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Abstract Background Data describing outcome of extracorporeal membrane oxygenation (ECMO) support in Tuberculosis (Tbc)-associated acute respiratory distress syndrome (ARDS) remain sparce and are mostly confined to singular case reports. The aim of this case series was to analyze intensive care unit (ICU) survival in patients with Tbc-associated ARDS receiving veno-venous (vv-) ECMO support and to compare those to patients not receiving ECMO. Case presentation ICU survival was analyzed retrospectively in 14 patients treated for Tbc-associated ARDS at three ECMO-referral university hospitals (Hannover Medical School, University Hospital Bonn (both Germany) and University Hospital Zurich (Switzerland)) during the last 14 years, of which eight patients received additional vv-ECMO support and six standard care only. ICU survival was significantly higher in patients receiving additional vv-ECMO support (62.5%, n = 5/8) compared to those that did not (16.7%, n = 1/6) (p = 0.021). ECMO support was associated with reduced ICU mortality (Hazard ratio adjusted for baseline SOFA score [adj. HR] 0.125 (95% confidence interval (CI): 0.023–0.689), p = 0.017). Median (IQR) time on ECMO and invasive ventilation in the vv-ECMO group were 20 (11–26) and 37 (27–53) days, respectively. Major bleeding defined as transfusion requirement of 4 units of blood or more or surgical and/or radiologic intervention occurred only in one patient, in whom pulmonary bleeding was fatal. Thromboembolic events occurred in none of the vv-ECMO patients. Discussion and conclusions This retrospective analysis from three large ECMO centers with similar SOPs suggests vv-ECMO support as a feasible approach in patients with severe Tbc-associated ARDS. Although affiliated with extended runtimes, vv-ECMO might be associated with improved survival in those patients. Vv-ECMO support should thus be considered in Tbc-associated ARDS to enable lung protective strategies during prolonged lung recovery.

Abstract Background The continuous exposure of blood to a non-biological surface during extracorporeal membrane oxygenation (ECMO) may lead to progressive thrombus formation in the oxygenator, hemolysis and consequently impaired gas exchange. In most centers oxygenator performance is monitored only on a once daily basis. Carboxyhemoglobin (COHb) is generated upon red cell lysis and is routinely measured with any co-oximetry performed to surveille gas exchange and acid–base homeostasis every couple of hours. This retrospective cohort study aims to evaluate COHb in the arterial blood gas as a novel marker of oxygenator dysfunction and its predictive value for imminent oxygenator change. Results Out of the 484 screened patients on ECMO 89, cumulatively requiring 116 oxygenator changes within 1833 patient days, including 19,692 arterial COHb measurements were analyzed. Higher COHb levels were associated with lower post-oxygenator pO2 (estimate for log(COHb): − 2.176 [95% CI − 2.927, − 1.427], p

Abstract Background Despite a lack of clear evidence extracorporeal blood purification (EBP) is increasingly used as an adjunctive treatment in septic shock based on its biological plausibility. However, current state of praxis and believes in both efficacy and level of evidence are very heterogeneous. Methods The “EXPLORATION” (Current Clinical Practice in using adjunctive extracorporeal blood purification in septic shock), a web-based survey endorsed by the European Society of Intensive Care Medicine (ESICM), questioned both the current local clinical practices as well as future perspectives of EBP in sepsis and septic shock. Results One hundred and two people participated in the survey. The majority of three quarters of participants (74.5%) use adjunctive EBP in their clinical routine with a varying frequency of description. Unselective cytokine adsorption (CA) (37.5%) and therapeutic plasma exchange (TPE) (34.1%) were by far the most commonly used modalities. While the overall theoretical rational was found to be moderate to high by the majority of the participants (74%), the effectively existing clinical evidence was acknowledged to be rather low (66%). Although CA was used most frequently in clinical practice, both the best existing clinical evidence endorsing its current use (45%) as well the highest potential to be explored in future clinical trials (51.5%) was attributed to TPE. Conclusions Although the majority of participants use EBP techniques in their clinical practice and acknowledge a subjective good theoretical rationale behind it, the clinical evidence is assessed to be limited. While both CA and TPE are by far the most common used technique, both clinical evidence as well as future potential for further exploration in clinical trials was assessed to be the highest for TPE.

Sepsis-associated coagulopathy increases risk of mortality. Impairment of the anticoagulant protein C (PC) pathway may contribute to the thrombotic phenotype in coronavirus disease 2019 (COVID-19) sepsis. This study assessed the functionality of this pathway in COVID-19 and non-COVID sepsis by measuring its key enzymes, thrombin and activated PC (APC). The study population included 30 patients with COVID-19, 47 patients with non-COVID sepsis, and 40 healthy controls. In healthy controls, coagulation activation and subsequent APC formation was induced by 15 µg/kg recombinant activated factor VII one hour before blood sampling. APC and thrombin in plasma were measured using oligonucleotide-based enzyme capture assays. The indirect thrombin markers prothrombin-fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) were also measured. Compared with stimulated healthy controls, median thrombin, F1+2, and TAT levels were higher in patients with COVID-19 (up to 6-fold, p < 2 × 10−6) and non-COVID sepsis (up to 4.7-fold, p < 0.010). APC levels were 2.4-fold higher in patients with COVID-19 (7.44 pmol/L, p = 0.011) and 3.4-fold higher in non-COVID sepsis patients (10.45 pmol/L, p = 2 × 10−4) than in controls (3.08 pmol/L). Thrombin markers and APC showed correlation in both COVID-19 (r = 0.364–0.661) and non-COVID sepsis patients (r = 0.535–0.711). After adjustment for PC levels, median APC/thrombin, APC/F1+2, and APC/TAT ratios were 2-fold (p = 0.036), 6-fold (p = 3 × 10−7) and 3-fold (p = 8 × 10−4) lower in the COVID-19 group than in the non-COVID sepsis group, and the latter two were also lower in the COVID-19 group than in stimulated healthy controls. In conclusion, it was found that a comparatively lower anticoagulant APC response in COVID-19 patients as compared to non-COVID sepsis patients, potentially linked to endothelial dysfunction, contributes to the prothrombotic phenotype of COVID-19 sepsis.

