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(1) Background : The use of extracorporeal membrane oxygenation (ECMO) in low cardiac output states after cardiac surgery may aid in patient recovery. However, in some patients, the clinical state may worsen, resulting in multiple organ failure and high mortality rates. In these circumstances, calculating a model of end-stage liver disease (MELD) score was shown to determine organ dysfunction and predicting mortality. (2) Methods : We evaluated whether serial MELD score determination increases mortality prediction in patients with postcardiotomy ECMO support. (3) Results : Statistically, a cutoff of a 2.5 MELD score increase within 48 h of ECMO initiation revealed an AUC of 0.722. Further, we found a significant association between hospital mortality and 48 h MELD increase (HR: 2.5, 95% CI: 1.33-4.75, p = 0.005) after adjustment for possible confounders. (4) Conclusions : Therefore, serial MELD score determinations on alternate days may be superior to single measurements in this special patient cohort.

The non-canonical inflammasome, which includes caspase-11 in mice and caspase-4 and caspase-5 in humans, is upregulated during inflammatory processes and activated in response to bacterial infections to carry out pyroptosis. Inadequate activity of the inflammasome has been associated with states of immunosuppression and immunopathological organ damage. However, the regulation of the receptors caspase-4 and caspase-5 during severe states of immunosuppression is largely not understood. We report that CASP4 and CASP5 are differentially regulated during acute-on-chronic liver failure and sepsis-associated immunosuppression, suggesting non-redundant functions in the inflammasome response to infection. While CASP5 remained upregulated and cleaved p20-GSDMD could be detected in sera from critically ill patients, CASP4 was downregulated in critically ill patients who exhibited features of immunosuppression and organ failure. Mechanistically, downregulation of CASP4 correlated with decreased gasdermin D levels and impaired interferon signaling, as reflected by decreased activity of the CASP4 transcriptional activators IRF1 and IRF2. Caspase-4 gene and protein expression inversely correlated with markers of organ dysfunction, including MELD and SOFA scores, and with GSDMD activity, illustrating the association of CASP4 levels with disease severity. Our results document the selective downregulation of the non-canonical inflammasome activator caspase-4 in the context of sepsis-associated immunosuppression and organ damage and provide new insights for the development of biomarkers or novel immunomodulatory therapies for the treatment of severe infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ghait, Duduskar, Rooney, Häfner, Reng, Göhrig, Reuken, Bloos, Bauer, Sponholz, Bruns and Rubio.)

Objective: Isolated tricuspid valve surgery is perceived as high-risk. This perception is nurtured by patients who often present with substantial liver dysfunction, which is inappropriately reflected in current surgical risk scores (eg, the Society of Thoracic Surgeons [STS] score has no specific tricuspid model). The Model for End-Stage Liver Disease (MELD) has was developed as a measure for the severity of liver dysfunction. We report scores and outcomes for our patient population., Methods: We calculated STS, European System for Cardiac Operative Risk Evaluation (EuroSCORE) II (ESII), and MELD scores for all of our patients who received isolated tricuspid valve surgery between 2011 and 2020 (n = 157). We determined the MELD score, stratified patients into 3 groups (MELD <10: low, n = 53; 10 to <20: intermediate, n = 78; ≥20: high, n = 26) and describe associated outcomes., Results: Patients were 72 ± 10 years old and 43% were male. Mean STS score was 4.9 ± 3.5% and ESII was 7.2 ± 6.6%. Mortality was 8.9% at 30 days and 65% at latest follow-up (95% CI, 51%-76%). Median follow-up was 4.4 years (range, 0-9.7 years). Although ESII and STS score accurately predicted 30-day mortality at low MELD scores (observed to expected [O/E] for ESII score = 0.8 and O/E for STS score = 1.0) and intermediate MELD (O/E for ESII score = 0.7, O/E for STS score = 1.0), mortality was underestimated at high MELD (O/E for ESII score = 3.0, O/E for STS score = 4.7). This subgroup also had higher incidence of new-onset hemodialysis. Besides MELD category, recent congestive heart failure, endocarditis, and hemodialysis were also associated with 30-day mortality., Conclusions: For isolated tricuspid valve regurgitation, classic surgical risk stratification with STS or ESII scores failed to predict perioperative mortality if there was evidence of severe liver dysfunction. Preoperative MELD assessment might be useful to assist in proper risk assessment for isolated tricuspid valve surgery., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Besides standard medical therapy and critical care monitoring, extracorporeal liver support may provide a therapeutic option in patients with liver failure. However, little is known about detoxification capabilities, efficacy, and efficiency among different devices., Methods: Retrospective single-center analysis of patients treated with extracorporeal albumin dialysis. Generalized Estimating Equations with robust variance estimator were used to account for repeated measurements of several cycles and devices per patient., Results: Between 2015 and 2021 n = 341 cycles in n = 96 patients were eligible for evaluation, thereof n = 54 (15.8%) treatments with Molecular Adsorbent Recirculating System, n = 64 (18.7%) with OpenAlbumin, n = 167 (48.8%) Advanced Organ Support treatments, and n = 56 (16.4%) using Single Pass Albumin Dialysis. Albumin dialysis resulted in significant bilirubin reduction without differences between the devices. However, ammonia levels only declined significantly in ADVOS and OPAL. First ECAD cycle was associated with highest percentage reduction in serum bilirubin. With the exception of SPAD all devices were able to remove the water-soluble substances creatinine and urea and stabilized metabolic dysfunction by increasing pH and negative base excess values. Platelets and fibrinogen levels frequently declined during treatment. Periprocedural bleeding and transfusion of red blood cells were common findings in these patients., Conclusions: From this clinical perspective ADVOS and OPAL may provide higher reduction capabilities of liver solutes (i.e. bilirubin and ammonia) in comparison to MARS and SPAD. However, further prospective studies comparing the effectiveness of the devices to support liver impairment (i.e. bile acid clearance or albumin binding capacity) as well as markers of renal recovery are warranted.

Surgery is indicated in about 50% of infective endocarditis patients, and bleeding or the transfusion of blood a common finding. The intraoperative use of cell salvage may reduce the perioperative transfusion requirement, but its use is limited in the underlying disease. In this retrospective study, we therefore evaluated n = 335 patients fulfilling the modified Duke criteria for infective endocarditis characterized by the use of intraoperative cell salvage with autologous blood retransfusion. Inflammation markers and organ dysfunction, including catecholamine dependency, were evaluated by using linear regression analysis. Between 2015 and 2020, 335 patients underwent surgery for left-sided heart valve endocarditis. Intraoperative cell salvage was used in 40.3% of the cases, especially in complex scenarios and reoperation. Intraoperative cell salvage significantly altered the white blood cell count after surgery. On average, leucocytes were 3.0 Gpt/L higher in patients with intraoperative cell salvage compared to patients without after adjustment for confounders (95% CI: 0.39-5.54). Although the difference in WBC was statistically significant, i.e., higher in the ICS group compared to the no-ICS group, this difference may be clinically unimportant. Organ dysfunction, including hemodynamic instability and lactate values, were comparable between groups. In conclusion, intraoperative cell salvage enhanced the re-transfusion of autologous blood, with minor effects on the postoperative course of inflammatory markers, but was not associated with increased hemodynamic instability or organ dysfunction in general. The restriction of intraoperative cell salvage in surgery for infective endocarditis should be re-evaluated, and more prospective data in this topic are needed.

Sepsis is defined by life-threatening organ dysfunction mediated by the host’s response to infection. This can result in septic dyslipidemia, which is involved in the neutralization of pathogen-related lipids. Knowledge of the regulatory mechanisms of septic dyslipidemia is incomplete. The cytokine betatrophin/Angiopoietin-like protein 8 (ANGPTL8) plays a role in the regulation of triacylglyceride metabolism, though its function in septic dyslipidemia remains unknown. Sixty-six patients were enrolled in a cross-sectional study. Circulating concentrations and adipose tissue (AT) mRNA expression of betatrophin/ANGPTL8 were studied in patients suffering from peritoneal sepsis. Insulin-resistant individuals and subjects without metabolic derangement/systemic inflammation were enrolled as controls. All underwent open abdominal surgery. Circulating betatrophin/ANGPTL8 was analyzed by an enzyme-linked immunosorbent assay and AT mRNA expression levels were assessed by real-time PCR. Standard laboratory analyses including lipid electrophoresis were evaluated. Sepsis patients showed pronounced septic dyslipidemia (p < 0.05 for all major lipid classes). Despite comparable betatrophin/ANGPTL8 mRNA expression in AT (p = 0.24), we found significantly increased circulating betatrophin/ANGPTL8 with septic dyslipidemia (p = 0.009). Expression levels of betatrophin/ANGPTL8 in AT correlated with circulating concentrations in both control groups (r = 0.61; p = 0.008 and r = 0.43; p = 0.034), while this association was undetectable in sepsis. After stratification, betatrophin/ANGPTL8 remained associated with hypertriacylglyceridemia (p < 0.05)., Competing Interests: All authors declare no conflict of interest with regards to the herein reported data.

