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Memory consolidation is a continuous transformative process between encoding and retrieval of mental representations. Recent research has shown that neural activity immediately after encoding is particularly associated with later successful retrieval. It is currently unclear whether post-encoding neural activity makes a distinct and causal contribution to memory consolidation. Here, we investigated the role of the post-encoding period for consolidation of spatial memory in neurologically normal human subjects. We used the GABA

(1) Background: Acute respiratory distress syndrome (ARDS) is a rare complication in multiply injured patients. Due to the rarity of ARDS development after trauma, little is known about outcomes of patients with trauma-associated ARDS compared to patients with non-trauma-associated ARDS. (2) Methods: This retrospective analysis included n = 1038 ARDS patients admitted to the ARDS center of Charité—Universitätsmedizin Berlin between 2007 and 2018. Patients with trauma-associated ARDS (n = 62) were compared to patients with non-trauma-associated ARDS (n = 976). In a secondary analysis, patients from the group with non-trauma-associated ARDS were 1:1 nearest neighbor matched to patients with trauma-associated ARDS. The primary outcomes were 28-day in-hospital mortality, 60-day in-hospital mortality, and overall in-hospital mortality. (3) Results: Overall in-hospital mortality in trauma-associated ARDS was 29.0% compared to 40.5% in all patients with non-trauma-associated ARDS (p = 0.074). The in-hospital mortality rate in matched patients with non-trauma-associated ARDS (33.9%) was comparable to the trauma-associated ARDS cohort (p = 0.701). Kaplan–Meier curves indicated time-sensitive variations in 28-day and 60-day in-hospital survival. (4) Conclusion: Mortality was not different in patients with trauma-associated ARDS compared to patients with non-trauma-associated ARDS. Survival rate in the Kaplan–Meier curves stabilized after the critical initial phase and throughout the further 60-day period in patients with trauma-associated ARDS compared to patients with non-trauma-associated ARDS. Since this divergence was less pronounced in the matched cohort, it may be related to the younger age, fewer comorbidities, and lower ARDS severity in patients with trauma-associated ARDS. Patients with trauma-associated ARDS remain a very different cohort compared to patients with non-trauma-associated ARDS. Therefore, the outcome comparison is limited, even after matching.

Intracerebral hemorrhage (ICH) is a devastating complication in patients treated with extracorporeal membrane oxygenation (ECMO) due to respiratory or cardiac issues. Neurosurgical evaluation and management of such cases has only insufficiently been studied. We conducted a retrospective, cohort study of adult patients treated with ECMO between January 2007 and January 2017 in a tertiary healthcare center. Demographics, clinical data, coagulation status, ICH characteristics, and treatment modalities were analyzed. The primary outcome parameter was defined as mortality caused by ICH during ECMO. 525 patients with ECMO therapy were eligible for analysis. An overall incidence for any type of intracranial bleeding of 12.3% was found. Small hemorrhages accounted for 6.4% and acute subdural and epidural hematoma for 1.2%. Twenty-four (4.6%) patients developed ICH, and 11 patients (46%) died due to the ICH. Mortality was significantly higher in patients with larger ICH volumes (86.8 ± 34.8 ml vs 9.9 ± 20.3 ml, p p = 0.01), and a fluid level inside the ICH (75% vs 31%, p = 0.04). All patients were classified according to the bleeding pattern on the initial CT scan into 3 types. Patients with type 1 bleeding were statistically more likely to die (p p = 0.01). This is the first study evaluating the course and management of patients experiencing an ICH under ECMO therapy and establishing an ICH classification based on the bleeding patterns. Early correction of the coagulation is of paramount importance in the treatment of these patients.

Objectives Intracranial hemorrhage is a serious complication in patients receiving venovenous extracorporeal membrane oxygenation during treatment of the acute respiratory distress syndrome. We analyzed timing, outcome, and risk factors of intracranial hemorrhage in patients on venovenous extracorporeal membrane oxygenation. Design Retrospective cohort study. Setting Single acute respiratory distress syndrome referral center. Patients Patients receiving venovenous extracorporeal membrane oxygenation were identified from a cohort of 1,044 patients with acute respiratory distress syndrome. Patients developing an intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy were compared with patients without evidence for intracranial hemorrhage. The primary objective was to assess the association of intracranial hemorrhage with 60-day mortality. Further objectives included the identification of risk factors for intracranial hemorrhage and the evaluation of clinical cutoff values. Interventions None. Measurements and main results Among 444 patients treated with venovenous extracorporeal membrane oxygenation, 49 patients (11.0% [95% CI, 8.3-14.4%]) developed an intracranial hemorrhage. The median time to intracranial hemorrhage occurrence was 4 days (95% CI, 2-7 d). Patients who developed an intracranial hemorrhage had a higher 60-day mortality compared with patients without intracranial hemorrhage (69.4% [54.4-81.3%] vs 44.6% [39.6-49.6%]; odds ratio 3.05 [95% CI, 1.54-6.32%]; p = 0.001). A low platelet count, a high positive end expiratory pressure, and a major initial decrease of Paco2 were identified as independent risk factors for the occurrence of intracranial hemorrhage. A platelet count greater than 100/nL and a positive end expiratory pressure less than or equal to 14 cm H2O during the first 7 days of venovenous extracorporeal membrane oxygenation therapy as well as a decrease of Paco2 less than 24 mm Hg during venovenous extracorporeal membrane oxygenation initiation were identified as clinical cutoff values to prevent intracranial hemorrhage (sensitivity 91% [95% CI, 82-99%], 94% [85-99%], and 67% [48-81%], respectively). Conclusions Intracranial hemorrhage occurs early during venovenous extracorporeal membrane oxygenation and is a determinant for 60-day mortality. Appropriate adjustment of identified modifiable risk factors might lower the prevalence of intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy.