Abstract Background Sepsis-induced immunosuppression is a frequent cause of opportunistic infections and death in critically ill patients. A better understanding of the underlying mechanisms is needed to develop targeted therapies. Circulating bile acids with immunosuppressive effects were recently identified in critically ill patients. These bile acids activate the monocyte G-protein coupled receptor TGR5, thereby inducing profound innate immune dysfunction. Whether these mechanisms contribute to immunosuppression and disease severity in sepsis is unknown. The aim of this study was to determine if immunosuppressive bile acids are present in endotoxemia and septic shock and, if so, which patients are particularly at risk. Methods To induce experimental endotoxemia in humans, ten healthy volunteers received 2 ng/kg E. coli lipopolysaccharide (LPS). Circulating bile acids were profiled before and after LPS administration. Furthermore, 48 patients with early (shock onset within 0.4 μg/kg/min) and 48 healthy age- and sex-matched controls were analyzed for circulating bile acids. To screen for immunosuppressive effects of circulating bile acids, the capability to induce TGR5 activation was computed for each individual bile acid profile by a recently published formula. Results Although experimental endotoxemia as well as septic shock led to significant increases in total bile acids compared to controls, this increase was mild in most cases. By contrast, there was a marked and significant increase in circulating bile acids in septic shock patients with severe liver failure compared to healthy controls (61.8 µmol/L vs. 2.8 µmol/L, p = 0.0016). Circulating bile acids in these patients were capable to induce immunosuppression, as indicated by a significant increase in TGR5 activation by circulating bile acids (20.4% in severe liver failure vs. 2.8% in healthy controls, p = 0.0139). Conclusions Circulating bile acids capable of inducing immunosuppression are present in septic shock patients with severe liver failure. Future studies should examine whether modulation of bile acid metabolism can improve the clinical course and outcome of sepsis in these patients. Graphical abstract

IntroductionAn increasing amount of longitudinal health data is available on critically ill septic patients in the age of digital medicine, including daily sequential organ failure assessment (SOFA) score measurements. Thus, the assessment in sepsis focuses increasingly on the evaluation of the individual disease's trajectory. Machine learning (ML) algorithms may provide a promising approach here to improve the evaluation of daily SOFA score dynamics. We tested whether ML algorithms can outperform the conventional ΔSOFA score regarding the accuracy of 30-day mortality prediction.MethodsWe used the multicentric SepsisDataNet.NRW study cohort that prospectively enrolled 252 sepsis patients between 03/2018 and 09/2019 for training ML algorithms, i.e. support vector machine (SVM) with polynomial kernel and artificial neural network (aNN). We used the Amsterdam UMC database covering 1,790 sepsis patients for external and independent validation.ResultsBoth SVM (AUC 0.84; 95% CI: 0.71-0.96) and aNN (AUC 0.82; 95% CI: 0.69-0.95) assessing the SOFA scores of the first seven days led to a more accurate prognosis of 30-day mortality compared to the ΔSOFA score between day 1 and 7 (AUC 0.73; 95% CI: 0.65-0.80; p = 0.02 and p = 0.05, respectively). These differences were even more prominent the shorter the time interval considered. Using the SOFA scores of day 1 to 3 SVM (AUC 0.82; 95% CI: 0.68 0.95) and aNN (AUC 0.80; 95% CI: 0.660.93) led to a more accurate prognosis of 30-day mortality compared to the ΔSOFA score (AUC 0.66; 95% CI: 0.58-0.74; p < 0.01 and p < 0.01, respectively). Strikingly, all these findings could be confirmed in the independent external validation cohort.ConclusionsThe ML-based algorithms using daily SOFA scores markedly improved the accuracy of mortality compared to the conventional ΔSOFA score. Therefore, this approach could provide a promising and automated approach to assess the individual disease trajectory in sepsis. These findings reflect the potential of incorporating ML algorithms as robust and generalizable support tools on intensive care units.

Abstract Background Optimal anticoagulation strategies for COVID-19 patients with the acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) remain uncertain. A higher incidence of intracerebral hemorrhage (ICH) during VV ECMO support compared to non-COVID-19 viral ARDS patients has been reported, with increased bleeding rates in COVID-19 attributed to both intensified anticoagulation and a disease-specific endotheliopathy. We hypothesized that lower intensity of anticoagulation during VV ECMO would be associated with a lower risk of ICH. In a retrospective, multicenter study from three academic tertiary intensive care units, we included patients with confirmed COVID-19 ARDS requiring VV ECMO support from March 2020 to January 2022. Patients were grouped by anticoagulation exposure into higher intensity, targeting anti-factor Xa activity (anti-Xa) of 0.3–0.4 U/mL, versus lower intensity, targeting anti-Xa 0.15–0.3 U/mL, cohorts. Mean daily doses of unfractionated heparin (UFH) per kg bodyweight and effectively measured daily anti-factor Xa activities were compared between the groups over the first 7 days on ECMO support. The primary outcome was the rate of ICH during VV ECMO support. Results 141 critically ill COVID-19 patients were included in the study. Patients with lower anticoagulation targets had consistently lower anti-Xa activity values over the first 7 ECMO days (p

