Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia.

The factors that influence survival during severe infection are unclear. Extracellular chromatin drives pathology, but the mechanisms enabling its accumulation remain elusive. Here, we show that in murine sepsis models, splenocyte death interferes with chromatin clearance through the release of the DNase I inhibitor actin. Actin-mediated inhibition was compensated by upregulation of DNase I or the actin scavenger gelsolin. Splenocyte death and neutrophil extracellular trap (NET) clearance deficiencies were prevalent in individuals with severe COVID-19 pneumonia or microbial sepsis. Activity tracing by plasma proteomic profiling uncovered an association between low NET clearance and increased COVID-19 pathology and mortality. Low NET clearance activity with comparable proteome associations was prevalent in healthy donors with low-grade inflammation, implicating defective chromatin clearance in the development of cardiovascular disease and linking COVID-19 susceptibility to pre-existing conditions. Hence, the combination of aberrant chromatin release with defects in protective clearance mechanisms lead to poor survival outcomes.

[Extracorporeal Support Strategies in Liver Failure - Focus on Albumin Dialysis and Therapeutic Plasma Exchange]. / Extrakorporale Unterstützungsstrategien beim Leberversagen.

Combining albumin dialysis for the removal of hydrophobic substances with classical haemodialysis in the treatment of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) has a strong theoretical rational and clinical data showed a positive effect on laboratory and partly clinical characteristics of ALF and ACLF. However, neither the MARS nor the Prometheus System has so far been able to demonstrate a mortality benefit in ALF or ACLF patients. To date, only the use of therapeutic plasma exchange (TPE) has demonstrated significant removal of pathogen-associated (PAMPs), damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines. In addition, TPE also acts simultaneously by replacing protective but depleted mediators, thus improving multiple key pathophysiological principles of both ALF and ACLF. In ALF, both high-volume and standard-volume TPE showed a significant improvement in survival. The data on the use of TPE in ACLF is still sparse, with only two Chinese monocentric studies in patients with exclusively hepatitis B-associated ACLF suggesting potentially improved survival with TPE. The currently recruiting APACHE study will include patients with the modern EASL-CLIF definition of ACLF.

Immunosuppressive effects of circulating bile acids in human endotoxemia and septic shock: patients with liver failure are at risk.

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 < 24 h) and severe septic shock (norepinephrine dose > 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.

Intracranial Hemorrhages on Extracorporeal Membrane Oxygenation: Differences Between COVID-19 and Other Viral Acute Respiratory Distress Syndrome.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) is a potentially lifesaving procedure in acute respiratory distress syndrome (ARDS) due to COVID-19. Previous studies have shown a high prevalence of clinically silent cerebral microbleeds in patients with COVID-19. Based on this fact, together with the hemotrauma and the requirement of therapeutic anticoagulation on ECMO support, we hypothesized an increased risk of intracranial hemorrhages (ICHs). We analyzed ICH occurrence rate, circumstances and clinical outcome in patients that received ECMO support due to COVID-19-induced ARDS in comparison to viral non-COVID-19-induced ARDS intracerebral hemorrhage. DESIGN: Multicenter, retrospective analysis between January 2010 and May 2021. SETTING: Three tertiary care ECMO centers in Germany and Switzerland. PATIENTS: Two-hundred ten ARDS patients on ECMO support (COVID-19, n = 142 vs viral non-COVID, n = 68). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Evaluation of ICH occurrence rate, parameters of coagulation and anticoagulation strategies, inflammation, and ICU survival. COVID-19 and non-COVID-19 ARDS patients showed comparable disease severity regarding Sequential Organ Failure Assessment score, while the oxygenation index before ECMO cannulation was higher in the COVID group (82 vs 65 mm Hg). Overall, ICH of any severity occurred in 29 of 142 COVID-19 patients (20%) versus four of 68 patients in the control ECMO group (6%). Fifteen of those 29 ICH events in the COVID-19 group were classified as major (52%) including nine fatal cases (9/29, 31%). In the control group, there was only one major ICH event (1/4, 25%). The adjusted subhazard ratio for the occurrence of an ICH in the COVID-19 group was 5.82 (97.5% CI, 1.9-17.8; p = 0.002). The overall ICU mortality in the presence of ICH of any severity was 88%. CONCLUSIONS: This retrospective multicenter analysis showed a six-fold increased adjusted risk for ICH and a 3.5-fold increased incidence of ICH in COVID-19 patients on ECMO. Prospective studies are needed to confirm this observation and to determine whether the bleeding risk can be reduced by adjusting anticoagulation strategies.