BACKGROUND Anticoagulation therapy with Heparin is a frequent treatment in intensive care units, which is monitored by activated partial thromboplastin clotting time (aPTT). It has been demonstrated that reaching an established anticoagulation target within 24 hours is associated with favorable outcomes. However, patients respond to heparin differently and reaching the anticoagulation target can be challenging. Machine learning algorithms may potentially support clinicians with improved dosing recommendations. OBJECTIVE This study evaluates a range of machine learning algorithms on their capability of predicting the patients’ response to heparin treatment. In the present analysis, we apply, for the first time, a model that considers time series. METHODS We extracted patient demographics, laboratory values, dialysis and ecmo treatments, and scores from the hospital information system. We set up a regression task for predicting the aPTT laboratory values 24 hours after continuous heparin infusion and evaluate seven different machine learning models. We consider all data before and within the first 12 hours of continuous heparin infusion as features and predict the aPTT value after 24 hours. RESULTS The distribution of aPTT in our cohort of 5926 hospital admissions is highly skewed. While most patients show aPTT values below 75 s, some outliers show much higher aPTT values. A recurrent neural network that consumes time series of features shows the highest performance on the test set. CONCLUSIONS A recurrent neural network that uses time series of features instead of only static and aggregated features, shows the highest performance of predicting aPTT after heparin treatment.

Background: The SARS-CoV-2 virus has been spreading in Germany since January 2020, with regional differences in incidence, morbidity, and mortality. Long-term exposure to air pollutants as nitrogen dioxide (NO2), nitrogen monoxide (NO), ozone (O3), and particulate matter (10, < 2.5µm PM2.5,) has a negative impact on respiratory functions. We analyze the association between long-term air pollution and the outcome of SARS-CoV-2 infections in Germany.Methods: We conducted a cross-sectional study in Germany on county-level, investigating the association between long-term (2010-2019) air pollutant exposure and COVID-19 incidence, morbidity, and mortality rate during the first outbreak of SARS-CoV-2. We used negative binominal models, including adjustment for risk factors (age, sex, days since first COVID-19 case, population density, socio-economic and health parameters). Results: After adjustment for risk factors in the tri-pollutant model (NO2, O3, PM2.5) an increase of 1µg/m³ NO2 was associated with an increase of the need for intensive care due to COVID-19 by 4.2% (95% CI 1.011–1.074), and mechanical ventilation by 4.6% (95% CI 1.010–1.084). A tendency towards an association of NO2 with COVID-19 incidence was indicated, as the results were just outside of the defined statistical significance (+1.6% (95% CI 1.000 -1.032)). Long-term annual mean NO2 level ranged from 4.6µg/m³ to 32µg/m³.Conclusions: Our results indicate that long-term NO2 exposure may have increased susceptibility for COVID-19 morbidity in Germany. The results demonstrate the need to reduce ambient air pollution to improve public health. Trial registration number and date of registration: not applicable

Packed red blood cells (PRBCs), stored for prolonged intervals, might contribute to adverse clinical outcomes in critically ill patients. In this study, short-term outcome after transfusion of PRBCs of two storage duration periods was analyzed in patients with Acute Respiratory Distress Syndrome (ARDS). Patients who received transfusions of PRBCs were identified from a cohort of 1044 ARDS patients. Patients were grouped according to the mean storage age of all transfused units. Patients transfused with PRBCs of a mean storage age ≤ 28 days were compared to patients transfused with PRBCs of a mean storage age > 28 days. The primary endpoint was 28-day mortality. Secondary endpoints included failure-free days composites. Two hundred and eighty-three patients were eligible for analysis. Patients in the short-term storage group had similar baseline characteristics and received a similar amount of PRBC units compared with patients in the long-term storage group (five units (IQR, 3–10) vs. four units (2–8), p = 0.14). The mean storage age in the short-term storage group was 20 (±5.4) days compared with 32 (±3.1) days in the long-term storage group (mean difference 12 days (95%-CI, 11–13)). There was no difference in 28-day mortality between the short-term storage group compared with the long-term storage group (hazard ratio, 1.36 (95%-CI, 0.84–2.21), p = 0.21). While there were no differences in ventilator-free, sedation-free, and vasopressor-free days composites, patients in the long-term storage group compared with patients in the short-term storage group had a 75% lower chance for successful weaning from renal replacement therapy (RRT) within 28 days after ARDS onset (subdistribution hazard ratio, 0.24 (95%-CI, 0.1–0.55), p < 0.001). Further analysis indicated that even a single PRBC unit stored for more than 28 days decreased the chance for successful weaning from RRT. Prolonged storage of PRBCs was not associated with a higher mortality in adults with ARDS. However, transfusion of long-term stored PRBCs was associated with prolonged dependence of RRT in critically ill patients with an ARDS.