Abstract Background Sepsis is as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. The mortality of sepsis and particular of septic shock is very high. Treatment mostly focuses on infection control but a specific intervention that targets the underlying pathological host response is lacking to the present time. The investigators hypothesize that early therapeutic plasma exchange (TPE) will dampen the maladaptive host response by removing injurious mediators thereby limiting organ dysfunction and improving survival in patients with septic shock. Although small prospective studies demonstrated rapid hemodynamic stabilization under TPE, no adequately powered randomized clinical trial has investigated hard outcomes. Methods This is a randomized, prospective, multicenter, open-label, controlled, parallel-group interventional trial to test the adjunctive effect of TPE in patients with early septic shock. Patients with a refractory (defined as norepinephrine (NE) ≥ 0.4 μg/kg/min ≥ 30 min OR NE 0.3 μg/kg/min + vasopressin) and early (shock onset

Hyperinflammation and immune dysfunction are key drivers of immunopathology in sepsis. Here the authors show microbial exploitation of phagocytic receptors is linked to triggering of sepsis and the immune cell mediated reduction in neutrophil life span.

Abstract Background Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy. Methods In the original RCT, patients with septic shock of

Abstract Background Inhalation of dust containing silica particles is associated with severe pulmonary inflammation and lung injury leading to chronic silicosis including fibrotic remodeling of the lung. Silicosis represents a major global health problem causing more than 45.000 deaths per year. The inflammasome-caspase-1 pathway contributes to the development of silica-induced inflammation and fibrosis via IL-1β and IL-18 production. Recent studies indicate that tetracycline can be used to treat inflammatory diseases mediated by IL-1β and IL-18. Therefore, we hypothesized that tetracycline reduces silica-induced lung injury and lung fibrosis resulting from chronic silicosis via limiting IL-1β and IL-18 driven inflammation. Methods To investigate whether tetracycline is a therapeutic option to block inflammasome-caspase-1 driven inflammation in silicosis, we incubated macrophages with silica alone or combined with tetracycline. The in vivo effect of tetracycline was determined after intratracheal administration of silica into the mouse lung. Results Tetracycline selectively blocks IL-1β production and pyroptotic cell death via inhibition of caspase-1 in macrophages exposed to silica particles. Consistent, treatment of silica-instilled mice with tetracycline significantly reduced pulmonary caspase-1 activation as well as IL-1β and IL-18 production, thereby ameliorating pulmonary inflammation and lung injury. Furthermore, prolonged tetracycline administration in a model of chronic silicosis reduced lung damage and fibrotic remodeling. Conclusions These findings suggest that tetracycline inhibits caspase-1-dependent production of IL-1β in response to silica in vitro and in vivo. The results were consistent with tetracycline reducing silica-induced pulmonary inflammation and chronic silicosis in terms of lung injury and fibrosis. Thus, tetracycline could be effective in the treatment of patients with silicosis as well as other diseases involving silicotic inflammation.

Introduction Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysis The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and dissemination The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration number NCT04647396.

Abstract Background Disruption of the endothelial glycocalyx (eGC) is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes. Besides this biomarker function, increased blood concentrations of shedded eGC constituents might play a mechanistic role in septic organ failure. We hypothesized that therapeutic plasma exchange (TPE) using fresh frozen plasma might influence eGC-related pathology by removing injurious mediators of eGC breakdown while at the time replacing eGC protective factors. Methods We enrolled 20 norepinephrine-dependent (NE > 0.4 μg/kg/min) patients with early septic shock (onset

ObjectivePatients with spinal metastasis (SM) are at advanced stages of systemic cancer disease. Surgical therapy for SM is a common treatment modality enabling histopathological diagnosis and the prevention of severe neurological deficits. However, surgery for SM in this vulnerable patient cohort may require prolonged postoperative intensive care treatment, which could adversely affect the anticipated benefit of the surgery. We therefore assessed postoperative prolonged mechanical ventilation (PMV) as an indicator for intensive care treatment with regard to potential correlations with early postoperative mortality and overall survival (OS).MethodsBetween 2015 and 2019, 198 patients were surgically treated for SM at the author´s neurosurgical department. PMV was defined as postoperative mechanical ventilation of more than 24 hours. A multivariate analysis was performed to identify pre- and perioperative collectable predictors for 30 days mortality.ResultsTwenty out of 198 patients (10%) with SM suffered from postoperative PMV. Patients with PMV exhibited a median OS rate of 1 month compared to 12 months for patients without PMV (p < 0.0001). The 30 days mortality was 70% and after one year 100%. The multivariate analysis identified “PMV > 24 hrs” (p < 0.001, OR 0.3, 95% CI 0.02-0.4) as the only significant and independent predictor for 30 days mortality (Nagelkerke’s R2 0.38).ConclusionsOur data indicate postoperative PMV to significantly correlate to high early postoperative mortality rates as well as to poor OS in patients with surgically treated SM. These findings might encourage the initiation of further multicenter studies to comprehensively investigate PMV as a so far underestimated negative prognostic factor in the course of surgical treatment for SM.