Background: Recent data suggest that anesthesiologic interventions-e.g., the choice of the anesthetic regimen or the administration of blood products-might play a major role in determining outcome after tumor surgery. In contrast to adult patients, only limited data are available regarding the potential association of anesthesia and outcome in pediatric cancer patients., Methods: A retrospective multicenter study assessing data from pediatric patients (0-18 years of age) undergoing surgery for nephroblastoma between 2004 and 2018 was conducted at three academic centers in Europe. Overall and recurrence-free survival were the primary outcomes of the study and were evaluated for a potential impact of intraoperative administration of erythrocyte concentrates, the use of regional anesthesia and the choice of the anesthetic regimen. The length of stay on the intensive care unit, the time to hospital discharge after surgery and blood neutrophil-to-lymphocyte ratio were defined as secondary outcomes., Results: In total, data from 65 patients were analyzed. Intraoperative administration of erythrocyte concentrates was associated with a reduction in recurrence-free survival (hazard ratio (HR) 7.59, 95% confidence interval (CI) 1.36-42.2, p = 0.004), whereas overall survival (HR 5.37, 95% CI 0.42-68.4, p = 0.124) was not affected. The use of regional anesthesia and the choice of anesthetic used for maintenance of anesthesia did not demonstrate an effect on the primary outcomes. It was, however, associated with fewer ICU transfers, a shortened time to discharge and a decreased postoperative neutrophil-to-lymphocyte ratio., Conclusions: The current study provides the first evidence for a possible association between blood transfusion as well as anesthesiologic interventions and outcome after pediatric cancer surgery.

Background: Pre-clinical psychiatric emergencies are generally treated by emergency medical staff. The subsequent clinical treatment is often conditioned by interaction problems between emergency medical staff and psychiatric clinical staff., Objectives: To identify problems affecting interaction between emergency medical and psychiatric care of mentally ill patients and pinpoint aspects of optimized emergency care., Methods: To shed light on the interaction problems an anonymous, questionnaire-based, nonrepresentative survey of 98 emergency physicians (EM) and 104 psychiatrists (PS) practicing in acute psychiatry was conducted between March 1, 2021 and October 1, 2021., Results: The chi-square test for multiple response sets revealed consistently significant differences (p < 0.001) between EM and PS with respect to the questions analyzed. Approximately 36% of EM reported not to be adequately qualified to handle psychiatric emergencies (p = 0.0001), while around 50% of respondents were neutral in their assessment in how to deal with psychiatric emergencies. 80% of EM reported a negative interaction (rejection of patients) with PS when referring a psychiatric emergency patient to the acute psychiatric unit. The most common reasons for refusal were intoxication (EM: 78.8%, PS: 88.2%), emergency physician therapy (EM: 53.8%, PS: 63.5%), and not resident in the catchment area of the hospital (EM 68.8%, PS: 48.2%). In the casuistry presented, most respondents would choose "talk down" for de-escalation (EM: 92.1%, PS: 91.3%). With respect to drug therapy, benzodiazepine is the drug of choice (EM: 70.4%, PS: 78.8%). More EM would choose an intravenously (i.v.) or a Mucosal Atomization Device (MAD) administration as an alternative to oral medication (i.v.: EM: 38.8%, PS: 3.8%, p = 0.001, MAD: EM: 36.7%, PS: 10.6%, p = 0.006). Significantly more EM would seek phone contact with the acute psychiatric hospital (EM: 84.7%, PS: 52.9%, p = 0.0107). A psychiatric emergency plan was considered useful in this context by more than 90% of respondents. The need for further training for EM with regard to treating psychiatric clinical syndromes was considered important by all respondents. In particular, the topics of "psychogenic seizure," "intoxication," and "legal aspects of psychiatric emergencies" were considered important (Mann-Whitney U test, p < 0.001)., Conclusion: The interaction-related problems identified in the emergency medical care of pre-clinical psychiatric patients relate to non-modifiable, structural problems, such as insufficient admission capacity and non-existent or inadequate monitoring capabilities in acute psychiatric hospitals. However, factors such as the education and training of EM and communication between EM and PS can be improved. Developing personalized emergency care plans for psychiatric patients could help to optimize their care., (© 2022. The Author(s).)

Background: The value of positive end-expiratory pressure (PEEP) in maintaining oxygenation during ventilation with a laryngeal mask airway (LMA) mask is unclear. To clarify the potential benefit or harm to PEEP application during positive pressure ventilation with a ProSeal LMA® mask, we compared the effect of PEEP versus zero end-expiratory pressure (ZEEP) on gas leakage and oxygenation. We hypothesized that a PEEP of 8 mbar (8.2 cm H 2 O) would be associated with an increased incidence of gas leakage compared to ZEEP., Methods: We designed a prospective, controlled, randomized, single-blinded, multicenter clinical trial. Patients >18 years of age with an American Society of Anesthesiologists (ASA) physical status I/II without increased risk of aspiration were enrolled if they were scheduled for elective surgery under general anesthesia with an LMA mask. Patients were randomized to a control group managed with ZEEP or an intervention group managed with a PEEP of 8 mbar. Both groups received positive pressure ventilation. The primary end point was the occurrence of gas leakage. The Student t test and χ 2 test were used for statistical analysis., Results: A total of 174 patients were enrolled in the ZEEP group, and 208 were enrolled in the PEEP group. The incidence of gas leakage did not differ between the 2 groups (ZEEP: 23/174, 13.2%; PEEP: 42/208, 20.2%; P = .071; odds ratio [OR], 1.611; 95% confidence interval [CI], 0.954-2.891). However, more patients required reseating of the LMA mask in the PEEP group (ZEEP: 5/174, 2.9%; PEEP: 18/208, 8.7%; P = .018; OR, 3.202; 95% CI, 1.164-8.812). The need for endotracheal intubation did not differ between groups (ZEEP: 2/174, 1.1%; PEEP: 7/208, 3.4%; P = .190; OR, 2.995; 95% CI, 0.614-14.608). After positive pressure ventilation for 25 minutes, the mean peripheral oxygen saturation (Sp o2 ) was higher in the PEEP than in the ZEEP group (98.5 [1.9]% vs 98.0 [1.4]%; P = .01). Peak inspiratory pressure (PIP; 16 [2] vs 12 [4] mbar; P < .001) and dynamic compliance (57 [14] vs 49 [14] mL/mbar; P < .001) were both higher in the PEEP group than in the ZEEP group., Conclusions: Use of PEEP did not affect the overall incidence of gas leakage. However, PEEP did result in a higher incidence of attempts to reseat the LMA mask compared to ZEEP, whereas the incidence of rescue intubation did not differ between groups. We concluded that a PEEP of 8 mbar did not increase overall gas leakage during positive pressure ventilation with an LMA mask, but it did slightly improve gas exchange and compliance. Overall, our study does not provide strong arguments for using PEEP during ventilation with an LMA mask in elective surgery., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Objective: Postoperative pulmonary complications (PPC) remain a main issue after cardiac surgery. The objective was to report the incidence and identify risk factors of PPC after cardiac surgery., Design: An international multicenter prospective study (42 international centers in 9 countries)., Participants: A total of 707 adult patients who underwent cardiac surgery under cardiopulmonary bypass., Interventions: None MEASUREMENTS AND MAIN RESULTS: During a study period of 2 weeks, the investigators included all patients in their respective centers and screened for PPCs. PPC was defined as the occurrence of at least 1 pulmonary complication among the following: atelectasis, pleural effusion, respiratory failure, respiratory infection, pneumothorax, bronchospasm, or aspiration pneumonitis. Among 676 analyzed patients, 373 patients presented with a PPC (55%). The presence of PPC was significantly associated with a longer intensive care length of stay and hospital length of stay. One hundred ninety (64%) patients were not intraoperatively ventilated during cardiopulmonary bypass. Ventilation settings were similar regarding tidal volume, respiratory rate, inspired oxygen. In the regression model, age, the Euroscore II, chronic obstructive pulmonary disease, preoxygenation modality, intraoperative positive end-expiratory pressure, the absence of pre- cardiopulmonary bypass ventilation, the absence of lung recruitment, and the neuromuscular blockade were associated with PPC occurrence., Conclusion: Both individual risk factors and ventilatory settings were shown to explain the high level of PPCs. These findings require further investigations to assess a bundle strategy for optimal ventilation strategy to decrease PPC incidence., Competing Interests: Conflict of Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Cardiac surgery often represents the only treatment option in patients with infective endocarditis (IE). However, IE surgery may lead to a sudden release of inflammatory mediators, which is associated with postoperative organ dysfunction. We investigated the effect of hemoadsorption during IE surgery on postoperative organ dysfunction., Methods: This multicenter, randomized, nonblinded, controlled trial assigned patients undergoing cardiac surgery for IE to hemoadsorption (integration of CytoSorb to cardiopulmonary bypass) or control. The primary outcome (change in sequential organ failure assessment score [ΔSOFA]) was defined as the difference between the mean total postoperative SOFA score, calculated maximally to the 9th postoperative day, and the basal SOFA score. The analysis was by modified intention to treat. A predefined intergroup comparison was performed using a linear mixed model for ΔSOFA including surgeon and baseline SOFA score as fixed effect covariates and with the surgical center as random effect. The SOFA score assesses dysfunction in 6 organ systems, each scored from 0 to 4. Higher scores indicate worsening dysfunction. Secondary outcomes were 30-day mortality, duration of mechanical ventilation, and vasopressor and renal replacement therapy. Cytokines were measured in the first 50 patients., Results: Between January 17, 2018, and January 31, 2020, a total of 288 patients were randomly assigned to hemoadsorption (n=142) or control (n=146). Four patients in the hemoadsorption and 2 in the control group were excluded because they did not undergo surgery. The primary outcome, ΔSOFA, did not differ between the hemoadsorption and the control group (1.79±3.75 and 1.93±3.53, respectively; 95% CI, -1.30 to 0.83; P =0.6766). Mortality at 30 days (21% hemoadsorption versus 22% control; P =0.782), duration of mechanical ventilation, and vasopressor and renal replacement therapy did not differ between groups. Levels of interleukin-1β and interleukin-18 at the end of integration of hemoadsorption to cardiopulmonary bypass were significantly lower in the hemoadsorption than in the control group., Conclusions: This randomized trial failed to demonstrate a reduction in postoperative organ dysfunction through intraoperative hemoadsorption in patients undergoing cardiac surgery for IE. Although hemoadsorption reduced plasma cytokines at the end of cardiopulmonary bypass, there was no difference in any of the clinically relevant outcome measures., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03266302.