Background Increased plasma concentrations of circulating cell-free hemoglobin (CFH) are supposed to contribute to the multifactorial etiology of acute kidney injury (AKI) in critically ill patients while the CFH-scavenger haptoglobin might play a protective role. We evaluated the association of CFH and haptoglobin with AKI in patients with an acute respiratory distress syndrome (ARDS) requiring therapy with VV ECMO. Methods Patients with CFH and haptoglobin measurements before initiation of ECMO therapy were identified from a cohort of 1044 ARDS patients and grouped into three CFH concentration groups using a risk stratification. The primary objective was to assess the association of CFH and haptoglobin with KDIGO stage 3 AKI. Further objectives included the identification of a target haptoglobin concentration to protect from CFH-associated AKI. Measurements and main results Two hundred seventy-three patients fulfilled the inclusion criteria. Of those, 154 patients (56.4%) had AKI at ECMO initiation. The incidence of AKI increased stepwise with increasing concentrations of CFH reaching a plateau at 15 mg/dl. Compared to patients with low [P = 0.012; and OR high vs. low, 5.47 [2.00–15.9], P = 0.001). Among patients with increased CFH concentrations, haptoglobin plasma levels were lower in patients with AKI compared to patients without AKI. A haptoglobin concentration greater than 2.7 g/l in the moderate and 2.4 g/l in the high CFH group was identified as clinical cutoff value to protect from CFH-associated AKI (sensitivity 89.5% [95% CI, 83–96] and 90.2% [80–97], respectively). Conclusions In critically ill patients with ARDS requiring therapy with VV ECMO, an increased plasma concentration of CFH was identified as independent risk factor for AKI. Among patients with increased CFH concentrations, higher plasma haptoglobin concentrations might protect from CFH-associated AKI and should be subject of future research.

We investigated the role of the post-encoding period for consolidation of self-centered (egocentric) and world-centered (allocentric) spatial memory in neurologically normal human subjects. We used the GABAA-ergic anesthetic propofol to transiently modulate neural activity during the early stage of spatial memory consolidation. A total of 52 patients undergoing minor surgery learned to navigate to a target in a five-armed maze derived from animal experiments immediately prior to injection of propofol (early group) or more than 60 minutes before injection (late group). Two hundred and forty minutes after anesthesia, subjects were tested for memory-guided navigation. Our results show a selective impairment of memory-guided navigation in the early group and near-normal performance in the late group. Both egocentric and allocentric navigation were affected, albeit with distinct error patterns. In the egocentric condition, early group patients navigated significantly more often to a wrong alley of the maze but showed normal navigation times, thus suggesting a deficit mainly for memory of sequences of path segments. By contrast, in the allocentric condition, early group patients mostly navigated to the correct alley of the maze but showed a significant increase in detours and prolonged navigation times, thus suggesting a weakened representation of the relationship between landmarks. We conclude that presumably hippocampus-dependent networks contribute to early consolidation of representations underlying both egocentric and allocentric memory-guided navigation. Distinct aspects of these representations are susceptible to GABAA-ergic modulation within a post-encoding time-window of less than 60 minutes, indicating a redistribution and reconfiguration of spatial memory networks early during consolidation.Significance statementPropofol modulates consolidation of spatial representations underlying human spatial navigation.Following administration of propofol, memory-guided navigation using self-centered (egocentric) and world-centered (allocentric) spatial information is impaired.Error patterns after administration of propofol suggest modulation of a post-encoding integration process relevant for ego- and allocentric memory representations.The transient susceptibility of this process to GABAA-ergic modulation is consistent with rapid reconfiguration of networks for spatial memory shortly after learning.Propofol provides a pharmacological tool to investigate spatial memory consolidation in humans.

ZusammenfassungAn der Charité – Universitätsmedizin Berlin wird gegenwärtig ein telemedizinisches Zentrum der Intensivmedizin etabliert. Ziel ist es, durch eine strukturierte Implementierung von Qualitätsindikatoren der DIVI Langzeitfolgen der Intensivmedizin zu verhindern. Pflegefachkräfte der Charité sind an der Aufbauarbeit dieses Zentrums beteiligt. In einem geförderten Pilotprojekt finden dort seit Dezember 2018 in einem regionalen Netzwerk aus Kliniken in Berlin und Brandenburg im Rahmen einer klinischen Studie multiprofessionelle Televisiten statt.

Background: Etomidate is typically used as an induction agent in cardiac surgery because it has little impact on hemodynamics. It is a known suppressor of adrenocortical function and may increase the risk for post-operative infections, sepsis, and mortality. The aim of this study was to evaluate whether etomidate increases the risk of postoperative sepsis (primary outcome) and infections (secondary outcome) compared to propofol. Methods: This was a retrospective before–after trial (IRB EA1/143/20) performed at a tertiary medical center in Berlin, Germany, between 10/2012 and 01/2015. Patients undergoing cardiac surgery were investigated within two observation intervals, during which etomidate and propofol were the sole induction agents. Results: One-thousand, four-hundred, and sixty-two patients, and 622 matched pairs, after caliper propensity-score matching, were included in the final analysis. Sepsis rates did not differ in the matched cohort (etomidate: 11.5% vs. propofol: 8.2%, p = 0.052). Patients in the etomidate interval were more likely to develop hospital-acquired pneumonia (etomidate: 18.6% vs. propofol: 14.0%, p = 0.031). Conclusion: Our study showed that a single-dose of etomidate is not statistically associated with higher postoperative sepsis rates after cardiac surgery, but is associated with a higher incidence of hospital-acquired pneumonia. However, there is a notable trend towards a higher sepsis rate.