ObjectiveVeno-venous (V-V) extracorporeal membrane oxygenation (ECMO) is increasingly used to support patients with severe acute respiratory distress syndrome (ARDS). In case of additional cardio-circulatory failure, some experienced centers upgrade the V-V ECMO with an additional arterial return cannula (termed V-VA ECMO). Here we analyzed short- and long-term outcome together with potential predictors of mortality.DesignMulticenter, retrospective analysis between January 2008 and September 2021.SettingThree tertiary care ECMO centers in Germany (Hannover, Bonn) and Switzerland (Zurich).PatientsSeventy-three V-V ECMO patients with ARDS and additional acute cardio-circulatory deterioration required an upgrade to V-VA ECMO were included in this study.Measurements and main resultsFifty-three patients required an upgrade from V-V to V-VA and 20 patients were directly triple cannulated. Median (Interquartile Range) age was 49 (28–57) years and SOFA score was 14 (12–17) at V-VA ECMO upgrade. Vasoactive-inotropic score decreased from 53 (12–123) at V-VA ECMO upgrade to 9 (3–37) after 24 h of V-VA ECMO support. Weaning from V-VA and V-V ECMO was successful in 47 (64%) and 40 (55%) patients, respectively. Duration of ECMO support was 12 (6–22) days and ICU length of stay was 32 (16–46) days. Overall ICU mortality was 48% and hospital mortality 51%. Two additional patients died after hospital discharge while the remaining patients survived up to two years (with six patients being lost to follow-up). The vast majority of patients was free from higher degree persistent organ dysfunction at follow-up. A SOFA score > 14 and higher lactate concentrations at the day of V-VA upgrade were independent predictors of mortality in the multivariate regression analysis.ConclusionIn this analysis, the use of V-VA ECMO in patients with ARDS and concomitant cardiocirculatory failure was associated with a hospital survival of about 50%, and most of these patients survived up to 2 years. A SOFA score > 14 and elevated lactate levels at the day of V-VA upgrade predict unfavorable outcome.

BackgroundInfections are an important complication after stroke and negatively affect clinical outcome. While pneumonia and urinary tract infections are well recognized after stroke, the incidence and consequences of sepsis remain unclear. The aim of this study was to evaluate the frequency and characteristics of sepsis in patients undergoing endovascular therapy for large vessel occlusion stroke, and its association with clinical outcome.MethodsWe analyzed a cohort of patients who underwent endovascular therapy at a single center between 2016 and 2020. The diagnosis and timing of infections and Sequential Organ Failure Assessment scores were evaluated retrospectively to identify patients with sepsis. Patients with sepsis were compared to controls regarding clinical characteristics and outcome.ResultsFifty-four of 406 patients (13.3%) were found to have sepsis. The median onset of sepsis was 2 days after admission. The majority of cases (85.2%) was caused by pneumonia. At 3 months, 72.5% of patients with sepsis were bedridden or dead compared to 25.7 and 42.7% of controls and patients with an infection without sepsis, respectively. The adjusted odds ratio (95% confidence interval) for a poor outcome was 5.4 (1.6–17.6) for patients with sepsis vs. controls, and 2.0 (0.8–5.2) for patients with sepsis vs. patients with an infection without sepsis.ConclusionsSepsis is a frequent complication after large vessel occlusion stroke, and may be associated with a poor clinical outcome. More studies are needed to determine specific risk factors and measures to early recognize and reduce the possibly negative impact of sepsis on outcome after stroke.

Abstract Background Extracorporeal membrane oxygenation (ECMO) support in acute respiratory failure may be lifesaving, but bleeding and thromboembolic complications are common. The optimal anticoagulation strategy balancing these factors remains to be determined. This retrospective study compared two institutional anticoagulation management strategies focussing on oxygenator changes and both bleeding and thromboembolic events. Methods We conducted a retrospective observational cohort study between 04/2015 and 02/2020 in two ECMO referral centres in Germany in patients receiving veno-venous (VV)-ECMO support for acute respiratory failure for > 24 h. One centre routinely applied low-dose heparinization aiming for a partial thromboplastin time (PTT) of 35–40 s and the other routinely used a high-dose therapeutic heparinization strategy aiming for an activated clotting time (ACT) of 140–180 s. We assessed number of and time to ECMO oxygenator changes, 15-day freedom from oxygenator change, major bleeding events, thromboembolic events, 30-day ICU mortality, activated clotting time and partial thromboplastin time and administration of blood products. Primary outcome was the occurrence of oxygenator changes depending on heparinization strategy; main secondary outcomes were the occurrence of severe bleeding events and occurrence of thromboembolic events. The transfusion strategy was more liberal in the low-dose centre. Results Of 375 screened patients receiving VV-ECMO support, 218 were included in the analysis (117 high-dose group; 101 low-dose group). Disease severity measured by SAPS II score was 46 (IQR 36–57) versus 47 (IQR 37–55) and ECMO runtime was 8 (IQR 5–12) versus 11 (IQR 7–17) days (P = 0.003). There were 14 oxygenator changes in the high-dose group versus 48 in the low-dose group. Freedom from oxygenator change at 15 days was 73% versus 55% (adjusted HR 3.34 [95% confidence interval 1.2–9.4]; P = 0.023). Severe bleeding events occurred in 23 (19.7%) versus 14 (13.9%) patients (P = 0.256) and thromboembolic events occurred in 8 (6.8%) versus 19 (19%) patients (P = 0.007). Mortality at 30 days was 33.3% versus 30.7% (P = 0.11). Conclusions In this retrospective study, ECMO management with high-dose heparinization was associated with lower rates of oxygenator changes and thromboembolic events when compared to a low-dose heparinization strategy. Prospective, randomized trials are needed to determine the optimal anticoagulation strategy in patients receiving ECMO support.