C-terminal peptides (CAAPs) of the highly abundant serine protease alpha-1-antitrypsin (A1AT) have been identified at various lengths in several human materials and have been proposed to serve as putative biomarkers for a variety of diseases. CAAPs are enzymatically formed and these enzymatic activities are often associated with excessive immune responses (e.g. sepsis, allergies). However, most of those CAAPs have been either detected using in vitro incubation experiments or in human materials which are not easily accessible. To gain a comprehensive understanding about the occurrence and function of CAAPs in health and disease, a LC-MS/MS method for the simultaneous detection of nine CAAPs was developed and validated for human plasma (EDTA and lithium-heparin) and serum. Using this newly developed method, we were able to detect and quantify five CAAPs in healthy individuals thereby providing an initial proof for the presence of C36, C37, C40 and C44 in human blood. Concentrations of four CAAPs in a clinical test cohort of patients suffering from sepsis were significantly higher compared to healthy controls. These results reveal that in addition to C42 other fragments of A1AT seem to play a crucial role during systemic infections. The proposed workflow is simple, rapid and robust; thus this method could be used as diagnostic tool in routine clinical chemistry as well as for research applications for elucidating the diagnostic potential of CAAPs in numerous diseases. To this end, we also provide an overview about the current state of knowledge for CAAPs identified in vitro and in vivo., (© 2022. The Author(s).)

Background: Infective endocarditis (IE) requires multidisciplinary management. We established an endocarditis team within our hospital in 2011 and a state-wide endocarditis network with referring hospitals in 2015. We aimed to investigate their impact on perioperative outcomes., Methods: We retrospectively analyzed data from patients operated on for IE in our center between 01/2007 and 03/2018. To investigate the impact of the endocarditis network on referral latency and pre-operative complications we divided patients into two eras: before ( n = 409) and after ( n = 221) 01/2015. To investigate the impact of the endocarditis team on post-operative outcomes we conducted multivariate binary logistic regression analyses for the whole population. Kaplan-Meier estimates of 5-year survival were reported., Results: In the second era, after establishing the endocarditis network, the median time from symptoms to referral was halved (7 days (interquartile range: 2-19) vs. 15 days (interquartile range: 6-35)), and pre-operative endocarditis-related complications were reduced, i.e., stroke (14% vs. 27%, p < 0.001), heart failure (45% vs. 69%, p < 0.001), cardiac abscesses (24% vs. 34%, p = 0.018), and acute requirement of hemodialysis (8% vs. 14%, p = 0.026). In both eras, a lack of recommendations from the endocarditis team was an independent predictor for in-hospital mortality (adjusted odds ratio: 2.12, 95% CI: 1.27-3.53, p = 0.004) and post-operative stroke (adjusted odds ratio: 2.23, 95% CI: 1.12-4.39, p = 0.02), and was associated with worse 5-year survival (59% vs. 40%, log-rank < 0.001)., Conclusion: The establishment of an endocarditis network led to the earlier referral of patients with fewer pre-operative endocarditis-related complications. Adhering to endocarditis team recommendations was an independent predictor for lower post-operative stroke and in-hospital mortality, and was associated with better 5-year survival.

Background: 30-80% of patients being treated in intensive care units in the perioperative period develop hyperglycemia. This stress hyperglycemia is induced and maintained by inflammatory-endocrine and iatrogenic stimuli and generally requires treatment. There is uncertainty regarding the optimal blood glucose targets for patients with diabetes mellitus., Methods: This review is based on pertinent publications retrieved by a selective search in PubMed and Google Scholar., Results: Patients in intensive care with pre-existing diabetes do not benefit from blood sugar reduction to the same extent as metabolically healthy individuals, but they, too, are exposed to a clinically relevant risk of hypoglycemia. A therapeutic range from 4.4 to 6.1 mmol/L (79-110 mg/dL) cannot be justified for patients with diabetes mellitus. The primary therapeutic strategy in the perioperative setting should be to strictly avoid hypoglycemia. Neurotoxic effects and the promotion of wound-healing disturbances are among the adverse consequences of hyperglycemia. Meta-analyses have shown that an upper blood sugar limit of 10 mmol/L (180 mg/dL) is associated with better outcomes for diabetic patients than an upper limit of less than this value. The target range of 7.8-10 mmol/L (140-180 mg/dL) proposed by specialty societies for hospitalized patients with diabetes seems to be the best compromise at present for optimizing clinical outcomes while avoiding hypoglycemia. The method of choice for achieving this goal in intensive care medicine is the continuous intravenous administration of insulin, requirng standardized, high-quality monitoring conditions., Conclusion: Optimal blood sugar control for diabetic patients in intensive care meets the dual objectives of avoiding hypoglycemia while keeping the blood glucose concentration under 10 mmol/L (180 mg/dL). Nutrition therapy in accordance with the relevant guidelines is an indispensable pre - requisite.

Sepsis is a potentially lethal syndrome resulting from a maladaptive response to infection. Upon infection, glucocorticoids are produced as a part of the compensatory response to tolerate sepsis. This tolerance is, however, mitigated in sepsis due to a quickly induced glucocorticoid resistance at the level of the glucocorticoid receptor. Here, we show that defects in the glucocorticoid receptor signaling pathway aggravate sepsis pathophysiology by lowering lactate clearance and sensitizing mice to lactate-induced toxicity. The latter is exerted via an uncontrolled production of vascular endothelial growth factor, resulting in vascular leakage and collapse with severe hypotension, organ damage, and death, all being typical features of a lethal form of sepsis. In conclusion, sepsis leads to glucocorticoid receptor failure and hyperlactatemia, which collectively leads to a lethal vascular collapse., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Video-assisted thoracoscopic procedures with preserved spontaneous breathing (NI-VATS = conscious video-assisted thoracic surgery) have enjoyed a revival in recent years. However, there have been few reports on proper patient selection, as well as surgical or anaesthesiologic management for these procedures in Germany. Therefore, we present our experience with NI-VATS procedures in the form of a case study and discuss the results with a current survey and the current literature., Method: Retrospective evaluation of all NI-VATS procedures at our local institution., Results: From June 2018 to January 2020 n = 17 (9 male and 8 female) patients underwent NI-VATS at our institution. Median age of patients was 68 [61 - 79] years. Fourteen patients suffered from progressive cancer as the underlying disease, leading to thoracic surgery. All patients had a number of comorbidities and were classified according to the ASA categories III (n = 9) or IV (n = 8). Surgical procedures were of short duration (in median 18 [15 - 27] min) and included 82% pleural procedures (pleurectomy, decortication or insertion of pleural drainage). All patients tolerated the surgical procedures under local anaesthesia and conscious sedation very well. Eleven patients could therefore be transferred to the normal ward after surgery, while the remaining patients underwent prolonged and intensified postoperative monitoring. Five of the 17 patients died within the hospital, in median 8 [3.0 - 33.5] days after surgery, in context of the underlying disease. None of the deaths could be associated with the surgical procedures., Discussion: In a well selected patient cohort and with our local experience, NI-VATS is a safe and practicable alternative to standard thoracotomy in general anaesthesia and one-lung ventilation. In our local institution, multimorbid patients with interventions of short duration and reasonable extent underwent successful NI-VATS and emerged as good candidates for this procedure. Careful patient selection and knowledge of the procedure and its side effects present important milestones for successful NI-VATS., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

The assessment of a patient's immune function is critical in many clinical situations. In complex clinical immune dysfunction like sepsis, which results from a loss of immune homeostasis due to microbial infection, a plethora of pro- and anti-inflammatory stimuli may occur consecutively or simultaneously. Thus, any immunomodulatory therapy would require in-depth knowledge of an individual patient's immune status at a given time. Whereas lab-based immune profiling often relies solely on quantification of cell numbers, we used an ex vivo whole-blood infection model in combination with biomathematical modeling to quantify functional parameters of innate immune cells in blood from patients undergoing cardiac surgery. These patients experience a well-characterized inflammatory insult, which results in mitigation of the pathogen-specific response patterns towards Staphylococcus aureus and Candida albicans that are characteristic of healthy people and our patients at baseline. This not only interferes with the elimination of these pathogens from blood, but also selectively augments the escape of C. albicans from phagocytosis. In summary, our model could serve as a valuable functional immune assay for recording and evaluating innate responses to infection.