Out of sight for the endoscopist? Gastrointestinal bleeding after aortic repair.

BACKGROUND AND STUDY AIM: Secondary Aortoenteric Fistulas (sAEF) are difficult to diagnose and usually result in fatal gastrointestinal (GI) bleeding following aortic repair. Outcomes are largely dependent on a timely diagnosis, but AEFs remain challenging to identify endoscopically and are usually diagnosed on computed tomography (CT) scans. The aim of our study was optimize diagnosis of AEF by identifying patients developing GI bleeding after aortic repair, investigate their clinical course and identify factors specific to different bleeding sources. METHODS: A retrospective, single-center study capturing all patients developing upper or lower GI bleeding after aortic surgery between January 2009 and March 2020 was performed. Electronic health records were screened for diagnostic codes of the relevant procedures. Bleeding was classified into three groups: AEF with demonstrable fistula, ischemic - macroscopic ulceration plus histological confirmation or imaging and "other" due to other recognized conventional cause, such as peptic ulcer disease. RESULTS: 47 GI bleeding episodes in 39 patients were identified. Of these, 10 episodes (21%) were caused by AEF, 16 (34%) by ischemic ulceration and 21 (45%) due to other causes. Patients with AEF exhibited more frequent hemodynamic instability requiring vasopressors and had higher mortality, while ischemic ulcerations were associated with more recent operation or hypotensive episode. CONCLUSIONS: GI bleeding complications are uncommon following aortic surgery. AEF and ischemic ulceration are however frequent bleeding causes in this cohort. In patients presenting with fulminant bleeding, primary CT-scanning should be considered.

Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial.

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 < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 µg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE. RESULTS: A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004). CONCLUSIONS: Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994 ).

Predictors of response to intra-arterial vasodilatory therapy of non-occlusive mesenteric ischemia in patients with severe shock: results from a prospective observational study.

BACKGROUND: Non-occlusive mesenteric ischemia (NOMI) is a life-threatening condition occurring in patients with shock and is characterized by vasoconstriction of the mesenteric arteries leading to intestinal ischemia and multi-organ failure. Although minimal invasive local intra-arterial infusion of vasodilators into the mesenteric circulation has been suggested as a therapeutic option in NOMI, current knowledge is based on retrospective case series and it remains unclear which patients might benefit. Here, we prospectively analyzed predictors of response to intra-arterial therapy in patients with NOMI. METHODS: This is a prospective single-center observational study to analyze improvement of ischemia (indicated by reduction of blood lactate > 2 mmol/l from baseline after 24 h, primary endpoint) and 28-day mortality (key secondary endpoint) in patients with NOMI undergoing intra-arterial vasodilatory therapy. Predictors of response to therapy concerning primary and key secondary endpoint were identified using a) clinical parameters as well as b) data from 2D-perfusion angiography and c) experimental biomarkers of intestinal injury. RESULTS: A total of 42 patients were included into this study. At inclusion patients had severe shock, indicated by high doses of norepinephrine (NE) (median (interquartile range (IQR)) 0.37 (0.21-0.60) µg/kg/min), elevated lactate concentrations (9.2 (5.2-13) mmol/l) and multi-organ failure. Patients showed a continuous reduction of lactate following intra-arterial prostaglandin infusion (baseline: (9.2 (5.2-13) mmol/l vs. 24 h: 4.4 (2.5-9.1) mmol/l, p < 0.001) with 22 patients (52.4%) reaching a lactate reduction > 2 mmol/l at 24 h following intervention. Initial higher lactate concentrations and lower NE doses at baseline were independent predictors of an improvement of ischemia. 28-day mortality was 59% in patients with a reduction of lactate > 2 mmol/l 24 h after inclusion, while it was 85% in all other patients (hazard ratio 0.409; 95% CI, 0.14-0.631, p = 0.005). CONCLUSIONS: A reduction of lactate concentrations was observed following implementation of intra-arterial therapy, and lactate reduction was associated with better survival. Our findings concerning outcome predictors in NOMI patients undergoing intra-arterial prostaglandin therapy might help designing a randomized controlled trial to further investigate this therapeutic approach. Trial registration Retrospectively registered on January 22, 2020, at clinicaltrials.gov (REPERFUSE, NCT04235634), https://clinicaltrials.gov/ct2/show/NCT04235634?cond=NOMI&draw=2&rank=1 .

