Effects of extracorporeal CO2 removal on gas exchange and ventilator settings: a systematic review and meta-analysis.

PURPOSE: A systematic review and meta-analysis to evaluate the impact of extracorporeal carbon dioxide removal (ECCO2R) on gas exchange and respiratory settings in critically ill adults with respiratory failure. METHODS: We conducted a comprehensive database search, including observational studies and randomized controlled trials (RCTs) from January 2000 to March 2022, targeting adult ICU patients undergoing ECCO2R. Primary outcomes were changes in gas exchange and ventilator settings 24 h after ECCO2R initiation, estimated as mean of differences, or proportions for adverse events (AEs); with subgroup analyses for disease indication and technology. Across RCTs, we assessed mortality, length of stay, ventilation days, and AEs as mean differences or odds ratios. RESULTS: A total of 49 studies encompassing 1672 patients were included. ECCO2R was associated with a significant decrease in PaCO2, plateau pressure, and tidal volume and an increase in pH across all patient groups, at an overall 19% adverse event rate. In ARDS and lung transplant patients, the PaO2/FiO2 ratio increased significantly while ventilator settings were variable. "Higher extraction" systems reduced PaCO2 and respiratory rate more efficiently. The three available RCTs did not demonstrate an effect on mortality, but a significantly longer ICU and hospital stay associated with ECCO2R. CONCLUSIONS: ECCO2R effectively reduces PaCO2 and acidosis allowing for less invasive ventilation. "Higher extraction" systems may be more efficient to achieve this goal. However, as RCTs have not shown a mortality benefit but increase AEs, ECCO2R's effects on clinical outcome remain unclear. Future studies should target patient groups that may benefit from ECCO2R. PROSPERO Registration No: CRD 42020154110 (on January 24, 2021).

NOX4-derived ROS are neuroprotective by balancing intracellular calcium stores.

Hyperexcitability is associated with neuronal dysfunction, cellular death, and consequently neurodegeneration. Redox disbalance can contribute to hyperexcitation and increased reactive oxygen species (ROS) levels are observed in various neurological diseases. NOX4 is an NADPH oxidase known to produce ROS and might have a regulating function during oxidative stress. We, therefore, aimed to determine the role of NOX4 on neuronal firing, hyperexcitability, and hyperexcitability-induced changes in neural network function. Using a multidimensional approach of an in vivo model of hyperexcitability, proteomic analysis, and cellular function analysis of ROS, mitochondrial integrity, and calcium levels, we demonstrate that NOX4 is neuroprotective by regulating ROS and calcium homeostasis and thereby preventing hyperexcitability and consequently neuronal death. These results implicate NOX4 as a potential redox regulator that is beneficial in hyperexcitability and thereby might have an important role in neurodegeneration.

Achieving Control over the Reduction/Coupling Dichotomy of N2 by Boron Metallomimetics.

We report a detailed computational and experimental study of the fixation and reductive coupling of dinitrogen with low-valent boron compounds. Consistent with our mechanistic findings, the selectivity toward nitrogen fixation or coupling can be controlled through either steric bulk or the reaction conditions, allowing for the on-demand synthesis of nitrogen chains. The electronic structure and intriguing magnetic properties of intermediates and products of the reaction of dinitrogen with borylenes are also elucidated using high-level computational approaches.

Add-On Prostaglandin E1 in Venovenous Extracorporeal Membrane Oxygenation: A Randomized, Double-Blind, Placebo-controlled Pilot Trial.