Abstract Background A dysbalanced coagulation system is part of the pathological host response to infection in sepsis. Activation of pro-coagulant pathways and attenuation of anti-coagulant activity ultimately lead to microvascular stasis and consequent organ failure. No treatment approaches specifically targeting this axis are available. We explored the effects of therapeutic plasma exchange (TPE) on microvascular coagulation dysbalance in septic shock. Methods We conducted a prospective single-center study enrolling 31 patients with early septic shock (onset 0.4 μg/kg/min). Clinical and biochemical data, including measurement of protein C; a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13); and von Willebrand factor antigen (vWF:Ag), were obtained before and after TPE against fresh frozen plasma. Results Antithrombotic acting proteins such as antithrombin-III (ATIII) and protein C were markedly reduced in septic patients, but their activity increased after TPE (ATIII, 51% (41–61) vs. 63% (48–70), p = 0.029; protein C, 47% (38–60) vs. 62% (54–69), p = 0.029). Median ADAMTS13 activity was increased by TPE from 27 (21–42) % before to 47 (38–62) % after TPE (p

Object: Inflammatory response is an important determinant of subsequent brain injury after deep-seated intracerebral hemorrhage (ICH). The ratio of red blood cell (RBC) distribution width to platelet count (RPR) has been established as a new index to reflect the severity of inflammation. To the best of our knowledge, no association between RPR and prognosis after spontaneous ICH has yet been reported.Methods: In all patients with deep-seated ICH treated at our Neurovascular Center from 2014 to 2020, initial laboratory values were obtained to determine RPR in addition to patient characteristics and known risk factors. Subsequent multivariate analysis was performed to identify independent risk factors for 90-day mortality after deep-seated ICH.Results: Hundred and two patients with deep-seated ICH were identified and further analyzed. Patients with an initial RPR < 0.06 exhibited significantly lower mortality rate after 90 days than those with an initial RPR ≥ 0.06 (27 vs. 57%; p = 0.003). Multivariate analysis identified “ICH score ≥ 3” (p = 0.001), “anemia on admission” (p = 0.01), and “elevated RPR ≥ 0.06” (p = 0.03) as independent predictors of 90-day mortality.Conclusions: The present study constitutes the first attempt to demonstrate that the ratio of RBC distribution width to platelets—as an independent inflammatory marker—might serve for prognostic assessment in deep-seated ICH.

First described in the mid-1960s, acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure with an overall mortality rate of approximately 40%. Despite significant advances in the understanding and treatment of ARDS, no substantive pharmacologic therapy has proven to be beneficial, and current management continues to be primarily supportive. Beyond their antibacterial activity, several antibiotics such as macrolides and tetracyclines exert pleiotropic immunomodulatory effects that might be able to rectify the dysregulated inflammatory response present in patients with ARDS. This review aims to provide an overview of preclinical and clinical studies that describe the immunomodulatory effects of antibiotics in ARDS. Moreover, the underlying mechanisms of their immunomodulatory properties will be discussed. Further studies are necessary to investigate their full therapeutic potential and to identify ARDS phenotypes which are most likely to benefit from their immunomodulatory effects.

ObjectIntra-tumoral hemorrhage is considered an imaging characteristic of advanced cancer disease. However, data on the influence of intra-tumoral hemorrhage in patients with brain metastases (BM) remains scarce. We aimed at investigating patients with BM who underwent neurosurgical resection of the metastatic lesion for a potential impact of preoperative hemorrhagic transformation on overall survival (OS).MethodsBetween 2013 and 2018, 357 patients with BM were surgically treated at the authors’ neuro-oncological center. Preoperative magnetic resonance imaging (MRI) examinations were assessed for the occurrence of malignant hemorrhagic transformation.Results122 of 375 patients (34%) with BM revealed preoperative intra-tumoral hemorrhage. Patients with hemorrhagic transformed BM exhibited a median OS of 5 months compared to 12 months for patients without intra-tumoral hemorrhage. Multivariate analysis revealed preoperative hemorrhagic transformation as an independent and significant predictor for worsened OS.ConclusionsThe present study identifies preoperative intra-tumoral hemorrhage as an indicator variable for poor prognosis in patients with BM undergoing neurosurgical treatment.

ObjectIn the light of an aging population and ongoing advances in cancer control, the optimal management in geriatric patients with brain metastases (BM) poses an increasing challenge, especially due to the scarce data available. We therefore analyzed our institutional data with regard to factors influencing overall survival (OS) in geriatric patients with BM.MethodsBetween 2013 and 2018, patients aged ≥ 65 years with surgically treated BM were included in this retrospective analysis. In search of preoperatively identifiable risk factors for poor OS, in addition to the underlying cancer, the preoperative frailty of patients was analyzed using the modified Frailty Index (mFI).ResultsA total of 180 geriatric patients with surgically treated BM were identified. Geriatric patients categorized as least-frail achieved a median OS of 18 months, whereas frailest patients achieved an OS of only 3 months (p5 mg/l” (p=0.01) and “frailest patients (mFI ≥ 0.27)” (p=0.002) as predictors for reduced OS in older patients undergoing surgical treatment for BM.ConclusionsIn this retrospective series, pre-operative frailty was associated with poor survival in elderly patients with BM requiring surgery. Our analyses warrant thorough counselling and support of affected elderly patients and their families.