Dynamics of disease characteristics and clinical management of critically ill COVID-19 patients over the time course of the pandemic: an analysis of the prospective, international, multicentre RISC-19-ICU registry.

BACKGROUND: It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic. METHODS: Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic. RESULTS: Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60-63] years vs 64 [62-66] years, p < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO2/FiO2 at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [76-86]% vs 74 [64-82]%, p < 0.001). The ICU mortality (23 [19-26]% vs 17 [12-25]%, p < 0.001) and length of stay (14 [13-16] days vs 11 [10-13] days, p < 0.001) decreased over 19 months of the pandemic. CONCLUSION: Characteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic.

Immunoglobulin deficiency as an indicator of disease severity in patients with COVID-19.

Despite the pandemic status of COVID-19, there is limited information about host risk factors and treatment beyond supportive care. Immunoglobulin G (IgG) could be a potential treatment target. Our aim was to determine the incidence of IgG deficiency and associated risk factors in a cohort of 62 critically ill patients with COVID-19 admitted to two German ICUs (72.6% male, median age: 61 yr). Thirteen (21.0%) of the patients displayed IgG deficiency (IgG < 7 g/L) at baseline (predominant for the IgG1, IgG2, and IgG4 subclasses). Patients who were IgG-deficient had worse measures of clinical disease severity than those with normal IgG levels (shorter duration from disease onset to ICU admission, lower ratio of [Formula: see text] to [Formula: see text], higher Sequential Organ Failure Assessment score, and higher levels of ferritin, neutrophil-to-lymphocyte ratio, and serum creatinine). Patients who were IgG-deficient were also more likely to have sustained lower levels of lymphocyte counts and higher levels of ferritin throughout the hospital stay. Furthermore, patients who were IgG-deficient compared with those with normal IgG levels displayed higher rates of acute kidney injury (76.9% vs. 26.5%; P = 0.001) and death (46.2% vs. 14.3%; P = 0.012), longer ICU [28 (6-48) vs. 12 (3-18) days; P = 0.012] and hospital length of stay [30 (22-50) vs. 18 (9-24) days; P = 0.004]. Univariable logistic regression showed increasing odds of 90-day overall mortality associated with IgG-deficiency (odds ratio 5.14, 95% confidence interval 1.3-19.9; P = 0.018). IgG deficiency might be common in patients with COVID-19 who are critically ill, and warrants investigation as both a marker of disease severity as well as a potential therapeutic target.

Comparison of anticoagulation strategies for veno-venous ECMO support in acute respiratory failure.

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.

Role of endothelial microRNA 155 on capillary leakage in systemic inflammation.

