefore, a prospective multicenter study with 25 healthy volunteers and 40 polytrauma patients (mean injury severity score = 30.3 ± 2.9) was performed. After polytrauma, serum was collected as early as possible at the scene, on admission to the emergency room (ER), and 4, 12, 24, 120, and 240 h post-trauma and analyzed for the complement profile. Complement hemolytic activity (CH-50) was massively reduced within the first 24 h after injury, recovered only 5 days after trauma, and discriminated between lethal and nonlethal 28-day outcome. Serum levels of the complement activation products C3a and C5a were significantly elevated throughout the entire observation period and correlated with the severity of traumatic brain injury and survival. The soluble terminal complement complex SC5b-9 and mannose-binding lectin showed a biphasic response after trauma. Key fluid-phase inhibitors of complement, such as C4b-binding protein and factor I, were significantly diminished early after trauma. The present data indicate an almost synchronical rapid activation and dysfunction of complement, suggesting a trauma-induced complementopathy early after injury. These events may participate in the impairment of the innate immune response observed after severe trauma.

Cement-augmented dorsal instrumentation of the spine as a safe adjunct to the multimodal management of metastatic pheochromocytoma: a case report.

Malignant pheochromocytoma is a neuroendocrine tumor that originates from chromaffin tissue. Although osseous metastases are common, metastatic dissemination to the spine rarely occurs.Five years after primary diagnosis of extra-adrenal, abdominal pheochromocytoma and laparoscopic extirpation, a 53-year old patient presented with recurrence of pheochromocytoma involving the spine, the pelvis, both proximal femora and the right humerus. Magnetic resonance imaging and computed tomography revealed osteolytic lesions of numerous vertebrae (T1, T5, T10, and T12). In the case of T10, total destruction of the vertebral body with involvement of the rear edge resulted in the risk of vertebral collapse and subsequent spinal stenosis. Thus, dorsal instrumentation (T8-T12) and cement augmentation of T12 was performed after perioperative alpha- and beta-adrenergic blockade with phenoxybenzamine and bisoprolol.After thorough preoperative evaluation to assess the risk for surgery and anesthesia, and appropriate perioperative management including pharmacological antihypertensive treatment, dorsal instrumentation of T8-T12 and cement augmentation of T12 prior to placing the corresponding pedicle screws did not result in hypertensive crisis or hemodynamic instability due to the release of catecholamines from metastatic lesions.To the authors' knowledge, this is the first report describing cement-augmentation in combination with dorsal instrumentation to prevent osteolytic vertebral collapse in a patient with metastatic pheochromocytoma. With appropriate preoperative measures, cement-augmented dorsal instrumentation represents a safe approach to stabilize vertebral bodies with metastatic malignant pheochromocytoma. Nevertheless, direct manipulation of metastatic lesions should be avoided as far as possible in order to minimize the risk of hemodynamic complications.