Abstract Background Acute respiratory distress syndrome (ARDS) is a life-threatening condition and the identification of the underlying direct (pulmonary) or indirect (non-pulmonary) cause is mandatory for a successful treatment. Intragastric balloon (IGB) therapy is a minimal invasive and supposedly harmless option to reduce body weight for the growing number of obese people. We present a case of a young patient who developed a direct ARDS due to initially undiagnosed abdominal pathologies caused by an IGB therapy. Case presentation A 23-year old woman was admitted because of a direct ARDS for extracorporeal membrane oxygenation (ECMO) therapy. Weeks before, an IGB has been removed because of abdominal pain and free intraabdominal air. Diagnostic work-up of free intraabdominal air, previous pain of the left shoulder and newly developed abscess pneumonia revealed a perforation of the posterior wall of the gastral antrum. This resulted in a left subphrenic abscess with destruction of the diaphragm, development of pneumonia per continuitatem and subsequent direct lung injury. The gastric perforation was endoscopically clipped and the ARDS was successfully treated under ECMO therapy. Conclusion This case illustrates that a patient presenting with direct ARDS may have upper abdominal pathologies caused by a rare complication of a supposedly harmless treatment.

Abstract Background Extra Corporeal Membrane Oxygenation (ECMO) has become an accepted treatment option for severely ill patients. Due to a limited availability of ECMO support therapy, patients must often be transported to a specialised centre before or after cannulation. According to the ELSO guidelines, an ECMO specialist should be present for such interventions. Here we describe the safety and efficacy of a reduced team approach involving one anaesthesiologist, experienced in specialised intensive care medicine, and a specialised critical care nurse. Methods This study is a 10 years retrospective, single institution analysis of all data collected between January 2007 and December 2016 from the medical records at the University Hospital Bonn, Germany. Results The Bonner mobile ECMO team was deployed in 170 cases for on-site evaluation for ECMO support therapy. 4 (2.4%) patients died prior to arrival or during the implementation of ECMO support. Of the remaining 166 patients, 126 were cannulated at the referring site, 40 were transported without ECMO. Of those, 21 were subsequently cannulated out our centre. 19 patients never received ECMO treatment. The primary indication for ECMO treatment was ARDS (159/166 patients). Veno-venous ECMO was initiated in 137, whilst 10 patients received veno-arterial ECMO treatment. Mean transportation time was 75 ± 36 min, and mean transport distance was 56 ± 57 km. In total, 26 complications were observed, three being directly transport-related. The overall survival was 55%. Conclusions Initiation of extracorporeal membrane oxygenation and subsequent transport can be safely and efficiently performed by a two-man team with good outcome.

Objective: The aim of this study was the verification of the Subdural Hematoma in the Elderly (SHE) score proposed by Alford et al. as a mortality predictor in patients older than 65 years with nontraumatic/minor trauma acute subdural hematoma (aSDH). Additionally, we evaluated further predictors associated with poor outcome. Methods: Patients were scored according to age (1 point is given if patients were older than 80 years), GCS by admission (1 point for GCS 5–12, 2 points for GCS 3–4), and SDH volume (1 point for volume 50 mL). The sum of points determines the SHE score. Multivariate logistic regression analysis was performed to identify additional independent risk factors associated with 30-day mortality. Results: We evaluated 131 patients with aSDH who were treated at our institution between 2008 and 2020. We observed the same 30-day mortality rates published by Alford et al.: SHE 0: 4.3% vs. 3.2%, p = 1.0; SHE 1: 12.2% vs. 13.1%, p = 1.0; SHE 2: 36.6% vs. 32.7%, p = 0.8; SHE 3: 97.1% vs. 95.7%, p = 1.0 and SHE 4: 100% vs. 100%, p = 1.0. Additionally, 18 patients who developed status epilepticus (SE) had a mortality of 100 percent regardless of the SHE score. The distribution of SE among the groups was: 1 for SHE 1, 6 for SHE 2, 9 for SHE 3, and 2 for SHE 4. The logistic regression showed the surgical evacuation to be the only significant risk factor for developing the seizure. All patients who developed SE underwent surgery (p = 0.0065). Furthermore, SHE 3 and 4 showed no difference regarding the outcome between surgical and conservative treatment. Conclusions: SHE score is a reliable mortality predictor for minor trauma acute subdural hematoma in elderly patients. In addition, we identified status epilepticus as a strong life-expectancy-limiting factor in patients undergoing surgical evacuation.

Background and Objectives: Treatment-limiting decisions (TLDs) are employed to actively withhold treatment/invasive interventions from patients in whom clinicians feel they would derive little to no benefit and/or suffer detrimental effects. Data regarding the employment of TLDs in patients with spontaneous intracerebral hemorrhage (ICH) remain sparse. Accordingly, this study sought to investigate both the prevalence of TLDs and factors driving TLDs in patients suffering from spontaneous ICH. Materials and Methods: This was a retrospective study of 249 consecutive patients with ICH treated from 2018–2019 at the Neurovascular Center of the University Hospital Bonn. Reasons deemed critical in the decision-making process with regard to TLD were ultimately extracted/examined via chart review of qualifying patients. Results: A total of 249 patients with ICH were included within the final analyses. During the time period examined, 49 patients (20%) had advanced directives in place, whereas in 53 patients (21%) consultation with relatives or acquaintances was employed before further treatment decisions. Overall, TLD ultimately manifested in 104 patients (42%). TLD was reached within 6 h after admission in 52 patients (50%). Congruent with severity of injury and expected outcomes, TLDs were more likely in patients with signs of cerebral herniation and an ICH score > 3 (p < 0.001). Conclusions: The present study examines details associated with TLDs in patients with spontaneous ICH. These data provide insight into key decisional processes and reinforce the need for further structured investigations in an effort to help guide patients and their families.