BACKGROUND: Capillary leakage is a key contributor to the pathological host response to infections. The underlying mechanisms remain incompletely understood, and the role of microRNAs (MIR) has not been investigated in detail. We hypothesized that specific MIRs might be regulated directly in the endothelium thereby contributing to vascular leakage. METHODS: SmallRNA sequencing of endotoxemic murine pulmonary endothelial cells (ECs) was done to detect regulated vascular MIRs. In vivo models: transgenic zebrafish (flk1:mCherry/l-fabp:eGFP-DPB), knockout/wildtype mouse (B6.Cg-Mir155tm1.1Rsky/J); disease models: LPS 17.5 mg/kgBW and cecal ligation and puncture (CLP); in vitro models: stimulated human umbilical vein EC (HUVECs), transendothelial electrical resistance. RESULTS: Endothelial MIR155 was identified as a promising candidate in endotoxemic murine pulmonary ECs (25 × upregulation). Experimental overexpression in a transgenic zebrafish line and in HUVECs was sufficient to induce spontaneous vascular leakage. To the contrary, genetic MIR155 reduction protects against permeability both in vitro and in endotoxemia in vivo in MIR155 heterozygote knockout mice thereby improving survival by 40%. A tight junction protein, Claudin-1, was down-regulated both in endotoxemia and by experimental MIR155 overexpression. Translationally, MIR155 was detectable at high levels in bronchoalveolar fluid of patients with ARDS compared to healthy human subjects. CONCLUSIONS: We found that MIR155 is upregulated in the endothelium in mouse and men as part of a systemic inflammatory response and might contribute to the pathophysiology of vascular leakage in a Claudin-1-dependent manner. Future studies have to clarify whether MIR155 could be a potential therapeutic target.

Effect of Therapeutic Plasma Exchange on Immunoglobulin Deficiency in Early and Severe Septic Shock.

BACKGROUND: Deficiency of immunoglobulins of the classes IgG, IgG1, IgA and IgM is associated with severity of disease and mortality in sepsis and septic shock. Therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) has recently gained attention as an adjunctive therapeutic option in early septic shock. We hypothesized that TPE might modulate immunoglobulin deficiencies besides sole elimination of circulating injurious molecules. METHODS: We conducted a prospective single center study with TPE in 33 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4µg/kg/min). Clinical and biochemical data, including measurement of immunoglobulin subgroups IgG, IgG1, IgM and IgA were obtained before and after TPE. The following immunoglobulin cut-off values were used to analyze subgroups with low immunoglobulin concentrations at baseline (IgG ≤ 6.5, IgG1 ≤ 3, IgM ≤ 1.5 and IgA ≤ 0.35 g/L). RESULTS: At inclusion, median (IQR) SOFA score was 18 (15-20) and NE dose was 0.8 (0.6-1.2) µg/kg/min. The majority of patients demonstrated profound reductions in immunoglobulins levels of all classes. Globally, immunoglobulin levels were not significantly changed after a single TPE session. However, in patients with low baseline immunoglobulin levels a significant increase in all classes was observed (IgG 1.92 (0.96-3) g/L (+41%), IgG1 2.1 (1.46-2.32) g/L (+96%), IgA 0.44 (0.12-0.62) g/L (59%) and IgM 0.18 (0.14-0.34) g/L (+55%), p < 0.001 for comparison to patients above cut-off). CONCLUSIONS: The majority of early and severe septic shock patients had reduced immunoglobulin levels and a single TPE could attenuate immunoglobulin deficiencies of all classes. The clinical relevance of this observation has to be investigated in a proper designed trial.

[Extracorporeal Strategies in Sepsis Treatment: Role of Therapeutic Plasma Exchange]. / Extrakorporale Behandlungsstrategien der Sepsis: die Rolle der Plasmapherese.

BACKGROUND: Mortality in sepsis remains high. Various techniques for extracorporeal cytokine removal have been investigated as additional therapeutic measures in sepsis and septic shock. OBJECTIVES: To summarize a selection of extracorporeal blood purification techniques, with a special focus on therapeutic plasma exchange, and their current evidence in clinical use. METHODS: Non-systematic literature review. RESULTS: Various extracorporeal blood purification techniques with different levels of evidence regarding cytokine removal, vasopressor sparing effects and reduction of mortality are currently in clinical use. Most extensively studied modalities include high-volume hemofiltration/dialysis with and without high cut-off filters a well as hemoadsorption techniques (including CytoSorb, and polymyxin-B filters). Despite partly encouraging observations regarding removal of inflammatory cytokines and hemodynamic stabilization, results from randomized studies did not show an effect on survival. Due to use of donor plasma as substitution fluid, therapeutic plasma exchange represents the only modality able to additionally replace protective and consumed factors. CONCLUSIONS: The use of extracorporeal blood purification methods cannot be recommended for sepsis patients outside of clinical trials given the current lack of evidence of their efficacy. Future investigations should aim to homogenize the studied patient collective in respect to clinical sepsis severity, time point of intervention and different inflammatory (sub-)phenotypes.

Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock.

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 < 12 h) requiring high doses of norepinephrine (NE > 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 < 0.001). In contrast, vWF:Ag was elevated and could be reduced by TPE (353 (206-492) IU/dL vs. 170 (117-232) IU/dL, p < 0.001). Regression analysis yielded a correlation between ADAMTS13 activity and platelet count (p = 0.001, R2 = 0.316). CONCLUSIONS: Septic shock was associated with activation of pro-coagulant pathways and simultaneous depletion of anti-coagulant factors. TPE partially attenuated this dysbalance by removing pro- and by replacing anti-coagulant factors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03065751. Retrospectively registered on 28 February 2017.

A Retrospective Analysis of Nonocclusive Mesenteric Ischemia in Medical and Surgical ICU Patients: Clinical Data on Demography, Clinical Signs, and Survival.

BACKGROUND: To analyze demography, clinical signs, and survival of intensive care patients diagnosed with nonocclusive mesenteric ischemia (NOMI) and to evaluate the effect of a local intra-arterial prostaglandin therapy. METHODS: Retrospective observational study screening 455 intensive care patients with acute arterial mesenteric perfusion disorder in a tertiary care hospital within the past 8 years. Lastly, 32 patients with NOMI were enrolled, of which 11 received local intra-arterial prostaglandin therapy. The diagnosis of NOMI was based on the clinical presentation and established biphasic computed tomography criteria. Clinical and biochemical data were obtained 24 hours before, at the time, and 24 hours after diagnosis. RESULTS: Patients were 60.5 (49.3-73) years old and had multiple comorbidities. Most of them were diagnosed with septic shock requiring high doses of norepinephrine (NE: 0.382 [0.249-0.627] µg/kg/min). The Sequential Organ Failure Assessment (SOFA) score was 18 (16-20). A decrease in oxygenation (Pao 2/Fio 2), pH, and bicarbonate and an increase in international normalized ratio, lactate, bilirubin, leucocyte count, and NE dose were early indicators of NOMI. Median SOFA score significantly increased in the last 24 hours before diagnosis of NOMI (16 vs 18, P < .0001). Overall, 28-day mortality was 75% (81% nonintervention vs 64% intervention cohort; P = .579). Median SOFA scores 24 hours after intervention increased by +5% in the nonintervention group and decreased by 5.5% in the intervention group (P = .0059). CONCLUSIONS: Our data suggest that NOMI is a detrimental disease associated with progressive organ failure and a high mortality. Local intra-arterial prostaglandin application might hold promise as a rescue treatment strategy. These data encourage future randomized controlled trials are desirable.

Nonocclusive Mesenteric Ischemia and Interventional Local Vasodilatory Therapy: A Meta-Analysis and Systematic Review of the Literature.

BACKGROUND: Intensive care patients with nonocclusive mesenteric ischemia (NOMI) show mortality rates of 70% to 90%. Besides emergency surgery, different interventional local vasodilatory treatment (LVT) attempts have been described. We performed a systematic review and a meta-analysis to evaluate feasibility, efficacy, and tolerability of LVT in patients with life-threatening NOMI. METHODS: Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed until February 2019. Measured outcomes included immediate technical success rates (as indicated by mesenteric vasodilation on angiography or clinical improvement) and adverse events (AEs). Therapeutic efficacy was measured by the assessment of overall mortality. RESULTS: Twelve studies (335 patients, 245 received LVT) from 1977 to 2018 were included. All studies were retrospective (4 comparative and 8 noncomparative). Different intra-arterial vasodilators (4× papaverine, 6× prostaglandin E1, 1× tolazoline/heparin, 1× tolazoline + iloprost) were reported. Initial technical success rate was 75.9% (95% confidence interval [CI], 55.1%-89%, P = .017) with an AE rate of 2.9% (95% CI: 1.3%-6.6%; P = .983). Overall mortality in LVT patients was 40.3% (95% CI: 28.7%-53%, P = .134). In 4 studies, outcomes were compared between patients receiving LVT to those who received standard of care (odds ratio for death in LVT patients was 0.261 [95% CI: 0.095-0.712, P = .009]). CONCLUSIONS: Local vasodilatory treatment appears to be safe in patients with NOMI and might have the potential to at least partially reverse mesenteric vasoconstriction features in control angiographies. However, with no randomized and prospective studies available yet, the overall quality of published studies has to be considered as low; therefore, it is not possible to draw generalizable conclusions from the present data concerning clinical end points. Its application might hold promise as a rescue treatment strategy and deserves further evaluation in randomized controlled trials.

