Intracellular immune sensing promotes inflammation via gasdermin D-driven release of a lectin alarmin.

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 ß-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.

Cytokine Hemoadsorption During Cardiac Surgery Versus Standard Surgical Care for Infective Endocarditis (REMOVE): Results From a Multicenter Randomized Controlled Trial.

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-1ß 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.

The Influence of Positive End-Expiratory Pressure on Leakage and Oxygenation Using a Laryngeal Mask Airway: A Randomized Trial.

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.

Postoperative Pulmonary Complications After Cardiac Surgery: The VENICE International Cohort Study.

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.

Emergency medical care of patients with psychiatric disorders - challenges and opportunities: Results of a multicenter survey.

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.

Monitoring of the Progression of the Perioperative Serum Lactate Concentration Improves the Accuracy of the Prediction of Acute Mesenteric Ischemia Development After Cardiovascular Surgery.

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.

[Videoassisted Thoracoscopy with Preserved Spontaneous Breathing - an Anaesthesiological Perspective]. / Videoassistierte Thorakoskopie unter Erhalt der Spontanatmung ­ eine anästhesiologische Perspektive.

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.

Association between high dose catecholamine support and liver dysfunction following cardiac surgery.

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.

Minimally-invasive parasternal aortic valve replacement-A slow learning curve towards improved outcomes.

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.

Labile heme impairs hepatic microcirculation and promotes hepatic injury.

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.

Coronary Artery Bypass Grafting using Bilateral Internal Thoracic Arteries through a Left-Sided Minithoracotomy: A Single-Center Starting Experience.

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.

Impact of higher-order heme degradation products on hepatic function and hemodynamics.

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-erbß. 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.

Molecular adsorbent recirculating system and single-pass albumin dialysis in liver failure--a prospective, randomised crossover study.

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.

Chemerin in peritoneal sepsis and its associations with glucose metabolism and prognosis: a translational cross-sectional study.

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 (ß = 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.

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.

Anticoagulation strategies in venovenous hemodialysis in critically ill patients: a five-year evaluation in a surgical intensive care unit.

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.

Predictive Value of Serial Model of End-Stage Liver Disease Score Determination in Patients with Postcardiotomy Extracorporeal Membrane Oxygenation.

(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.

Risk stratification for isolated tricuspid valve surgery assisted using the Model for End-Stage Liver Disease score.

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.

Extracorporeal albumin dialysis in critically ill patients with liver failure: Comparison of four different devices-A retrospective analysis.

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.

Intraoperative Cell Savage, Infection and Organ Failure in Infective Endocarditis Patients-A Retrospective Single Center Evaluation.

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.