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.

The non-canonical inflammasome activators Caspase-4 and Caspase-5 are differentially regulated during immunosuppression-associated organ damage.

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.

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.

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.

Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis.

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).

Association between Intraoperative Blood Transfusion, Regional Anesthesia and Outcome after Pediatric Tumor Surgery for Nephroblastoma.

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.

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.

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.

Multiplex quantification of C-terminal alpha-1-antitrypsin peptides provides a novel approach for characterizing systemic inflammation.

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.

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.

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.

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 Euro score 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.

Blood Sugar Targets in Surgical Intensive Care­Management and Special Considerations in Patients With Diabetes

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.

Impact of an In-Hospital Endocarditis Team and a State-Wide Endocarditis Network on Perioperative Outcomes.

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.

Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis.

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.

Ex vivo immune profiling in patient blood enables quantification of innate immune effector functions.

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.

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.

Circulating Bile Acids in Liver Failure Activate TGR5 and Induce Monocyte Dysfunction.

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.

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.