Rationale: Prostaglandin E1 (alprostadil; PGE1), in addition to low-dose unfractionated heparin, increases the biocompatibility of extracorporeal systems and enhances the efficacy of artificial organs without increasing bleeding risk. Objectives: We investigated the safety and efficacy of PGE1 in adults receiving venovenous extracorporeal membrane oxygenation (ECMO). Methods: This study was a randomized, double-blind, placebo-controlled phase II pilot trial at two medical intensive care units at the Medical University of Vienna, Austria. Adults with venovenous ECMO were randomly assigned to receive an intravenous infusion of 5 ng/kg/min PGE1 or placebo (0.9% saline) in addition to standard anticoagulation with unfractionated heparin. Measurements and Main Results: The primary outcome was the rate of transfused packed red blood cells per ECMO day. Secondary outcomes were the incidence of and time to clinically overt bleeding and thromboembolic events. A post hoc subgroup analysis included only patients with coronavirus disease (COVID-19). Between September 2016 and April 2021, of 133 screened patients, 50 patients were randomized, of whom 48 received the assigned study medication (24 per group). The transfusion rate was similar between groups (0.41 vs. 0.39; P = 0.733). PGE1 was associated with fewer thromboembolic events (7 vs. 16; P = 0.020) and longer thromboembolism-free time (hazard ratio [HR], 0.302; P = 0.01), fewer clinically overt bleeding events (2 vs. 11; P = 0.017), and longer bleeding-free time (HR, 0.213; P = 0.047). In patients with COVID-19 (n = 25), the HRs for clinically overt bleeding and thromboembolism were 0.276 (95% confidence interval, 0.035-2.186) and 0.521 (95% confidence interval, 0.149-1.825), respectively. Conclusions: Add-on treatment with PGE1 was safe but did not meet the primary endpoint of reducing the rate of red blood cell transfusions in patients receiving venovenous ECMO. Larger studies need to evaluate the safety and efficacy of additional PGE1 in ECMO. Clinical trial registered with EudraCT (2015-005014-30) and www.clinicaltrials.gov (NCT02895373).

Immune response to SARS-CoV-2 vaccination in relation to peripheral immune cell profiles among patients with multiple sclerosis receiving ocrelizumab.

BACKGROUND: Vaccination has proven to be effective in preventing SARS-CoV-2 transmission and severe disease courses. However, immunocompromised patients have not been included in clinical trials and real-world clinical data point to an attenuated immune response to SARS-CoV-2 vaccines among patients with multiple sclerosis (MS) receiving immunomodulatory therapies. METHODS: We performed a retrospective study including 59 ocrelizumab (OCR)-treated patients with MS who received SARS-CoV-2 vaccination. Anti-SARS-CoV-2-antibody titres, routine blood parameters and peripheral immune cell profiles were measured prior to the first (baseline) and at a median of 4 weeks after the second vaccine dose (follow-up). Moreover, the SARS-CoV-2-specific T cell response and peripheral B cell subsets were analysed at follow-up. Finally, vaccination-related adverse events were assessed. RESULTS: After vaccination, we found anti-SARS-CoV-2(S) antibodies in 27.1% and a SARS-CoV-2-specific T cell response in 92.7% of MS cases. T cell-mediated interferon (IFN)-γ release was more pronounced in patients without anti-SARS-CoV-2(S) antibodies. Antibody titres positively correlated with peripheral B cell counts, time since last infusion and total IgM levels. They negatively correlated with the number of previous infusion cycles. Peripheral plasma cells were increased in antibody-positive patients. A positive correlation between T cell response and peripheral lymphocyte counts was observed. Moreover, IFN-γ release was negatively correlated with the time since the last infusion. CONCLUSION: In OCR-treated patients with MS, the humoral immune response to SARS-CoV-2 vaccination is attenuated while the T cell response is preserved. However, it is still unclear whether T or B cell-mediated immunity is required for effective clinical protection. Nonetheless, given the long-lasting clinical effects of OCR, monitoring of peripheral B cell counts could facilitate individualised treatment regimens and might be used to identify the optimal time to vaccinate.

Vesseg: An Open-Source Tool for Deep Learning-Based Atherosclerotic Plaque Quantification in Histopathology Images-Brief Report.