Care for patients with acute respiratory distress syndrome (ARDS) has changed considerably over the 50 years since its original description. Indeed, standards of care continue to evolve as does how this clinical entity is defined and how patients are grouped and treated in clinical practice. In this narrative review we discuss current standards - treatments that have a solid evidence base and are well established as targets for usual care - and also evolving standards - treatments that have promise and may become widely adopted in the future. We focus on three broad domains of ventilatory management, ventilation adjuncts, and pharmacotherapy. Current standards for ventilatory management include limitation of tidal volume and airway pressure and standard approaches to setting PEEP, while evolving standards might focus on limitation of driving pressure or mechanical power, individual titration of PEEP, and monitoring efforts during spontaneous breathing. Current standards in ventilation adjuncts include prone positioning in moderate-severe ARDS and veno-venous extracorporeal life support after prone positioning in patients with severe hypoxemia or who are difficult to ventilate. Pharmacotherapy current standards include corticosteroids for patients with ARDS due to COVID-19 and employing a conservative fluid strategy for patients not in shock; evolving standards may include steroids for ARDS not related to COVID-19, or specific biological agents being tested in appropriate sub-phenotypes of ARDS. While much progress has been made, certainly significant work remains to be done and we look forward to these future developments.

Background: Chronic alcohol consumption is a major cause of liver injury. However, the molecular mechanisms by which alcohol impairs hepatocellular function and induces cell death remain unclear. Macroautophagy (hereafter called 'autophagy') is a degradation pathway involved in the survival or death of cells during conditions of cellular stress. This study examines the effect of chronic alcohol consumption on hepatocellular autophagy in an animal model. Methods: During a 12-week period male Wistar rats were fed a Lieber-DeCarli diet containing 5% alcohol (EtOH group; n=10), or an isocaloric diet (control group; n=10). Hepatic expression of key regulatory autophagy proteins (e.g. Beclin-1, ATG-3, ATG-5, p62/SQSTM1 and LC3) were detected by real-time polymerase chain reaction and Western blot analysis. Markers of cellular stress and apoptotic cell death (e.g. HO-1, caspase-3, PARP-1 and Bcl-2) were determined, and levels of reduced and oxidized glutathione were measured. Results: Chronic alcohol consumption caused cellular and oxidative stress in the liver. Transcriptional and translational expression of Beclin-1 and ATG-5 was significantly impaired. The protein expression of LC3-I and LC3-II was significantly increased, while the ratio of LC3I/II remained unchanged in the EtOH group compared with controls. Hepatocellular expression of p62/SQSTM1 and markers of apoptotic cell death (such as cleaved caspase-3 and cleaved PARP-1) were significantly increased in the EtOH group indicating a disrupted autophagic flux and increased rate of apoptosis in the liver. Conclusions: In this model, chronic alcohol consumption impaired hepatocellular autophagy and induced apoptotic cell death. It appears that changes in autophagy might contribute to alcohol-induced structural and functional hepatocellular injury.

Maintenance of memory across time is crucial for adaptive behavior. Current theories posit that the underlying consolidation process depends on stabilization of synapses and reorganization of interactions between hippocampus and neocortex. However, the temporal properties of hippocampal-neocortical network reconfiguration during consolidation are still a matter of debate. Translational research on this issue is challenged by the paucity of techniques to transiently interfere with memory in the healthy human brain. Here, we report a neuro-pharmacological approach with the GABAA-ergic anesthetic propofol and a memory task sensitive to hippocampal dysfunction. Patients undergoing minor surgery learned word lists before injection of an anesthetic dose of propofol. Results show that administration of the drug shortly after learning (∼13 min) impairs recall after awakening but spares recognition. By contrast, later administration (∼105 min) has no effect. These findings suggest significant changes in memory networks very early after learning that are decisive for later recall. Propofol general anesthesia provides an experimental tool to modulate the first steps of hippocampus-mediated memory consolidation in humans. Significance statement Consolidation of memories depends both on mechanisms at the synaptic and the systems level. How and when these mechanisms interact is currently unclear. Here, we have used the anesthetic drug propofol to create a transient pharmacological ‘lesion’ of the neural substrates of memory consolidation in humans undergoing minor surgery. Our results show that there is a brief time window after learning where hippocampus-dependent memories are susceptible to GABA-ergic modulation with propofol. Later recall appears to depend significantly on integrity of these first steps of memory formation. We infer that there is significant rearrangement of memory networks during the first hours after learning. Propofol general anesthesia provides an experimental approach to interfere with early memory consolidation in humans.