Objectives: To examine the sensitivity and specificity of perioperative lactate gradients for the prediction of subsequent acute mesenteric ischemia development in patients undergoing cardiovascular surgery., Design: Retrospective, single-center, case-control study., Setting: University hospital., Participants: The study comprised 108 (1.15%) patients with acute mesenteric ischemia who were selected from 9,385 patients who underwent cardiovascular surgery and were matched to 324 control patients by age and surgery type., Interventions: None., Measurements and Main Results: Univariate and logistic regression analyses were used to examine intraoperative and early postoperative lactate levels in patients with and without mesenteric ischemia after cardiac surgery. Late intraoperative lactate concentrations were significantly greater in patients who subsequently developed mesenteric ischemia (p < 0.001). Patients with lactate levels >3 mmol/L had a four-fold increased risk of mesenteric ischemia development (odds ratio [OR] 4.2, 95% confidence interval [CI] 2.4-7.5; area under the curve [AUC] 0.597; p < 0.002). Patients whose lactate levels remained >3 mmol/L on the first postoperative day had a nearly eight-fold increased risk (OR 7.8, 95% CI 4.6-13.3; AUC 0.68; p < 0.001), indicating that mesenteric ischemia developed at an early stage in almost every second patient (p < 0.001). For patients with normal or less elevated lactate levels, similar results were obtained for a >200% increase between the intraoperative and early postoperative periods (OR 4.1, 95% CI 2.4-6.8; AUC 0.62; p < 0.001)., Conclusion: Late intraoperative and early postoperative lactate levels >3 mmol/L and increases >200%, even when remaining within the normal range, should raise the suspicion of subsequent mesenteric ischemia development., Competing Interests: Conflicts of Interest The authors declare that they have no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Extracorporeal albumin dialysis (ECAD) represents a supplemental therapy for patients with liver failure. Most experience was gained with the molecular adsorbent recirculating system (MARS). However, the ADVanced Organ Support (ADVOS) system was recently introduced. This study aims to compare effects of MARS and ADVOS on biochemical and clinical parameters in critically ill patients with liver failure using a retrospective analysis of ECAD at Jena University Hospital. Laboratory parameters, health scoring values, and need for transfusion were recorded before and after treatment. Generalized estimating equations were used to account for repeated measurements of multiple ECAD cycles per patient. Between 2012 and 2017, n = 75 MARS and n = 58 ADVOS cycles were evaluated. Although ADVOS runs significantly longer, both devices provided comparable reduction rates of bilirubin (MARS: -48 [-80.5 to -18.5] μmol/L vs ADVOS: -35 [-87.8 to -2.0] μmol/L, P = .194), a surrogate for detoxification capacity, while urea and lactate levels were more significantly lowered by the ADVOS system. In cycles with similar treatment times, both systems provided comparable reduction rates for bilirubin, renal replacement, coagulation, and metabolic parameters. Citrate was the preferred anticoagulant in case of bleeding. Neither bleeding tendency nor fibrinogen levels or platelets were altered by the type of anticoagulation. No adverse events were reported, but two sessions (one MARS and one ADVOS) were terminated early due to filter clotting. Experience is needed in the application of ADVOS and more prospective trials comparing the detoxification capacity of ECAD devices are needed to support and enlarge the findings of the current evaluation., (© 2020 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers pyroptosis and the concurrent release of damage-associated molecular patterns (DAMPs). Collectively, DAMPs are key determinants that shape the aftermath of inflammatory cell death. However, the identity and function of the individual DAMPs released are poorly defined. Our proteomics study revealed that cytosolic LPS sensing triggered the release of galectin-1, a β-galactoside-binding lectin. Galectin-1 release is a common feature of inflammatory cell death, including necroptosis. In vivo studies using galectin-1-deficient mice, recombinant galectin-1 and galectin-1-neutralizing antibody showed that galectin-1 promotes inflammation and plays a detrimental role in LPS-induced lethality. Mechanistically, galectin-1 inhibition of CD45 (Ptprc) underlies its unfavorable role in endotoxin shock. Finally, we found increased galectin-1 in sera from human patients with sepsis. Overall, we uncovered galectin-1 as a bona fide DAMP released as a consequence of cytosolic LPS sensing, identifying a new outcome of inflammatory cell death.

Background & Aims: Retention of bile acids in the blood is a hallmark of liver failure. Recent studies have shown that increased serum bile acid levels correlate with bacterial infection and increased mortality. However, the mechanisms by which circulating bile acids influence patient outcomes still are elusive., Methods: Serum bile acid profiles in 33 critically ill patients with liver failure and their effects on Takeda G-protein-coupled receptor 5 (TGR5), an immunomodulatory receptor that is highly expressed in monocytes, were analyzed using tandem mass spectrometry, novel highly sensitive TGR5 bioluminescence resonance energy transfer using nanoluciferase (NanoBRET, Promega Corp, Madison, WI) technology, and in vitro assays with human monocytes., Results: Twenty-two patients (67%) had serum bile acids that led to distinct TGR5 activation. These TGR5-activating serum bile acids severely compromised monocyte function. The release of proinflammatory cytokines (eg, tumor necrosis factor α or interleukin 6) in response to bacterial challenge was reduced significantly if monocytes were incubated with TGR5-activating serum bile acids from patients with liver failure. By contrast, serum bile acids from healthy volunteers did not influence cytokine release. Monocytes that did not express TGR5 were protected from the bile acid effects. TGR5-activating serum bile acids were a risk factor for a fatal outcome in patients with liver failure, independent of disease severity., Conclusions: Depending on their composition and quantity, serum bile acids in liver failure activate TGR5. TGR5 activation leads to monocyte dysfunction and correlates with mortality, independent of disease activity. This indicates an active role of TGR5 in liver failure. Therefore, TGR5 and bile acid metabolism might be promising targets for the treatment of immune dysfunction in liver failure., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Cardiac surgery in patients with infective endocarditis (IE) and preoperative intracranial haemorrhage (pre-ICH) is a highly debatable issue, and guidelines are still not well defined. The goal of this study was to investigate the effect of cardiac surgery and its timing on the clinical outcomes of patients with IE and pre-ICH., Methods: We did a single-centre retrospective analysis of data from patients with preoperative brain imaging who had surgery for left-sided IE between January 2007 and May 2018., Results: Among the 363 patients included in the study, 34 had pre-ICH. Hospital mortality was similar between the patients with and without pre-ICH (29% vs 27%, respectively; P = 0.84). Unadjusted, postoperative neurological deterioration appeared higher in patients with pre-ICH (24% vs 17%; P = 0.35). In multivariable analysis, pre-ICH did not qualify as an independent predictor for either postoperative neurological deterioration [odds ratio 1.10, 95% confidence interval (CI) 0.44-2.73; P = 0.84] or hospital mortality (odds ratio 1.02, 95% CI 0.43-2.40; P = 0.96). Postoperative partial thromboplastin time was significantly elevated in 4 patients with relevant post-ICH compared with those patients without relevant post-ICH (65.5 vs 37.6, respectively; P = 0.004)., Conclusions: Pre-ICH was not an independent predictor for postoperative neurological deterioration or hospital mortality in patients with IE. Postoperative coagulation management seems to be crucial in patients with IE with ICH. Although this is to date the largest monocentric study addressing surgical decision and timing, the number of patients with pre-ICH was low. Therefore, these conclusions should be regarded with caution; randomized clinical trials are needed., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Cardiac surgery using cardiopulmonary bypass is a well-established procedure. However, up to 20% to 30% of patients require high dose vasopressor or inotropic support following surgery, enhancing the risk of organ dysfunction and impacting mortality. Nonalcoholic fatty liver disease (NAFLD) is a frequent finding in these patients and may be involved in the pathophysiology of vasoplegia and cardiac failure., Methods: Retrospective analysis of 463 patients undergoing elective cardiac surgery in 2014 at our institution. NAFLD was defined using the NAFLD fibrosis score and the vasoactive-inotropy score was used to determine postoperative vasopressor and inotropic dependency., Results: Patients with NAFLD more often presented with high vasopressor or inotropic support compared to patients without NAFLD, resulting in significant differences after 6 hours (n = 20 [27.0%] of 74 patients), 12 hours (n = 20 [27.0%] of 74 patients), and on the first postoperative day (n = 12 [16.4%] of 73 patients) of intensive care unit (ICU) treatment. Multivariate analysis revealed time of catecholamine application (P = .001), preoperative left ventricular ejection fraction (P = .001), type of surgery (P = .001), model of endstage liver disease on hospital admission (P = .002), pre-existing pulmonary hypertension (P = .004) and NAFLD-time interaction (P = .05) as independent predictors of high vasopressor and inotropic support. Patients with NAFLD had higher degrees of extrahepatic organ dysfunction, were more dependent on hemodialysis, spent more days in the ICU and within the hospital. Patients with NAFLD and high catecholamine support had the highest mortality rates among the study population., Conclusions: NAFLD is a common finding in elective cardiac surgery patients. Anesthesiologists and intensivists should be sensitive for the specific risk profile of this population., (© 2020 Wiley Periodicals, Inc.)