Objective: Manual plaque segmentation in microscopy images is a time-consuming process in atherosclerosis research and potentially subject to unacceptable user-to-user variability and observer bias. We address this by releasing Vesseg a tool that includes state-of-the-art deep learning models for atherosclerotic plaque segmentation. Approach and Results: Vesseg is a containerized, extensible, open-source, and user-oriented tool. It includes 2 models, trained and tested on 1089 hematoxylin-eosin stained mouse model atherosclerotic brachiocephalic artery sections. The models were compared to 3 human raters. Vesseg can be accessed at https://vesseg .online or downloaded. The models show mean Soerensen-Dice scores of 0.91+/-0.15 for plaque and 0.97+/-0.08 for lumen pixels. The mean accuracy is 0.98+/-0.05. Vesseg is already in active use, generating time savings of >10 minutes per slide. Conclusions: Vesseg brings state-of-the-art deep learning methods to atherosclerosis research, providing drastic time savings, while allowing for continuous improvement of models and the underlying pipeline.

A bi-centric experience of extracorporeal carbon dioxide removal (ECCO2 R) for acute hypercapnic respiratory failure following allogeneic hematopoietic stem cell transplantation.

Acute respiratory failure (ARF) is the main reason for ICU admission following allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal CO2 removal (ECCO2 R) can be used as an adjunct to mechanical ventilation in patients with severe hypercapnia but has not been assessed in HSCT recipients. Retrospective analysis of all allogeneic HSCT recipients ≥18 years treated with ECCO2 R at two HSCT centers. 11 patients (m:f = 4:7, median age: 45 [IQR: 32-58] years) were analyzed. Acute leukemia was the underlying hematologic malignancy in all patients. The time from HSCT to ICU admission was 37 [8-79] months, and 9/11 (82%) suffered from chronic graft-versus-host disease (GVHD) with lung involvement. Pneumonia was the most frequent reason for ventilatory decompensation (n = 9). ECCO2 R was initiated for severe hypercapnia (Pa CO2 : 96 [84-115] mm Hg; pH: 7.13 [7.09-7.27]) despite aggressive mechanical ventilation (invasive, n = 9; non-invasive, n = 2). ECCO2 R effectively resolved blood gas disturbances in all patients, but only 2/11 (18%) could be weaned off ventilatory support, and one (9%) patient survived hospital discharge. Progressive respiratory and multiorgan dysfunction were the main reasons for treatment failure. ECCO2 R was technically feasible but resulted in a low survival rate in our cohort. A better understanding of the prognosis of ARF in patients with chronic GVHD and lung involvement is necessary before its use can be reconsidered in this setting.

Highly Colored Boron-Doped Thiazolothiazoles from the Reductive Dimerization of Boron Isothiocyanates.

Reduction of (CAAC)BBr2 (NCS) (CAAC=cyclic alkyl(amino)carbene) in the presence of a Lewis base L yields tricoordinate (CAAC)LB(NCS) borylenes which undergo reversible E/Z-isomerization. The same reduction in the absence of L yields deep blue, bis(CAAC)-stabilized, boron-doped, aromatic thiazolothiazoles resulting from the dimerization of dicoordinate (CAAC)B(NCS) borylene intermediates.

Trapping of a Borirane Intermediate in the Reductive Coupling of an Arylborane to a Diborene.

The reductive coupling of a N-heterocyclic carbene (NHC)-stabilized aryldibromoborane yields a mixture of trans- and cis-diborenes in which the aryl groups are coplanar with the diborene core. Under dilute reduction conditions two diastereomers of a borirane-borane intermediate are isolated, which upon further reduction give rise to the aforementioned diborene mixture. DFT calculations suggest a mechanism proceeding via nucleophilic attack of a dicoordinate borylene intermediate on the aryl ring and subsequent intramolecular B-B bond formation.

Oxidation, Coordination, and Nickel-Mediated Deconstruction of a Highly Electron-Rich Diboron Analogue of 1,3,5-Hexatriene.