Objective Delirium in critically ill patients is considered a risk factor for various long-term consequences. We evaluated delirium and associated long-term outcomes in patients with acute respiratory distress syndrome with non-H1N1 and H1N1- associated severe community-acquired pneumonia (sCAP) who had been recommended to take antiviral drugs associated with delirious symptoms as adverse effects. Methods Of 64 patients, 42 survivors (H1N1, 15; non-H1N1, 27) were analyzed regarding the relationship between medication and the duration of delirium in the intensive care unit. During follow-up (n = 23), we assessed cognitive abilities, post-traumatic stress disorder (PTSD), physical capacity, and health-related quality of life (HRQoL). Results The incidence of delirium was 88%. There was no difference in the incidence and duration of delirium between patients with H1N1 and non-H1N1 infection. The haloperidol and opioid doses were associated with a longer delirium duration. The delirium duration was correlated with reduced cognitive performance in motor skills, memory function, and learning efficiency. Patients with PTSD (16%) had a significantly longer delirium duration and low mental HRQoL. Conclusions H1N1 infection and corresponding antiviral medication had no impact on delirium. The duration of delirium in these patients was associated with impairments in various outcome parameters, illustrating the burden of sCAP.

Mario Menk, Jan Adriaan Graw, Clarissa von Haefen, Hendrik Steinkraus, Burkhard Lachmann, Claudia D Spies, David Schwaiberger Department of Anesthesiology and Operative Intensive Care Medicine, Charité – University Medicine Berlin, FreieUniversität Berlin, Humboldt-Universitätzu Berlin, and Berlin Institute of Health, Germany Purpose: Although the role of the angiotensin II type 2 (AT2) receptor in acute lung injury is not yet completely understood, a protective role of this receptor subtype has been suggested. We hypothesized that, in a rodent model of acute lung injury, stimulation of the AT2 receptor with the direct agonist Compound 21 (C21) might have a beneficial effect on pulmonary inflammation and might improve pulmonary gas exchange. Materials and methods: Male adult rats were divided into a treatment group that received pulmonary lavage followed by mechanical ventilation (LAV, n=9), a group receiving pulmonary lavage, mechanical ventilation, and direct stimulation of the AT2 receptor with C21 (LAV+C21, n=9), and a control group that received mechanical ventilation only (control, n=9). Arterial blood gas analysis was performed every 30 min throughout the 240-min observation period. Lung tissue and plasma samples were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid were assessed and the wet/dry-weight ratio of lungs was determined. Transcriptional and translational regulation of pro- and antiinflammatory cytokines IL-1β, tumor necrosis factor-alpha, IL-6, IL-10, and IL-4 was determined in lungs and in plasma. Results: Pulmonary lavage led to a significant impairment of gas exchange, the formation of lung edema, and the induction of pulmonary inflammation. Protein content of lavage fluid was increased and contained washed-out surfactant. Direct AT2 receptor stimulation with C21 led to a significant inhibition of tumor necrosis factor-alpha and IL-6 expressions in the lungs, whereas the expressions of IL-1, IL-10, and IL-4 remained unchanged. During the 240-min observation period, AT2 receptor stimulation did not improve pulmonary gas exchange or lung edema. Conclusion: In this rodent model of acute lung injury after repeated pulmonary lavage, AT2 receptor stimulation attenuates pulmonary inflammation but does not improve gas exchange. Keywords: AT2 receptor, lung failure, ARDS, acute lung injury, Compound 21 (C21)

Background Nucleated red blood cells (NRBCs) in critically ill patients are associated with increased mortality and poor outcome. The aim of the present study was to evaluate the predictive value of NRBCs in patients with acute respiratory distress syndrome (ARDS). Methods This observational study was conducted at an ARDS referral center and included patients from 2007 to 2014. Daily NRBC counts were assessed and the predictive validity of NRBCs on mortality was statistically evaluated. A cutoff for prediction of mortality based on NRBCs was evaluated using ROC analysis and specified according to Youden’s method. Multivariate nonparametric analysis for longitudinal data was applied to prove for differences between groups over the whole time course. Independent predictors of mortality were identified with multiple logistic and Cox’ regression analyses. Kaplan–Meier estimations visualized the survival; the corresponding curves were tested for differences with the log-rank test. Results A total of 404 critically ill ARDS patients were analyzed. NRBCs were found in 75.5% of the patients, which was associated with longer length of ICU stay [22 (11; 39) vs. 14 (7; 26) days; p 220/µl (OR 1.81; 95% CI 1.1–2.97; p

Temporary extracorporeal membrane oxygenation (ECMO) has been established as an essential part of therapy in patients with pulmonary or cardiac failure. As physiological gaseous exchange is artificially altered in this patient group, it is debatable whether a (13) C-breath test can be carried out. In this proof of technical feasibility report, we assess the viability of the (13) C-breath test LiMAx (maximum liver function capacity) in patients on ECMO therapy. All breath probes for the test device were obtained directly via the membrane oxygenator. Data of four patients receiving liver function assessment with the (13) C-breath test LiMAx while having ECMO therapy were analyzed. All results were compared with validated scenarios of the testing procedures. The LiMAx test could successfully be carried out in every case without changing ECMO settings. Clinical course of the patients ranging from multiorgan failure to no sign of liver insufficiency was in accordance with the results of the LiMAx liver function test. The (13) C-breath test is technically feasible in the context of ECMO. Further evaluation of (13) C-breath test in general would be worthwhile. The LiMAx test as a (13) C-breath test accessing liver function might be of particular predictive interest if patients with ECMO therapy develop multiorgan failure.