Introduction: Infective endocarditis (IE) is associated with high mortality and morbidity. Multiple organ failure is the main cause of death after surgery for IE. Cardiopulmonary bypass (CPB) can cause a systemic inflammatory response. In a pilot study (REMOVE-pilot (Revealing mechanisms and investigating efficacy of hemoad-sorption for prevention of vasodilatory shock in cardiac surgery patients with infective endocarditis - a multicentric randomized controlled group sequential trial)), we found that plasma profiles of cytokines during and after CPB were higher in patients with IE compared with patients with non-infectious valvular heart disease. Sequential Organ Failure Assessment (SOFA) scores on the first and second postoperative days and in-hospital mortality were also higher in IE patients. This protocol describes the design of the REMOVE trial on cytokine-adsorbing columns, for example, CytoSorb, for non-selective removal of cytokines. The aim of the REMOVE study is to demonstrate efficacy of CytoSorb on the prevention of multiorgan dysfunction in patients with IE undergoing cardiac surgery., Methods and Analysis: The REMOVE study is an interventional randomised controlled multicenter trial with a group sequential (Pocock) design for assessing efficacy of CytoSorb in patients undergoing cardiac surgery for IE. The change in mean total SOFA (∆ SOFA) score between preoperative and postoperative care will be used as primary endpoint. Data on 30-day mortality, changes in cytokines levels, duration of mechanical ventilation, length of intensive care unit and hospital stay, and postoperative stroke will be collected as secondary endpoints. An interim analysis will be conducted after including 25 participating patients per study arm (with a focus on feasibility of the recruitment as well as differences in cytokines and cell-free DNA levels)., Ethics and Dissemination: The protocol was approved by the institutional review board and ethics committee of the University of Jena as well as by the corresponding ethics committee of each participating study centre. The results will be published in a renowned international medical journal, irrespective of the outcomes of the study., Trial Registration Number: The ClinicalTrials.gov registry (NCT03266302)., Competing Interests: Competing interests: FMB reports grants and personal fees from CytoSorbents Europe,outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We report our starting experience with parasternal minimally-invasive aortic valve replacement., Methods: From 7/14 to 8/18, 192 received classic aortic valve surgery using a 5 cm parasternal incision and percutaneous groin cannulation. Patients were selected based on anatomic feasibility judged by preoperative computed tomography-scan. Except for porcelain aorta, left-sided aortic location, or endocarditic abscess, there were no exclusions., Results: Patients were divided into two groups (first and second half of experience). Demographics were equal. Patients' mean ejection fraction was 59%, with preoperative stroke (12%), severe chronic obstructive pulmonary disorder (11%), and endocarditis (2%). All cases were elective or urgent. The Euroscore II was 3.37 ± 3.31 in the first and 3.68 ± 3.97 in the second group (n.s.). Biological prostheses were implanted in 90%. Operating times in the first group were just under 3 hours, with bypass times of 129 ± 32 minutes and clamp times of 77 ± 20 minutes. In the second group, these times changed only minimally. There were three conversions to sternotomy in the first, but only one in the second group. Similarly, three patients died in the first and one in the second group. There were fewer complications in the second group regarding revision for bleeding (7 vs 1%), stroke (4 vs 0%) dialysis (3 vs 1%), and pericardial effusions (3 vs 1%). The O/E ratio dropped from 0.93 to 0.28., Conclusions: Parasternal minimally-invasive aortic valve replacement is a feasible technique associated with a slow learning curve but the potential to achieve improved outcomes. Considering the transcatheter alternatives, the relative risk reduction may be worth investigating in future trials., (© 2020 The Authors. Journal of Cardiac Surgery published by Wiley Periodicals, Inc.)

Background: More than 50% of patients with infective endocarditis (IE) develop an indication for surgery. Despite its benefit, surgery is associated with a high incidence of multiple organ dysfunction syndrome (MODS) and mortality, which may be linked to increased release of inflammatory mediators during cardiopulmonary bypass (CPB). We therefore assessed plasma cytokine profiles in patients undergoing valve surgery with or without IE., Methods: We performed a prospective case-control pilot study comparing patients undergoing cardiac valve surgery with or without IE. Plasma profiles of inflammatory mediators were measured at 7 defined time points and reported as median (interquartile). The degree of MODS was measured using sequential organ failure assessment (SOFA) score., Results: Between May and December 2016 we included 40 patients (20 in each group). Both groups showed similar distribution of age and gender. Patients with IE had higher preoperative SOFA (6.9± 2.6 vs 3.8 ± 1.1, p<0.001) and operative risk scores (EuroSCORE II 18.6±17.4 vs. 1.8±1.3, p<0.001). In-hospital mortality was higher in IE patients (35% vs. 5%; p<0.001). Multiple organ failure was the cause of death in all non-survivors. At the end of CPB, median levels of following inflammatory mediators were higher in IE compared to control group: IL-6 (119.73 (226.49) vs. 24.48 (40.09) pg/ml, p = 0.001); IL-18 (104.82 (105.99) vs. 57.30 (49.53) pg/ml, p<0.001); Mid-regional pro-adrenomedullin (MR-proADM) (2.06 (1.58) vs. 1.11 (0.53) nmol/L, p = 0.003); MR- pro-atrial natriuretic peptide (MR-proANP) (479.49 (224.74) vs. 266.55 (308.26) pmol/l, p = 0.028). IL-1β and TNF- α were only detectable in IE patients and first after starting CPB. Plasma levels of IL-6, IL-18, MRproADM, and MRproANP during CPB were significantly lower in survivors than in those who died., Conclusion: The presence of infective endocarditis during cardiac valve surgery is associated with increased inflammatory response as evident by higher plasma cytokine levels and other inflammatory mediators. Actively reducing inflammatory response appears to be a plausible therapeutic concept., Trial Registration: ClinicalTrials.gov, ID: NCT02727413., Competing Interests: All other authors declare no competing interests

Sepsis is a life-threatening clinical syndrome defined as a deregulated host response to infection associated with organ dysfunction. Mechanisms underlying the pathophysiology of septic liver dysfunction are incompletely understood. Among others, the iron containing tetrapyrrole heme inflicts hepatic damage when released into the circulation during systemic inflammation and sepsis. Accordingly, hemolysis and decreased concentrations of heme-scavenging proteins coincide with an unfavorable outcome of critically ill patients. As the liver is a key organ in heme metabolism and host response to infection, we investigated the impact of labile heme on sinusoidal microcirculation and hepatocellular integrity. We here provide experimental evidence that heme increases portal pressure via a mechanism that involves hepatic stellate cell-mediated sinusoidal constriction, a hallmark of microcirculatory failure under stress conditions. Moreover, heme exerts direct cytotoxicity in vitro and aggravates tissue damage in a model of polymicrobial sepsis. Heme binding by albumin, a low-affinity but high-capacity heme scavenger, attenuates heme-mediated vasoconstriction in vivo and prevents heme-mediated cytotoxicity in vitro. We demonstrate that fractions of serum albumin-bound labile heme are increased in septic patients. We propose that heme scavenging might be used therapeutically to maintain hepatic microcirculation and organ function in sepsis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background:  Coronary artery bypass grafting (CABG) using bilateral internal thoracic artery (BITA) is associated with the best long-term survival. However, using BITA increases the risk of sternal wound infections with conventional sternotomy. We describe here our initial results of minimally invasive CABG (MICS-CABG) using BITA., Methods:  Patients were operated through an incision similar to that of standard minimally invasive direct CABG. All operations were performed off-pump. We evaluated patient's quality of life (QoL) using the Medical Outcomes trust, 36-Item Short Form Health Survey (SF-36)., Results:  Between February 2016 and August 2017, we performed 21 cases of MICS-CABG using BITA. There was no intraoperative complication and no conversion to sternotomy or to on-pump. Two patients required reexploration through the same minithoracotomy for postoperative bleeding. Two cases of early postoperative graft failure were identified. There was no stroke or in-hospital mortality. The median duration of follow-up was 13 months, with a maximum of 19 months. Relief of angina was achieved in all patients. There was one readmission for superficial wound infection, which was conservatively treated. An 84-year-old man died 4 months after the operation. The remaining 20 patients attested good QoL with the SF-36 questionnaire., Conclusions:  Myocardial revascularization using BITA can be safely achieved off-pump through a left-sided minithoracotomy with good postoperative and short-term outcomes., Competing Interests: The authors report no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Over the past two decades, minimally invasive techniques for classic heart valve surgery and isolated bypass surgery have been developed that enable access to the heart via partial sternotomy for most aortic valve procedures and via sternotomy-free mini-thoracotomy for other procedures., Methods: We review the current evidence on minimally invasive cardiac surgery on the basis of pertinent randomized studies and database studies retrieved by a selective search in the MEDLINE and PubMed Central databases, as well as by the Google Scholar search engine., Results: A PubMed search employing the search term "minimally invasive cardiac surgery" yielded nearly 10 000 hits, among which there were 7 prospective, randomized, controlled trials (RCTs) on aortic valve replacement, with a total of 477 patients, and 3 RCTs on mitral valve surgery, with a total of 340 patients. Only limited reports of specified centers are currently available for multiple valvular procedures and multiple coronary artery bypass procedures. The RCTs reveal that the minimally invasive techniques are associated with fewer wound infections and faster mobilization, without any difference in survival. Minimally invasive procedures are technically demanding and have certain anatomical prerequisites, such as appropriate coronary morphology for multiple bypass operations and the position of the aorta in the chest for sternotomy-free aortic valve procedures. The articles reviewed here were presumably affected by selection bias, in that patients in the published studies were preselected, and there may have been negative studies that were not published at all., Conclusion: Specialized surgeons and centers can now carry out many cardiac valvular and bypass operations via minithoracotomy rather than sternotomy. According to current evidence, these minimally invasive techniques yield results that are at least as good as classic open-heart surgery.