The reductive coupling of an N-heterocyclic carbene (NHC) stabilized (dibromo)vinylborane yields a 1,2-divinyldiborene, which, although isoelectronic to a 1,3,5-triene, displays no extended π conjugation because of twisting of the C2 B2 C2 chain. While this divinyldiborene coordinates to copper(I) and platinum(0) in an η2 -B2 and η4 -C2 B2 fashion, respectively, it undergoes a complex rearrangement to an η4 -1,3-diborete upon complexation with nickel(0).

trans-Selective Insertional Dihydroboration of a cis-Diborene: Synthesis of Linear sp3 -sp2 -sp3 -Triboranes and Subsequent Cationization.

The reaction of aryl- and amino(dihydro)boranes with dibora[2]ferrocenophane 1 leads to the formation 1,3-trans-dihydrotriboranes by formal hydrogenation and insertion of a borylene unit into the B=B bond. The aryltriborane derivatives undergo reversible photoisomerization to the cis-1,2-µ-H-3-hydrotriboranes, while hydride abstraction affords cationic triboranes, which represent the first doubly base-stabilized B3 H4 + analogues.

ECMO without anticoagulation in patients with disease-related severe thrombocytopenia: Feasible but futile?

Severe thrombocytopenia poses a high risk for bleeding thus representing a relative contraindication for anticoagulation and therefore extracorporeal membrane oxygenation (ECMO). We herein report on a series of immunocompromised patients with severe thrombocytopenia undergoing long-term ECMO without systemic anticoagulation. We retrospectively identified seven adult patients with anticoagulation withdrawal for ≥3 days (range 5-317) during venovenous ECMO therapy due to thrombocytopenia < 50 G/L treated in a university-affiliated hospital from January 2013 to April 2017. All ECMO systems used were heparin coated. Overall, 530 ECMO days were observed, 404 (76%) of them without systemic anticoagulation. Platelet count during ECMO treatment was 24 G/L (median, range 1-138), ECMO duration was 35 days (5-317), and ECMO was run without any anticoagulation for 20 days (5-317). Altogether, five clotting events were seen leading to oxygenator exchanges. Bleeding was common including one fatal intracerebral hemorrhage. Altogether, 29 platelet concentrates per patient (7-207) were administered, which correspond to 0.8 per day (0.6-1.3). One patient survived ICU and hospital. In patients with thrombocytopenia, ECMO can be run without anticoagulation even for considerably long periods of time. Bleeding remains common, while clotting events seem to be rare. However, prognosis of this patient population undergoing ECMO support seems grim.

Diboryldiborenes: π-Conjugated B4 Chains Isoelectronic to the Butadiene Dication.

B(sp2 )-B(sp3 ) diborane species based on bis(catecholato)diboron and N-heterocyclic carbenes (NHCs) underwent catechol/bromide exchange selectively at the sp3 -hybridized boron atom. The reduction of the resulting 1,1-dibromodiborane adducts led to reductive coupling and isolation of doubly NHC-stabilized 1,2-diboryldiborenes. These compounds are the first examples of molecules exhibiting π-electron delocalization over an all-boron chain.

Interactions of Isonitriles with Metal-Boron Bonds: Insertions, Coupling, Ring Formation, and Liberation of Monovalent Boron.

Boryl, borylene, and base-stabilized borylene complexes of manganese and iron undergo a range of different reactions when treated with isonitriles including single, double, and partial isonitrile insertions into metal-boron bonds, ring formation, isonitrile coupling, and the liberation of new monovalent boron species. Two of the resulting cyclic species have also been found to react selectively with anhydrous HCl to form ring-opened products. The diverse isonitrile-promoted reactivity of transition-metal-boron compounds has been explored computationally.

Prognostic factors, long-term survival, and outcome of cancer patients receiving chemotherapy in the intensive care unit.