Repeated pulmonary lavage allows to reliably reproduce failure of gas exchange and major histological findings of acute lung injury (ALI). However, because the capacity of pulmonary lavage to induce pulmonary inflammation is not well established in rodents, this study aims to characterize the induction of pulmonary inflammation in a rat model of ALI.Male adult rats were divided into a treatment group (n = 9) that received pulmonary lavage with consecutive mechanical ventilation, and a control group that received mechanical ventilation only (n = 9). Arterial blood gas analyses were performed every 30 min throughout the study. Pressure-volume curves, and lung tissue and plasma samples, were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid was assessed. Transcriptional and translational regulation of pro- and anti-inflammatory cytokines IL-1β, TNF-α, IL-6, and IL-10 was determined in lungs and plasma. Markers of cellular stress were measured in lung tissue.Pulmonary lavage significantly decreased lung compliance, induced hypoxia and hypercapnia, and mediated respiratory acidosis. Protein content of lavage fluid was significantly increased and contained washed out surfactant. Expression of IL-1β, TNF-α, and IL-6 mRNA and protein expression of IL-1β and TNF-α was significantly induced in lavaged lungs, without spillover into the systemic circulation. Markers of cellular stress were significantly upregulated in lavaged lungs.This model of ALI applied in rats can induce pulmonary inflammation. The model might be used to develop therapeutic strategies that target pulmonary inflammation in ALI.

Recently, AT2 receptors have been discovered on the surface of human immunocompetent cells such as monocytes. Data on regulative properties of this receptor on the cellular immune response are poor. We hypothesized that direct stimulation of the AT2 receptor mediates anti-inflammatory responses in these cells. Human monocytic THP-1 and U937 cells were stimulated with lipopolysaccharide (LPS) and the selective AT2 receptor agonist Compound 21 (C21). Expression of pro- and anti-inflammatory cytokines IL-6, IL-10, tumor necrosis factor-alpha (TNF alpha), and IL-1 beta were analyzed on both the transcriptional and the translational level over course of time. Treatment with C21 attenuated the expression of TNF alpha, IL-6, and IL-10 after LPS challenge in both cell lines in a time- and dose-dependent manner. We conclude that selective AT2 receptor stimulation acts anti-inflammatory in human monocytes. Modulation of cytokine response by AT2 receptor activation might be a beneficial and novel treatment concept in inflammatory conditions.

Background. Interactions between alcohol, infection, and surgery and their effect on differentiation and functionality of T helper cells are not yet completely understood. We hypothesized that alcohol and surgery disturb differentiation of T helper cells and contribute to an impaired immune response.Methods. Mice were treated with alcohol for two weeks. Saline treatment served as control. Clinical performance and weight were assessed. On day 14, a median laparotomy was performed and animals were challenged withKlebsiella pneumoniaeintranasally. Bacterial load was determined in lungs and blood. T helper cell subpopulations and the released cytokines were assessed in lungs, spleens, and plasma. Key transcription factors of T cell differentiation were evaluated.Results. Alcohol significantly impaired clinical appearance and body weight of animals with postsurgical infection(p<0.05). Bacterial load was significantly higher after alcohol treatment(p<0.05). T helper cell subsets and released cytokine levels were significantly altered in lung, but not in spleen. Expression of transcription factors of T helper cell lineage commitment did not translate into different counts of T helper cells.Conclusions. Alcohol and surgery lead to significant cellular and functional modulations of T helper cells during postsurgical infection. These effects may contribute to an impaired immune response after surgery.

Background Extracorporeal membrane oxygenation (ECMO) or pumpless extracorporeal lung assist (pECLA) requires effective anticoagulation. Knowledge on the use of argatroban in patients with acute respiratory distress syndrome (ARDS) undergoing ECMO or pECLA is limited. Therefore, this study assessed the feasibility, efficacy and safety of argatroban in critically ill ARDS patients undergoing extracorporeal lung support. Methods This retrospective analysis included ARDS patients on extracorporeal lung support who received argatroban between 2007 and 2014 in a single ARDS referral center. As controls, patients who received heparin were matched for age, sex, body mass index and severity of illness scores. Major and minor bleeding complications, thromboembolic events, administered number of erythrocyte concentrates, thrombocytes and fresh-frozen plasmas were assessed. The number of extracorporeal circuit systems and extracorporeal lung support cannulas needed due to clotting was recorded. Also assessed was the efficacy to reach the targeted activated partial thromboplastin time (aPTT) in the first consecutive 14 days of therapy, and the controllability of aPTT values is within a therapeutic range of 50–75 s. Fisher’s exact test, Mann–Whitney U tests, Friedman tests and multivariate nonparametric analyses for longitudinal data (MANOVA; Brunner’s analysis) were applied where appropriate. Results Of the 535 patients who met the inclusion criteria, 39 receiving argatroban and 39 matched patients receiving heparin (controls) were included. Baseline characteristics were similar between the two groups, including severity of illness and organ failure scores. There were no significant differences in major and minor bleeding complications. Rates of thromboembolic events were generally low and were similar between the two groups, as were the rates of transfusions required and device-associated complications. The controllability of both argatroban and heparin improved over time, with a significantly increasing probability to reach the targeted aPTT corridor over the first days (p