Background & Aims: Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive products. Z-BOX A and Z-BOX B arise upon oxidation with unknown implications for hepatocellular function and integrity. We studied the impact of Z-BOX A and B on hepatic functions and explored their alterations in health and cholestatic conditions., Methods: Functional implications and mechanisms were investigated in rats, hepatocytic HepG2 and HepaRG cells, human immortalized hepatocytes, and isolated perfused livers. Z-BOX A and B were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in acute and acute-on-chronic liver failure and hereditary unconjugated hyperbilirubinemia., Results: Z-BOX A and B are found in similar amounts in humans and rodents under physiological conditions. Serum concentrations increased ∼20-fold during cholestatic liver failure in humans (p<0.001) and in hereditary deficiency of bilirubin glucuronidation in rats (p<0.001). Pharmacokinetic studies revealed shorter serum half-life of Z-BOX A compared to its regio-isomer Z-BOX B (p=0.035). While both compounds were taken up by hepatocytes, Z-BOX A was enriched ∼100-fold and excreted in bile. Despite their reported vasoconstrictive properties in the brain vasculature, BOXes did not affect portal hemodynamics. Both Z-BOX A and B showed dose-dependent cytotoxicity, affected the glutathione redox state, and differentially modulated activity of Rev-erbα and Rev-erbβ. Moreover, BOXes-triggered remodeling of the hepatocellular cytoskeleton., Conclusions: Our data provide evidence that higher-order heme degradation products, namely Z-BOX A and B, impair hepatocellular integrity and might mediate intra- and extrahepatic cytotoxic effects previously attributed to hyperbilirubinemia., Lay Summary: Degradation of the blood pigment heme yields the bile pigment bilirubin and the oxidation products Z-BOX A and Z-BOX B. Serum concentrations of these bioactive molecules increase in jaundice and can impair liver function and integrity. Amounts of Z-BOX A and Z-BOX B that are observed during liver failure in humans have profound effects on hepatic function when added to cultured liver cells or infused into healthy rats., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Infective endocarditis (IE) is still associated with high morbidity and mortality. The impact of pre-operative stroke on mortality and long-term survival is controversial. In addition, data on the severity of neurological disability due to pre-operative stroke are scarce. We analysed the impact of pre-operative stroke and the severity of its related neurological disability on short- and long-term outcome., Methods: We retrospectively reviewed our data from patients operated for left-sided IE between 01/2007 and 04/2013. We performed univariate (Chi-Square and independent samples t test) and multivariate analyses., Results: Among 308 consecutive patients who underwent cardiac surgery for left-sided IE, pre-operative stroke was present in 87 (28.2 %) patients. Patients with pre-operative stroke had a higher pre-operative risk profile than patient without it: higher Charlson comorbidity index (8.1 ± 2.6 vs. 6.6 ± 3.3) and higher incidence of Staphylococcus aureus infection (43 vs. 17 %) and septic shock (37 vs. 19 %). In-hospital mortality was equal but 5-year survival was significantly worse with pre-operative stroke (33.1 % vs. 45 %, p = 0.006). 5-year survival was worst in patients with severe neurological disability compared to mild disability (19.0 vs. 0.58 %, p = 0.002). However, neither pre-operative stroke nor the degree of neurological disability appeared as an independent risk factor for short or long-term mortality by multivariate analysis., Conclusions: Pre-operative stroke and the severity of neurological disability do not independently affect short- and long-term mortality in patients with infective endocarditis. It appears that patients with pre-operative stroke present with a generally higher risk profile. This information may substantially affect decision-making.

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. For its clinical course, host genetic factors are important and rare genomic variants are suspected to contribute. We sequenced the exomes of 59 Greek and 15 German patients with bacterial sepsis divided into two groups with extremely different disease courses. Variant analysis was focusing on rare deleterious single nucleotide variants (SNVs). We identified significant differences in the number of rare deleterious SNVs per patient between the ethnic groups. Classification experiments based on the data of the Greek patients allowed discrimination between the disease courses with estimated sensitivity and specificity>75%. By application of the trained model to the German patients we observed comparable discriminatory properties despite lower population-specific rare SNV load. Furthermore, rare SNVs in genes of cell signaling and innate immunity related pathways were identified as classifiers discriminating between the sepsis courses. Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in 740 adult septic patients and focused on 28day mortality as outcome. Variants with suggestive evidence for an association (p≤10 -5 ) were validated in two additional GWA studies (n=3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n=74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p≤10 -5 ). The best association signal (rs117983287; p=8.16×10 -8 ) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p=0.03) and sequencing data (p=0.04). Furthermore, CRISPLD2 (p=5.99×10 -6 ) and a region on chromosome 13q21.33 (p=3.34×10 -7 ) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Hydrogen sulfide (H2S) is a gaseous signalling molecule involved in many physiological and pathological processes. There is increasing evidence that H2S is implicated in aging and lifespan control in the diet-induced longevity models. However, blood sulfide concentration of naturally long-lived species is not known. Here we measured blood sulfide in the long-lived naked mole-rat and five other mammalian species considerably differing in lifespan and found a negative correlation between blood sulfide and maximum longevity residual. In addition, we show that the naked mole-rat cystathionine β-synthase (CBS), an enzyme whose activity in the liver significantly contributes to systemic sulfide levels, has lower activity in the liver and is activated to a higher degree by S-adenosylmethionine compared to other species. These results add complexity to the understanding of the role of H2S in aging and call for detailed research on naked mole-rat transsulfuration., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Sepsis is the systemic inflammatory host response to infection. Cystathionine beta-synthase (CBS)-dependent homocysteine (Hcy) pathway was demonstrated to affect disease severity and mortality in patients with severe sepsis/septic shock. Independent studies identified a single-nucleotide polymorphism (SNP, rs6586282, hg19 chr21:g.44478497C>T) in intron 14 of the CBS-coding gene (CBS) associated with Hcy plasma levels. We aimed to describe the association of this SNP and variants of a splice donor-affecting variable-number tandem repeat (VNTR, NG&#95;008938.1:g.22763&#95;22793[16&#95;22]) 243 bp downstream of rs6586282 with severe human sepsis. We analyzed the VNTR structure and genotyped variants of rs6586282 and a neighboring SNP (rs34758144, hg19 chr21:g.44478582G>A) in two case-control studies including patients with severe sepsis/septic shock from Germany (n=168) and Greece (n=237). In both studies, we consistently observed an association of CBS VNTR alleles with sepsis susceptibility. Risk linearly increased with number of tandem repeats (per allele odds ratio in the adjusted analysis 1.34; 95% confidence interval (CI)=1.17-1.55; P<0.001). Association had also been shown for rs34758144 whose risk allele is in linkage disequilibrium with one long VNTR allele (19 repeat). In contrast, we observed no evidence for an effect on 28-day survival in patients with severe sepsis/septic shock (per allele hazard ratio in the adjusted analysis for VNTR 1.10; 95% CI=0.95-1.28; P=0.20). In a minigene approach, we demonstrated alternative splicing in distinct VNTR alleles, which, however, was independent of the number of tandem units. In conclusion, there is no ordinary conjunction between human CBS and severe sepsis/septic shock, but CBS genotypes are involved in disease susceptibility.