Summary: Memory B cells seem to be more durable than antibodies and thus crucial for the long-term immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here we investigate SARS-CoV-2 spike-specific memory B cells and their dependence on CD4+ T cell help in different settings of coronavirus disease 2019 (COVID-19). Compared with severely ill individuals, those who recovered from mild COVID-19 develop fewer but functionally superior spike-specific memory B cells. Generation and affinity maturation of these cells is best associated with IL-21+CD4+ T cells in recovered individuals and CD40L+CD4+ T cells in severely ill individuals. The increased activation and exhaustion of memory B cells observed during COVID-19 correlates with CD4+ T cell functions. Intriguingly, CD4+ T cells recognizing membrane protein show a stronger association with spike-specific memory B cells than those recognizing spike or nucleocapsid proteins. Overall, we identify CD4+ T cell subsets associated with the generation of B cell memory during SARS-CoV-2 infection.

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease harboring significant morbidity and mortality despite recent advances in therapy. Regardless of disease severity acute exacerbations (IPF-AEs) may occur leading to considerable loss of function and are the leading cause of death in IPF. Histologic features of IPF-AE are very similar to acute respiratory distress syndrome (ARDS), but the underlying mechanisms are incompletely understood. We investigated the role of the NLRP3 inflammasome in IPF and IPF-AE. Bronchoalveolar lavage (BAL) cells were sampled from patients with IPF (n = 32), IPF-AE (n = 10), ARDS (n = 7) and healthy volunteers (HV, n = 37) and the NLRP3-inflammasome was stimulated in-vitro. We found the NLRP3 inflammasome to be hyper-inducible in IPF compared to HV with increased IL-1ß and pro-IL-1ß levels on ELISA upon stimulation as well as increased caspase-1 activity measured by caspase-1p20 immunoblotting. In IPF-AE, IL-1ß was massively elevated to an extent similar to ARDS. To evaluate potential mechanisms, we co-cultured BAL cells with radiated A549 cells (a model to simulate apoptotic alveolar epithelial cells), which led to increased NLRP3 mRNA expression and increased caspase-1 dependent IL-1ß production. In the presence of a reactive oxygen species (ROS) inhibitor (diphenyleneiodonium) and a cathepsin B inhibitor (E64D), NLRP3 expression was suppressed indicating that induction of NLRP3 activation following efferocytosis of apoptotic A549 cells is mediated via ROS and cathepsin-B. In summary, we present evidence of involvement of the NLRP3 inflammasome-caspase pathway in the pathogenesis of IPF-AE, similarly to ARDS, which may be mediated by efferocytosis of apoptotic alveolar epithelial cells in IPF.

ObjectiveSurgical resection represents a common treatment modality in patients with brain metastasis (BM). Postoperative prolonged mechanical ventilation (PMV) might have an enormous impact on the overall survival (OS) of these patients suffering from advanced cancer disease. We therefore have analyzed our institutional database with regard to a potential impact of PMV on OS of patients who had undergone surgery for brain metastases.Methods360 patients with surgically treated brain metastases were included. The definition of PMV consisted of postoperative mechanical ventilation lasting for more than 48 hours. Analysis of survival incorporating established prognostic factors such as age, location of BM, and preoperative physical status was performed.Results14 of 360 patients with BM (4%) suffered from postoperative PMV after surgical treatment of BM. Patients with PMV presented in a significantly more impaired neurological condition preoperatively than patients without (p

Objective: The need for continuous renal replacement therapy (CRRT) in patients with deep-seated intracerebral hemorrhage (ICH) requires sustained intensive care and often postpones further rehabilitation therapy. Therefore, an early identification of patients at risk is essential.Methods: From 2014 to 2019, all patients with deep-seated ICH who were admitted to intensive care for >3 days were included in the further analysis and retrospectively reviewed for the need for CRRT. All patients underwent CRRT with regional citrate anticoagulation for continuous veno-venous hemodialysis (CVVHD). Outcome was evaluated after 3 months using the modified Rankin scale. A multivariate analysis was performed to identify potential predictors for CRRT in patients with deep-seated ICH.Results: After applying the inclusion criteria, a total of 87 patients with deep-seated spontaneous ICH were identified and further analyzed. During the first 48 h after admission, 21 of these patients developed early acute kidney injury (AKI; 24%). During treatment course, CRRT became necessary in nine patients suffering from deep-seated ICH (10%). The multivariate analysis revealed “development of AKI during the first 48 h” [p = 0.025, odds ratio (OR) 6.1, 95% confidence interval (CI) 1.3–29.8] and “admission procalcitonin (PCT) value >0.5 μg/l” (p = 0.02, OR 7.7, 95% CI 1.4–43.3) as independent and significant predictors for CRRT in patients with deep-seated ICH.Conclusions: Elevated serum levels of procalcitonin on admission as well as early development of acute renal injury are independent predictors of the need for renal replacement therapy in patients with deep-seated intracerebral bleeding. Therefore, further research is warranted to identify these vulnerable patients as early as possible to enable adequate treatment.