Background Currently there is no ARDS definition or classification system that allows optimal prediction of mortality in ARDS patients. This study aimed to examine the predictive values of the AECC and Berlin definitions, as well as clinical and respiratory parameters obtained at onset of ARDS and in the course of the first seven consecutive days. Methods The observational study was conducted at a 14-bed intensive care unit specialized on treatment of ARDS. Predictive validity of the AECC and Berlin definitions as well as PaO2/FiO2 and FiO2/PaO2*Pmean (oxygenation index) on mortality of ARDS patients was assessed and statistically compared. Results Four hundred forty two critically-ill patients admitted for ARDS were analysed. Multivariate Cox regression indicated that the oxygenation index was the most accurate parameter for mortality prediction. The third day after ARDS criteria were met at our hospital was found to represent the best compromise between earliness and accuracy of prognosis of mortality regarding the time of assessment. An oxygenation index of 15 or greater was associated with higher mortality, longer length of stay in ICU and hospital and longer duration of mechanical ventilation. In addition, non-survivors had a significantly longer length of stay and duration of mechanical ventilation in referring hospitals before admitted to the national reference centre than survivors. Conclusions The oxygenation index is suggested to be the most suitable parameter to predict mortality in ARDS, preferably assessed on day 3 after admission to a specialized centre. Patients might benefit when transferred to specialized ICU centres as soon as possible for further treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12871-016-0272-4) contains supplementary material, which is available to authorized users.

Background: Acute ethanol intoxication has the potential to alter immune reactivity by various pathways. The aim of this study was to investigate T-helper cell subsets transcription factors and cytokines in human peripheral blood mononuclear cells (PBMCs) following a single dose of lipopolysaccharide (LPS) with or without ethanol exposure. Methods: Human PBMCs were cultured in the presence of 100 mM ethanol and/or 100 ng/ml LPS for various time periods (1, 3, 8, and 24 hours) and analyzed for the kinetics of gene expression by quantitative real-time PCR of selected transcription factors (T-bet, GATA3, Foxp3, and RORγt) and cytokines (TNF-α, IL-6, IL-10, and IFN-γ). The proportion of Th17 and Treg cells was identified 24 hours after treatment with ethanol and LPS by multiparameter flow cytometry. Viability and amount of dead cells were analyzed after 24 and 48 hours by MTT assay and flow cytometry. Results: Following LPS challenge, gene expression of Foxp3 increased, whereas RORγt decreased after 3 hours, GATA3 decreased within 1 hour, whereas expression of T-bet did not change at any time. Gene expression of TNF-α, interferon-γ (IFN-γ), and IL-6 peaked after 3 hours, expression of IL-10 peaked after 8 hours. Ethanol suppressed the LPS-induced gene expression of Foxp3, RORγt, and T-bet after 8 hours, expression of TNF-α and IFN-γ was also suppressed after 3 and 8 hours. Markers of inflammation including TNF-α and IL-1β in supernatant of PBMCs were significantly decreased, while levels of IL-10 and IL-6 remained unchanged following ethanol exposure. Furthermore, ethanol-treated cells alone or in combination with LPS had significantly fewer IL-17- and IFN-γ-secreting CD4+ T cells but constant proportion of Treg cells when compared to control cells. Proliferation and viability of the cells were not influenced under these conditions. Conclusions: Alcohol interferes with the kinetics of Foxp3, RORγt, and T-bet gene expression and the production of TNF-α and IL-1s and influences the balance of Treg/Th17 cells following LPS exposure.

Molecular mechanisms accompanying ethanol-induced cytotoxicity remain to be defined. The renin–angiotensin system with its respective receptors, the angiotensin AT1 and AT2 receptor (AT1R and AT2R), has been implicated in these processes. The AT2R seems to counteract the pro-inflammatory, pro-hypertrophic, and pro-fibrotic actions of the AT1R and is involved in cellular differentiation and tissue repair. Recently, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a novel negative transcriptional regulator of the AT2R. However, the complex interactions between ethanol, PARP-1, and the AT2R are largely unknown. In this in vitro study, we aimed to clarify whether acute ethanol treatment modifies AT2R promoter activity or AT2R mRNA and protein levels and whether PARP-1 is involved in ethanol-mediated regulation of the AT2R. Murine fibroblasts of the R3T3 and MEF line (murine embryonic fibroblasts) were exposed to ethanol for 24 h. AT2R promoter activity, mRNA and protein levels were analyzed with and without PARP-1 inhibition and in PARP-1 knockout MEF cells. Expression of PARP-1 was analyzed over course of time, and cell viability and DNA fragmentation were measured on single-cell level by flow cytometry. Ethanol exposition induced substantial downregulation of the AT2R on promoter, mRNA and protein levels in a dose-dependent manner. Pharmacological inhibition or ablation of PARP-1 completely abolished this effect. Ethanol treatment did not have any effect on AT1R mRNA and protein levels in MEF cells. Further, acute ethanol treatment promoted DNA fragmentation and caused transcriptional induction of PARP-1. Our findings reveal that PARP-1 is an upstream transcriptional regulator of the AT2 receptor in the context of ethanol exposure and represses the AT2R gene in fibroblasts in vitro. Variations in expression of the potentially tissue-protective AT2R might contribute to ethanol-mediated pathology.