Serum levels of the lipid mediator sphingosine-1-phosphate (S1P) are reduced in septic patients and are inversely associated with disease severity. We show that serum S1P is reduced in human sepsis and in murine models of sepsis. We then investigated whether pharmacological or genetic approaches that alter serum S1P may attenuate cardiac dysfunction and whether S1P signaling might serve as a novel theragnostic tool in sepsis. Mice were challenged with lipopolysaccharide and peptidoglycan (LPS/PepG). LPS/PepG resulted in an impaired systolic contractility and reduced serum S1P. Administration of the immunomodulator FTY720 increased serum S1P, improved impaired systolic contractility and activated the phosphoinositide 3-kinase (PI3K)-pathway in the heart. Cardioprotective effects of FTY720 were abolished following administration of a S1P receptor 2 (S1P2) antagonist or a PI3K inhibitor. Sphingosine kinase-2 deficient mice had higher endogenous S1P levels and the LPS/PepG-induced impaired systolic contractility was attenuated in comparison with wild-type mice. Cardioprotective effects of FTY720 were confirmed in polymicrobial sepsis. We show here for the first time that the impaired left ventricular systolic contractility in experimental sepsis is attenuated by FTY720. Mechanistically, our results indicate that activation of S1P2 by increased serum S1P and the subsequent activation of the PI3K-Akt survival pathway significantly contributes to the observed cardioprotective effect of FTY720.

Objectives: Infective endocarditis (IE) is associated with high mortality (20-40%) and neurological complications (20-50%). Postoperative intracranial haemorrhage (ICH) is a feared complication especially in patients with preoperative cerebral infarcts. The aim of this study was to determine the radiological characteristics of cerebral lesions that could predict the occurrence of postoperative ICH in IE patients., Methods: We retrospectively reviewed all charts, brain imaging and follow-up data from patients operated for left-sided endocarditis between January 2007 and April 2013., Results: A total of 308 patients (age 62.0 ± 13.9) underwent surgery for IE. Preoperative cerebrovascular complications were present in 122 patients (39.6%), representing stroke in 87, silent cerebral infarctions in 31 patients and transient ischaemic attacks in 4 patients. Among 118 patients with cerebral lesions, the aetiological classification of the lesions was ischaemic in 63.6%, ischaemic with haemorrhagic transformation (HT) in 17.8%, ischaemic with concomitant microbleeds in 16.1% and intracerebral bleeding in 2.5%. Postoperative ICH occurred in 17 patients and its incidence was slightly higher in patients with preoperative cerebral infarcts compared with those without preoperative cerebral infarcts [7.6 vs 4.2%, respectively, odds ratio (OR) 1.88, 95% confidence interval (CI) 0.70-5.02, P = 0.21]. However, the difference was not statistically significant. Similarly, the incidence of postoperative ICH was higher in cases of HT of ischaemic infarcts than in cases of ischaemic infarcts not complicated with HT (19.0 vs 5.3%). However, the difference was not statistically significant (P = 0.24). The radiological pattern of preoperative cerebral lesions was single in 35.6% and multiple in 60.0% of cases. Multiple cerebral lesions were associated with a non-significantly lower incidence of postoperative ICH than single lesions (5.6 vs 11.9%, respectively, OR: 0.44, CI: 0.11-1.73, P = 0.29)., Conclusions: The results suggest that the incidence of postoperative ICH in IE patients was slightly higher in the presence of preoperative cerebral infarcts. In addition, preoperative cerebral ischaemic infarcts complicated with HT tended to have a higher incidence of postoperative ICH than those not complicated with HT. However, the difference was not statistically significant. Multiple preoperative cerebral infarcts were not associated with higher incidence of postoperative ICH compared with single cerebral infarcts., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Stress hyperglycaemia (SHG) is a common complication in sepsis associated with poor outcome. Chemerin is an adipocytokine associated with inflammation and impaired glucose homeostasis in metabolic diseases such as type 2 diabetes (T2D). We aimed to investigate how alterations of circulating chemerin levels and corresponding visceral adipose tissue (VAT) expression are linked to glucose metabolism and prognosis in sepsis., Methods: Clinical data and tissue samples were taken from a cross-sectional study including control, T2D and sepsis patients, all undergoing laparotomy. A second independent patient cohort of patients with sepsis was included to evaluate associations with prognosis. This was complemented by a murine model of peritoneal infection and a high-fat diet. We analysed circulating chemerin by enzyme-linked immunosorbent assay and VAT messenger RNA (mRNA) expression by real-time polymerase chain reaction., Results: Circulating chemerin was increased in sepsis 1.69-fold compared with controls (p = 0.012) and 1.47-fold compared with T2D (p = 0.03). Otherwise, chemerin VAT mRNA expression was decreased in patients with sepsis (p = 0.006) and in septic diabetic animals (p = 0.009). Circulating chemerin correlated significantly with intra-operative glucose (r = 0.662; p = 0.01) and in trend with fasting glucose (r = 0.528; p = 0.052). After adjusting for body mass index or haemoglobin A1c, chemerin correlated in trend with insulin resistance evaluated using the logarithmised homeostasis model assessment of insulin resistance (r = 0.539, p = 0.071; r = 0.553, p = 0.062). Chemerin was positively associated with Acute Physiology and Chronic Health Evaluation II score in patients with sepsis (p = 0.036) and with clinical severity in septic mice (p = 0.031). In an independent study population, we confirmed association of chemerin with glucose levels in multivariate linear regression analysis (β = 0.556, p = 0.013). In patients with sepsis with SHG, non-survivors had significantly lower chemerin levels than survivors (0.38-fold, p = 0.006), while in patients without SHG, non-survivors had higher chemerin levels, not reaching significance (1.64-fold, p = 0.089). No difference was apparent in patients with pre-existing T2D (p = 0.44)., Conclusions: We show, for the first time to our knowledge, that chemerin is increased in sepsis and that it associates with impaired glucose metabolism and survival in these patients. It could be further evaluated as a biomarker to stratify mortality risk of patients with SHG.

Background: The aim of extracorporeal albumin dialysis (ECAD) is to reduce endogenous toxins accumulating in liver failure. To date, ECAD is conducted mainly with the Molecular Adsorbents Recirculating System (MARS). However, single-pass albumin dialysis (SPAD) has been proposed as an alternative. The aim of this study was to compare the two devices with a prospective, single-centre, non-inferiority crossover study design with particular focus on reduction of bilirubin levels (primary endpoint) and influence on paraclinical and clinical parameters (secondary endpoints) associated with liver failure., Methods: Patients presenting with liver failure were screened for eligibility and after inclusion were randomly assigned to be started on either conventional MARS or SPAD (with 4% albumin and a dialysis flow rate of 700 ml/h). Statistical analyses were based on a linear mixed-effects model., Results: Sixty-nine crossover cycles of ECAD in 32 patients were completed. Both systems significantly reduced plasma bilirubin levels to a similar extent (MARS: median -68 μmol/L, interquartile range [IQR] -107.5 to -33.5, p = 0.001; SPAD: -59 μmol/L, -84.5 to +36.5, p = 0.001). However, bile acids (MARS: -39 μmol/L, -105.6 to -8.3, p < 0.001; SPAD: -9 μmol/L, -36.9 to +11.4, p = 0.131), creatinine (MARS: -24 μmol/L, -46.5 to -8.0, p < 0.001; SPAD: -2 μmol/L, -9.0 to +7.0/L, p = 0.314) and urea (MARS: -0.9 mmol/L, -1.93 to -0.10, p = 0.024; SPAD: -0.1 mmol/L, -1.0 to +0.68, p = 0.523) were reduced and albumin-binding capacity was increased (MARS: +10%, -0.8 to +20.9%, p < 0.001; SPAD: +7%, -7.5 to +15.5%, p = 0.137) only by MARS. Cytokine levels of interleukin (IL)-6 and IL-8 and hepatic encephalopathy were altered by neither MARS nor SPAD., Conclusions: Both procedures were safe for temporary extracorporeal liver support. While in clinical practice routinely assessed plasma bilirubin levels were reduced by both systems, only MARS affected other paraclinical parameters (i.e., serum bile acids, albumin-binding capacity, and creatinine and urea levels). Caution should be taken with regard to metabolic derangements and electrolyte disturbances, particularly in SPAD using regional citrate anti-coagulation., Trial Registration: German Clinical Trials Register ( www.drks.de) DRKS00000371. Registered 8 April 2010.

Acid sphingomyelinase (ASM or sphingomyelin phosphodiesterase, SMPD) activity engages a critical role for regulation of immune response and development of organ failure in critically ill patients. Beside genetic variation in the human gene encoding ASM (SMPD1), alternative splicing of the mRNA is involved in regulation of enzymatic activity. Here we show that the patterns of alternatively spliced SMPD1 transcripts are significantly different in patients with systemic inflammatory response syndrome and severe sepsis/septic shock compared to control subjects allowing discrimination of respective disease entity. The different splicing patterns might contribute to the better understanding of the pathophysiology of human sepsis.