ObjectiveAlthough the treatment of glioblastoma patients is well established in neuro-oncological surgery, precious scarce data is available on patients with glioblastoma requiring postoperative prolonged mechanical ventilation (PMV). Therefore, the aim of the present study was to determine the influence of PMV on overall survival (OS) in patients with glioblastoma.MethodsPatients with newly diagnosed glioblastoma who had undergone surgical therapy and complete subsequent neuro-oncological treatment at the authors’ neuro-oncological center from January 2013 to December 2018 were selected and included in the further analysis. PMV was defined as mechanical ventilation for more than 24 h after surgery. Survival analyses were performed, including established prognostic factors such as age, Karnofsky performance score, MGMT-promoter methylation status and extent of resection.ResultsA total of 240 patients with newly diagnosed glioblastoma and subsequent surgical treatment were identified. 13 patients (5%) suffered from PMV during the treatment course of glioblastoma. All but one patient were successfully weaned from mechanical ventilation. Patients suffering from PMV achieved significantly less often favorable functional outcome after 3, 6, 9, and 12 months compared to patients without PMV. Multivariate analysis revealed PMV to constitute a significant prognostic factor for OS, independent of other prognostic factors (p

(1) Background: As elements of the standard admission blood panel, lactate and glucose represent potential biomarkers for outcome prediction. In patients with intracranial hemorrhage (ICH), data on the predictive value of these blood values is exceedingly sparse. (2) Methods: Between 2014 and August 2020, all patients with deep-seated ICH referred to the neurovascular center at the authors’ institution were included in the subsequent study. Serum levels of lactate and glucose at the time of admission were compared with mortality at 90 days. In addition, a multivariate analysis was performed in order to identify independent admission predictors for 90-day mortality. (3) Results: Among the 102 patients with deep-seated ICH, elevated lactate and glucose levels on admission were significantly associated with increased mortality at 90 days. Multivariate logistic regression analysis identified “ICH score ≥3” (p = 0.004) along with “admission hyperlactatemia” (p = 0.025) and “admission hyperglycemia” (p = 0.029) as independent and significant predictors of 90-day mortality in patients with deep-seated ICH. (4) Conclusions: Initially elevated lactate and glucose levels after spontaneous intracerebral hemorrhage are associated with poor outcome, suggesting a potential application for future prognostic models when considered in conjunction with other parameters.

Intracerebral hemorrhage (ICH) is a frequently disabling or fatal disease. The localization of ICH often allows an etiological association. However, in atypical/lobar ICH, the cause of bleeding is less obvious. Therefore, we present prospective histopathological and radiological studies which were conducted within the diagnostic workup to identify causes for lobar ICH other than hypertension. From 2016 to 2018, 198 patients with spontaneous, non-traumatic ICH requiring neurosurgical monitoring were enrolled in an institutional prospective patient registry. Patients with deep-seated ICH and/or hemorrhagically transformed cerebral infarcts were excluded from further analysis. Data to evaluate the source of bleeding based on histopathological and/or radiological workup were prospectively evaluated and analyzed. After applying the inclusion criteria and excluding patients with incomplete diagnostic workup, a total of 52 consecutive patients with lobar ICH were further analyzed. Macrovascular disease was detected in 14 patients with lobar ICH (27%). In 11 patients, diagnostic workup identified cerebral amyloid angiopathy-related ICH (21%). In addition, five patients with tumor-related ICH (10%) and six patients with ICH based on infectious pathologies (11%) were identified. In four patients, the cause of bleeding remained unknown despite extensive diagnostic workup (8%). The present prospective registry study demonstrates a higher probability to identify a cause of bleeding other than hypertension in patients with lobar ICH. Therefore, a thorough diagnostic work-up in patients with ICH is essential to accelerate treatment and further improve outcome or prevent rebleeding.

(1) Background: With the rise of multi-/pan-drug resistant (MDR/PDR) pathogens, the less utilized antibiotic Colistin has made a comeback. Colistin fell out of favor due to its small therapeutic range and high potential for toxicity. Today, it is used again as a last resort substance in treating MDR/PDR pathogens. Although new guidelines with detailed recommendations for Colistin dosing are available, finding the right dose in critically ill patients with renal failure remains difficult. Here, we evaluate the efficiency of the current guidelines’ recommendations by using high resolution therapeutic drug monitoring of Colistin. (2) Methods: We analyzed plasma levels of Colistin and its prodrug colisthimethate sodium (CMS) in 779 samples, drawn from eight PDR-infected ICU patients, using a HPLC-MS/MS approach. The impact of renal function on proper Colistin target levels was assessed. (3) Results: CMS levels did not correlate with Colistin levels. Over-/Underdosing occurred regardless of renal function and mode of renal replacement therapy. Colistin elimination half-time appeared to be longer than previously reported. (4) Conclusion: Following dose recommendations from the most current guidelines does not necessarily lead to adequate Colistin plasma levels. Use of Colistin without therapeutic drug monitoring might be unsafe and guideline adherence does not warrant efficient target levels in critically ill patients.

Synthetic oligonucleotides containing repetitive TTAGGG motifs mimic the immunosuppressive activity of telomeric DNA. These suppressive oligonucleotides (Sup ODN) are effective in the treatment/prevention of various inflammatory and autoimmune diseases in mice. The therapeutic activity of Sup ODN was originally attributed to the inhibition of Th1 cell activation. Current results indicate that Sup ODN also promote the maturation of naive CD4(+) T cells into Th17 effectors. The generation of Th17 cells is linked to the prolonged activation of signal transducer and activator of transcription (STAT)3 mediated by suppressor of cytokine signaling 3 (SOCS3) inhibition. In vivo studies show that treatment with Sup ODN promotes Th17 responsiveness under physiological conditions, increasing host resistance to Candida albicans infection. These findings support the development of Sup ODN to suppress pathological inflammatory conditions and improve host resistance to fungal pathogens.