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular and neuronal (patho-)physiology. The angiotensin AT2 receptor (AT2R) seems to counteract the proinflammatory, prohypertrophic and profibrotic actions of the AT1 receptor. Recently, we identified a novel protein, termed "AT2R binding protein" (ATBP/ATIP) which seems essential for AT2R-mediated growth inhibition. Poly(ADP-ribose) polymerase-1 (PARP-1) can act as a nuclear integrator of angiotensin II-mediated cell signalling, and has been implicated in the pathogenesis of cardiovascular and neuronal disease. In this study, promoters of human AT2R and ATIP1 were cloned and two transcriptional start sites in the ATIP1 promoter were identified whereas only one was detected in the AT2R promoter. Promoter assays indicated that the exon 1-intron 1 region of AT2R is necessary and sufficient for AT2R promoter activity. Inverse cloning experiments indicated that this regulatory region is a promoter but not an enhancer element implicating (a) further start site(s) in this region. Consistently, the exon 1-intron 1 region of AT2R was shown to tether the basal transcriptional machinery. Overexpression, pharmacological inhibition and ablation of PARP demonstrated that PARP-1 activates the ATIP1 gene but represses the AT2R on promoter and mRNA levels in vitro, and in brain tissue in vivo. Additional experiments indicated that AT2R activation does not modulate PARP-1 transcript levels but increases AT2R promoter activity, thereby creating a positive feedback mechanism. Our results demonstrate that PARP-1 acts as novel node within the RAS network based on its ability to regulate downstream targets such as AT2R and its adapter protein ATBP.

Despite the implementation of a multimodal concept of treatment, the acute respiratory distress syndrome (ARDS) is still afflicted with high mortality rates. A reasonable application and combination of possible treatment strategies, such as prone position, positive end-expiratory pressure (PEEP), restrictive volume therapy or nitric oxide (NO), requires pathophysiological and epidemiological knowledge. In the following article we describe basic pathophysiological parameters in development, progression and therapy of ARDS. Furthermore, we try to elucidate possible reasons for considerable limitations of multicentric studies in this field.

Fewer than 2% of all peripartal patients need intensive care unit admission. But due to some anatomic and physiologic changes in pregnancy, respiratory failure can be promoted. This article reviews several obstetric and nonobstetric diseases that lead to respiratory failure and the treatment of these. Furthermore, invasive and noninvasive ventilation in pregnancy is discussed and suggestions of medication during ventilation are given.

Temporary extracorporeal membrane oxygenation (ECMO) has been established as an essential part of therapy in patients with pulmonary or cardiac failure. As physiological gaseous exchange is artificially altered in this patient group, it is debatable whether a (13) C-breath test can be carried out. In this proof of technical feasibility report, we assess the viability of the (13) C-breath test LiMAx (maximum liver function capacity) in patients on ECMO therapy. All breath probes for the test device were obtained directly via the membrane oxygenator. Data of four patients receiving liver function assessment with the (13) C-breath test LiMAx while having ECMO therapy were analyzed. All results were compared with validated scenarios of the testing procedures. The LiMAx test could successfully be carried out in every case without changing ECMO settings. Clinical course of the patients ranging from multiorgan failure to no sign of liver insufficiency was in accordance with the results of the LiMAx liver function test. The (13) C-breath test is technically feasible in the context of ECMO. Further evaluation of (13) C-breath test in general would be worthwhile. The LiMAx test as a (13) C-breath test accessing liver function might be of particular predictive interest if patients with ECMO therapy develop multiorgan failure.

Purpose The purpose of the study is to compare H1N1-induced acute respiratory distress syndrome (ARDS) with ARDS due to other causes of severe community-acquired pneumonia focusing on pulmonary function. Materials and methods This is a retrospective data analysis of adult ARDS patients between January 2009 and December 2010 in an ARDS referral center. Patient characteristics, severity of illness scores, modalities, and duration of extracorporeal lung support were evaluated as well as intensive care unit stay and survival. Parameters of mechanical ventilation and pulmonary function were analyzed on day of admission and over the consecutive 10 days using a nonparametric analysis of longitudinal data in a 2-factorial design. In a logistic regression analysis, risk factors for extracorporeal lung support were investigated. Results Twenty-one patients with H1N1-ARDS and 41 with non-H1N1-ARDS were identified. Gas exchange was more severely impaired in patients with H1N1-ARDS over course of time. Extracorporeal membrane oxygenation was more frequently needed in H1N1-ARDS. Despite significantly prolonged weaning off extracorporeal lung support and intensive care unit stay in H1N1 patients, the proportion of survivors did not differ significantly. Only Sepsis-Related Organ Failure Assessment score could be identified as an independent predictor of extracorporeal lung support. Conclusions Clinical course of H1N1-ARDS is substantially different from non-H1N1-ARDS. Affected patients may require extensive therapy including extracorporeal lung support in ARDS referral centers.