Prognostic factors and outcomes of cancer patients with acute organ failure receiving chemotherapy (CT) in the intensive care unit (ICU) are still incompletely described. We therefore retrospectively studied all patients who received CT in any ICU of our institution between October 2006 and November 2013. Fifty-six patients with hematologic (n = 49; 87.5 %) or solid (n = 7; 12.5 %) malignancies, of which 20 (36 %) were diagnosed in the ICU, were analyzed [m/f ratio, 33:23; median age, 47 years (IQR 32 to 62); Charlson Comorbidity Index (CCI), 3 (2 to 5); Simplified Acute Physiology Score II (SAPS II), 50 (39 to 61)]. The main reasons for admission were acute respiratory failure, acute kidney failure, and septic shock. Mechanical ventilation and vasopressors were employed in 34 patients (61 %) respectively, hemofiltration in 22 (39 %), and extracorporeal life support in 7 (13 %). Twenty-seven patients (48 %) received their first CT in the ICU. Intention of therapy was cure in 46 patients (82 %). Tumor lysis syndrome (TLS) developed in 20 patients (36 %). ICU and hospital survival was 75 and 59 %. Hospital survivors were significantly younger; had lower CCI, SAPS II, and TLS risk scores; presented less often with septic shock; were less likely to develop TLS; and received vasopressors, hemofiltration, and thrombocyte transfusions in lower proportions. After discharge, 88 % continued CT and 69 % of 1-year survivors were in complete remission. Probability of 1- and 2-year survival was 41 and 38 %, respectively. Conclusively, administration of CT in selected ICU cancer patients was feasible and associated with considerable long-term survival as well as long-term disease-free survival.

Extracorporeal membrane oxygenation in adult patients with hematologic malignancies and severe acute respiratory failure.

INTRODUCTION: Acute respiratory failure (ARF) is the main reason for intensive care unit (ICU) admissions in patients with hematologic malignancies (HMs). We report the first series of adult patients with ARF and HMs treated with extracorporeal membrane oxygenation (ECMO). METHODS: This is a retrospective cohort study of 14 patients with HMs (aggressive non-Hodgkin lymphoma (NHL) n = 5; highly aggressive NHL, that is acute lymphoblastic leukemia or Burkitt lymphoma, n = 5; Hodgkin lymphoma, n = 2; acute myeloid leukemia, n = 1; multiple myeloma, n = 1) receiving ECMO support because of ARF (all data as medians and interquartile ranges; age, 32 years (22 to 51 years); simplified acute physiology score II (SAPS II): 51 (42 to 65)). Etiology of ARF was pneumonia (n = 10), thoracic manifestation of NHL (n = 2), sepsis of nonpulmonary origin (n = 1), and transfusion-related acute lung injury (n = 1). Diagnosis of HM was established during ECMO in four patients, and five first received (immuno-) chemotherapy on ECMO. RESULTS: Before ECMO, the PaO2/FiO2 ratio was 60 (53 to 65), (3.3 to 3.7). Three patients received venoarterial ECMO because of acute circulatory failure in addition to ARF; all other patients received venovenous ECMO. All patients needed vasopressors, and five needed hemofiltration. Thrombocytopenia occurred in all patients (lowest platelet count was 20 (11 to 21) G/L). Five major bleeding events were noted. ECMO duration was 8.5 (4 to 16) days. ICU and hospital survival was 50%. All survivors were alive at follow-up (36 (10 to 58) months); five patients were in complete remission, one in partial remission, and one had relapsed. CONCLUSIONS: ECMO therapy is feasible in selected patients with HMs and ARF and can be associated with long-term disease-free survival.

Comparison of Weaning Strategies in Patients Receiving Venovenous Extracorporeal Membrane Oxygenation: An Exploratory Retrospective Study.