Therapeutic plasma exchange in acute on chronic liver failure.

BACKGROUND: Acute on chronic liver failure (ACLF) has been identified as a distinct syndrome due to acute decompensation of liver cirrhosis accompanied by extra-hepatic organ failure, primarily caused by an overwhelming systemic immune response. Therapeutic plasma exchange (TPE) has been demonstrated in a randomized controlled trial to improve transplant free survival in acute liver failure. Here we investigated if TPE might have comparable beneficial effects in patients with ACLF. METHODS: Thirty-one patients with ACLF that were treated with TPE were enrolled into this retrospective analysis and 1:1 matched to an ACLF cohort treated with standard medical therapy (SMT) only. RESULTS: Patients considered for a bridge to recovery (n = 21 each group) approach had a 30-day mortality >90% that was not improved by TPE (P = .185). Deaths occurred in the SMT group at significant earlier time points compared to the patients treated with TPE (mortality at 5 days: 33.3% for TPE and 66.7% for SMT, P = .048). However, patients who received TPE as a bridge to transplant strategy (n = 10) survived in 60% of cases and demonstrated 24 hours after study inclusion a stabilization of organ dysfunction (organ failures at inclusion: 4 (3-5) vs 24 hours after inclusion: 3 (2-4), P = .031 and CLIF-C-ACLF score: 64 (49-76) vs 54 (49-66), P = .043) not seen in SMT patients. CONCLUSIONS: Although these retrospective data need to be interpreted with caution, they suggest that TPE in ACLF patients is feasible but not suitable as a bridge to recovery strategy. In selected patients TPE might assist as bridge to transplant.

Therapeutic plasma exchange in acute liver failure.

BACKGROUND: Multi-organ dysfunction in acute liver failure (ALF) has been attributed to a systemic inflammatory response directly triggered by the injured liver. High-volume therapeutic plasma exchange (HV-TPE) has been demonstrated in a large randomized controlled trial to improve survival. Here, we investigated if a more cost-/ resource effective low-volume (LV) TPE strategy might have comparable beneficial effects. METHODS: This retrospective study evaluated the effect of LV-TPE on remote organ failure, hemodynamical and biochemical parameters as well as on survival in patients with ALF. Twenty patients treated with LV-TPE in addition to standard medical therapy (SMT) were identified and 1:1 matched to a historical ALF cohort treated with SMT only. Clinical and biochemical parameters were recorded at admission to the intensive care unit and the following 7 days after LV-TPE. RESULTS: Mean arterial pressure increased following first LV-TPE treatments (d0: 68 [61-75] mm Hg vs d7: 88 [79-98] mm Hg, P = .003) and norepinephrine dose was reduced (d0: 0.264 [0.051-0.906] µg/kg/min vs d3: 0 [0-0.024] µg/kg/min, P = .016). Multi-organ dysfunction was significantly diminished following LV-TPE (CLIF-SOFA d0: 17 [13-20] vs d7: 7 [3-11], P = .001). Thirty-day in-hospital survival was 65% in the LV-TPE cohort and 50% in the SMT cohort (Hazard-ratio for TPE: 0.637; 95% CI: 0.238-1.706, P = .369). CONCLUSIONS: Patients treated with LV-TPE showed improved surrogate parameters comparable with the effects reported with HV-TPE. These data need to be interpreted with caution due to their retrospective character. Future controlled studies are highly desirable.