Kidney injury with concomitant hemodialysis is a common finding in perioperative care of liver transplant patients. The aim of this study was to evaluate disturbances in acid-base status, electrolyte balance and citrate accumulation during hemodialysis with regional citrate anticoagulation in perioperative care of liver transplant recipients. A retrospective, single center evaluation was conducted of patients with severe liver dysfunction receiving renal replacement therapy in the perioperative care of liver transplantation in a multidisciplinary ICU of a university hospital. Within 5 days of ICU stay, 89 patients undergoing liver transplantation received regional citrate anticoagulation for hemodialysis. During the study period pH (7.39 [7.33/7.43] vs. 7.44 [7.39/7.47], P-value = 0.014), base excess values (-0.9 [-5.08/2.35] vs. 4.3 [1.93/8.21], P-value = 0.001) and standard bicarbonate (23.6 [20/26.9] vs. 28.2 [26.2/32.2], P-value = 0.001) significantly increased, whereas lactate levels (2.6 [1.60/4.45] vs. 1.25 [0.98/1.9], P-value = 0.071) and Catot /Caion -ratio decreased or remained below the upper reference. Hypocalcemia appeared mostly within 48 h after dialysis initiation. Although sodium levels increased during the observation, rates of hypernatremia were comparable between hemodialysis days 1 and 5. Hemodialysis using regional citrate anticoagulation remains a challenge in the perioperative care of liver transplant recipients. Major attention must be paid to acid-base disturbances and citrate accumulation within 48 h after dialysis initiation. Nevertheless, regional citrate anticoagulation in liver dysfunction is a feasible and valuable tool, when limitations and pitfalls are adequately considered., (© 2014 The Authors. Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis.)

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.

Background: Management of cardiac surgery patients is a very standardized procedure in respective local institutions. Yet only very limited evidence exists concerning optimal indication, safety and efficacy of hemodynamic monitoring catecholamine and fluid therapy., Methods: Between April and May 2013, all 81 German anaesthesia departments involved in cardiac surgery care were asked to participate in a questionnaire addressing the institutional specific current practice in hemodynamic monitoring, catecholamine and volume therapy., Results: 51 (63%) questionnaires were completed and returned. All participating centers used basic hemodynamic monitoring (i.e. invasive arterial blood pressure and central venous pressure), supplemented by transesophageal echocardiography. Pulmonary arterial catheter and calibrated trend monitoring devices were also routinely available. In contrast, non-calibrated trend monitoring and esophageal doppler ultrasound devices were not commonly in use. Cerebral oximetry is increasingly emerging, but lacks clear indications. The majority of patients undergoing cardiac surgery, especially in university hospitals, required catecholamines during perioperative care, In case of low cardiac output syndrome, dobutamine (32%), epinephrine (30%) or phosphodiesterase inhibitors (8%) were first choice. In case of hypotension following vasoplegia, norepinephrine (96%) represented the most common catecholamine. 88% of the participating centers reported regular use of colloid fluids, with hydroxyethyl starches (HES) being first choice (64%)., Conclusions: Choice of hemodynamic monitoring is homogenous throughout German centers treating cardiac surgery patients. Norepinephrine is the first line catecholamine in cases of decrease in peripheral vascular resistance. However, catecholamine choice for low cardiac output syndrome varies considerably. HES was the primary colloid used for fluid resuscitation. After conduct of this survey, HES use was restricted by European regulatory authorities in critically ill patients and should only be considered as second-line fluid in surgical patients without renal impairment or severe coagulopathy. Large clinical studies addressing catecholamine and fluid therapy in cardiac surgery patients are lacking.

Renal failure is a common complication among critically ill patients. Timing, dosage, and mode of renal replacement (RRT) are under debate, but also anticoagulation strategies and vascular access interfere with dialysis success. We present a retrospective, five-year evaluation of patients requiring RRT on a multidisciplinary 50-bed surgical intensive care unit of a university hospital with special regard to anticoagulation strategies and vascular access. Anticoagulation was preferably performed with unfractionated heparin or regional citrate application (RAC). Bleeding and suspected HIT-II were most common causes for RAC. In CVVHD mode filter life span was significantly longer under RAC compared to heparin or other anticoagulation strategies (P=0.001). Femoral vascular access was associated with reduced filter life span (P=0.012), especially under heparin anticoagulation (P=0.015). Patients on RAC had higher rates of metabolic alkalosis (P=0.001), required more transfusions (P=0.045), and showed higher illness severity measured by SOFA scores (P=0.001). RRT with unfractionated heparin represented the most common anticoagulation strategy in this study population. However, patients with bleeding risk and severe organ dysfunction were more likely placed on RAC. Citrate provided longer filter life spans regardless of vascular access site. Attention has to be paid to metabolic disturbances.

The single nucleotide polymorphism rs2071746 and a (GT)n microsatellite within the human gene encoding heme oxygenase-1 (HMOX1) are associated with incidence or outcome in a variety of diseases. Most of these associations involve either release of heme or oxidative stress. Both polymorphisms are localized in the promoter region, but previously reported correlations with heme oxygenase-1 expression remain not coherent. This ambiguity suggests a more complex organization of the 5' gene region which we sought to investigate more fully. We evaluated the 5' end of HMOX1 and found a novel first exon 1a placing the two previously reported polymorphisms in intronic or exonic positions within the 5' untranslated region respectively. Expression of exon 1a can be induced in HepG2 hepatoma cells by hemin and is a repressor of heme oxygenase-1 translation as shown by luciferase reporter assays. Moreover, minigene approaches revealed that the quantitative outcome of alternative splicing within the 5' untranslated region is affected by the (GT)n microsatellite. This data supporting an extended HMOX1 gene model and provide further insights into expression regulation of heme oxygenase-1. Alternative splicing within the HMOX1 5' untranslated region contributes to translational regulation and is a mechanistic feature involved in the interplay between genetic variations, heme oxygenase-1 expression and disease outcome.

Heme and its breakdown products CO, Fe, and bilirubin are being recognized as signaling molecules or even therapeutic agents, but also exert adverse effects when released at high concentrations. Manipulating the pathway confers protection in rodent sepsis models via both control of free heme and formation of its first and higher-order products. Thus, regulatory elements present in human heme oxygenase 1 (HMOX1) and biliverdin reductases (BLVRA/B) genes might impact outcome. We tested whether a highly polymorphic (GT)n microsatellite and single-nucleotide polymorphisms in HMOX1 and BLVRA/B genes are associated with outcome of sepsis. Two cohorts (n = 430 and 398 patients) with severe sepsis were screened for single-nucleotide polymorphisms and/or the microsatellite by fragment length analysis and genotyping techniques. Heme oxygenase 1 plasma levels were determined in additional patients with severe sepsis (n = 92) by enzyme-linked immunosorbent assay. Based on mean Sepsis-related Organ Failure Assessment scores, patients homozygous for rs2071746 A allele or medium length (GT)n microsatellites of HMOX1 showed higher 28-day mortality (P = 0.047 and P = 0.033) in one cohort compared with other genotypes, whereas 90-day mortality rates showed no association. The T allele was less frequently observed in both cohorts than would be expected according to Hardy-Weinberg equilibrium. Heme oxygenase 1 plasma levels were elevated in septic patients, independent of the genotype. Single-nucleotide polymorphisms within BLVRA/B showed no association with outcome. Short (GT)n repeats that are in linkage disequilibrium with the T allele of rs2071746 in HMOX1 are associated with favorable outcome, whereas no association with gene variants of BLVRA/B, involved in the generation of higher-order metabolites, was noticed.

Background: Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests., Methods and Findings: In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87)., Conclusions: Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice. Please see later in the article for the Editors' Summary.

Despite improvement in critical care, liver failure is still associated with high mortality. Therapeutic concepts are aimed at restoring endogenous liver function or to bridge the time to liver transplantation. In addition to standard medical treatment, extracorporeal liver support with albumin dialysis is used for this purpose. The aim of this study was to analyze the efficacy of single pass albumin dialysis (SPAD) in comparison to the molecular adsorbent recirculating system (MARS) in patients treated at our university hospital intensive care unit between July 2004 and August 2008. In this retrospective analysis we studied patients presenting with liver failure who were treated with albumin dialysis. Laboratory parameters, daily health scoring, the number of transfusions, and mortality were recorded. The (paired) t-test, Mann-Whitney U-test, and Wilcoxon test were used for statistical analysis. In all, 163 albumin dialysis treatments, 126 with MARS and 37 with SPAD, in 57 patients were performed. MARS resulted in a significant decrease in bilirubin (-38 +/- 66.5 micromol/L from a baseline of 301 +/- 154.6 micromol/L), gamma-glutamyltransferase (gamma-GT), alanine aminotransferase, creatinine, and urea. SPAD resulted in a significant decrease in bilirubin (-41 +/- 111.2 micromol/L from a baseline of 354 +/- 189.4 micromol/L) and gamma-GT, while lactate levels increased. No differences in the need for blood transfusion, health scoring, or mortality between the two treatment modalities were detected. This retrospective analysis suggests equal efficacy of MARS and SPAD; however, prospective assessment to further define the role of SPAD in the treatment of acute or acute-on-chronic liver failure is needed.