Venovenous extracorporeal membrane oxygenation (VV ECMO) facilitates the reduction of mechanical ventilation (MV) support in acute respiratory failure. Contrary to increasing evidence regarding its initiation, the optimal timing of VV ECMO weaning in interaction with MV weaning is undetermined. In this retrospective study, 47 patients who received VV ECMO between 2013 and 2021 and survived ≥1 day after ECMO cessation were divided according to their MV status before ECMO removal: 28 patients were classified into an "ECMO weaning during assisted MV/spontaneous breathing" group and 19 into an "ECMO weaning during controlled MV" group. Extracorporeal membrane oxygenation duration was longer in the "assisted MV/spontaneous breathing" group (17 [Interquartile range (IQR) = 11-35] vs. 6 [5-11] days, p < 0.001). These patients had a longer intensive care unit (ICU) stay after ECMO start (48 [29-66] vs. 31 [15-40] days, p = 0.01). No significant differences were found for MV duration after ECMO start (30 [19-45] vs. 19 [12-30] days, p = 0.06) and further ICU survival (86% vs. 89%, p ≥ 0.9). There was a trend toward more patients with mechanical ECMO complications in the "assisted MV/spontaneous breathing" group (57% vs. 32%, p = 0.08). Thus, our results suggest a possible benefit of early ECMO weaning during controlled MV.

Lactate as a Predictor of 30-Day Mortality in Cardiogenic Shock.

Background/Objectives: This study sought to evaluate the efficacy of various lactate measurements within the first 24 h post-intensive care unit (ICU) admission for predicting 30-day mortality in cardiogenic shock patients. It compared initial lactate levels, 24 h levels, peak levels, and 24 h clearance, alongside the Simplified Acute Physiology Score 3 (SAPS3) score, to enhance early treatment decision-making. Methods: A retrospective analysis of 64 patients assessed the prognostic performance of lactate levels and SAPS3 scores using logistic regression and AUROC calculations. Results: Of the baseline parameters, only the SAPS3 score predicted survival independently. The lactate level after 24 h (LL) was the most accurate predictor of mortality, outperforming initial levels, peak levels, and 24 h-clearance, and showing a significant AUROC. LL greater than 3.1 mmol/L accurately predicted mortality with high specificity and moderate sensitivity. Conclusions: Among lactate measurements for predicting 30-day mortality in cardiogenic shock, the 24 h lactate level was the most effective one, suggesting its superiority for early prognostication over initial or peak levels and lactate clearance.

Enhancing SAPS-3 Predictive Accuracy with Initial, Peak, and Last Lactate Measurements in Septic Shock.

Background/Objectives: Septic shock is a severe condition with high mortality necessitating precise prognostic tools for improved patient outcomes. This study aimed to evaluate the collective predictive value of the Simplified Acute Physiology Score 3 (SAPS-3) and lactate measurements (initial, peak, last, and clearance rates within the first 24 h) in patients with septic shock. Specifically, it sought to determine how these markers enhance predictive accuracy for 28-day mortality beyond SAPS-3 alone. Methods: This retrospective cohort study analyzed data from 66 septic shock patients at two ICUs of Vienna General Hospital (2017-2019). SAPS-3 and lactate levels (initial, peak, last measurement within 24 h, and 24 h clearance) were obtained from electronic health records. Logistic regression models were constructed to identify predictors of 28-day mortality, and receiver operating characteristic (ROC) curves assessed predictive accuracy. Results: Among 66 patients, 36 (55%) died within 28 days. SAPS-3 scores significantly differed between survivors and non-survivors (76 vs. 85 points; p = 0.016). First, last, and peak lactate were significantly higher in non-survivors compared to survivors (all p < 0.001). The combination of SAPS-3 and first lactate produced the highest predictive accuracy (AUC = 80.6%). However, 24 h lactate clearance was not predictive of mortality. Conclusions: Integrating SAPS-3 with lactate measurements, particularly first lactate, improves predictive accuracy for 28-day mortality in septic shock patients. First lactate serves as an early, robust prognostic marker, providing crucial information for clinical decision-making and care prioritization. Further large-scale studies are needed to refine these predictive tools and validate their efficacy in guiding treatment strategies.