[Prone positioning for acute respiratory distress syndrome in adults : Update on the physiological effects, indications and implementation]. / Bauchlagerung beim akuten Lungenversagen des Erwachsenen : Update zu den physiologischen Effekten, den Indikationen und der Durchführung.

The prone position is an immediately available and easily implemented procedure that was introduced more than 50 years ago as a method for improvement of gas exchange in patients with acute respiratory distress syndrome (ARDS). In the meantime, a survival advantage could also be shown in patients with severe ARDS, which led to the recommendation of the prone position for treatment of severe ARDS by expert consensus and specialist society guidelines. The continuing coronavirus disease 2019 (COVID-19) pandemic moved the prone position to the forefront of medicine, including the widespread implementation of the prone position for awake, spontaneously breathing nonintubated patients with acute hypoxemic respiratory insufficiency. The survival advantage is possible due to a reduction of the ventilator-associated lung damage. In this article, the physiological effects, data on clinical results, practical considerations and open questions with respect to the prone position are discussed.

Health-related quality of life and participation after inpatient rehabilitation of sepsis survivors with severe sequelae: a cohort study.

OBJECTIVE: To describe health-related quality of life and participation after rehabilitation of severely affected sepsis survivors. DESIGN: Cohort study. SUBJECTS/PATIENTS: Patients with severe sequelae after sepsis treated in a multidisciplinary rehabilitation pathway were included. METHODS: Patient characteristics at the time of diagnosis, and the outcome 3 months after discharge from rehabilitation are described. At that time, health-related quality of life, social participation, and the rate of living at home were measured. RESULTS: Of the 498 patients enrolled, 100 severely impaired patients were transferred for a multidisciplinary rehabilitation approach. Fifty-five of them were followed up at 3 months. Descriptive and inference statistics showed that 69% were living at home with or without care. Health-related quality of life and participation scores were 0.64 ± 0.32 for the EQ-5D utility index and 54.98 ± 24.97 for the Reintegration of Normal Living Index. A multivariate regression model explaining health-related quality of life at 3 months included age, lower limb strength, and walking ability during rehabilitation (r2 = 0.5511). Participation at 3 months was explained by age, body mass index, lower limb strength, and duration of tracheal intubation (r2 = 0.6229). CONCLUSION: Patients who have experienced serious sepsis with severe sequelae can achieve a moderate level of quality of life and participation within a multidisciplinary pathway.

[Prehospital ultrasound in emergency medicine]. / Prähospitaler Ultraschall in der Notfallmedizin.

Small, portable hand-held ultrasound devices nowadays enable a widespread use of prehospital point-of-care ultrasound (pPOCUS), which has so far only been used hesitantly, especially in ground-based emergency services. Many critical or even life-threatening conditions or internal injuries can often be better diagnosed or ruled out using pPOCUS, which can enable faster and more suitable goal-directed treatment and hospital transport. This article critically discusses relevant data, clinical benefits, limitations and challenges to be overcome when using pPOCUS for the most important life-threatening situations and aims to call for intensifying training and the extensive use of pPOCUS.

Nucleated red blood cells as a prognostic marker for mortality in patients with SARS-CoV-2-induced ARDS: an observational study.

BACKGROUND: The presence of nucleated red blood cells (NRBCs) in the peripheral blood of critically ill patients is associated with poor outcome. Evidence regarding the predictive value of NRBCs in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) remains elusive. The aim of this study was to evaluate the predictive validity of NRBCs in these patients. METHODS: Daily NRBC values of adult patients with SARS-CoV-2-induced ARDS were assessed and their predictive validity for mortality was statistically evaluated. A cut-off level based on the patient's maximum NRBC value during ICU stay was calculated and further specified according to Youden's method. Based on this cut-off value, further analyses such as logistic regression models and survival were performed. RESULTS: 413 critically ill patients with SARS-CoV-2-induced ARDS were analyzed. Patients who did not survive had significantly higher NRBC values during their ICU stay compared to patients who survived (1090/µl [310; 3883] vs. 140/µl [20; 500]; p < 0.0001). Patients with severe ARDS (n = 374) had significantly higher NRBC values during ICU stay compared to patients with moderate ARDS (n = 38) (490/µl [120; 1890] vs. 30/µl [10; 476]; p < 0.0001). A cut-off level of NRBC ≥ 500/µl was found to best stratify risk and was associated with a longer duration of ICU stay (12 [8; 18] vs. 18 [13; 27] days; p < 0.0001) and longer duration of mechanical ventilation (10 [6; 16] vs. 17 [12; 26] days; p < 0.0001). Logistic regression analysis with multivariate adjustment showed NRBCs ≥ 500/µl to be an independent risk factor of mortality (odds ratio (OR) 4.72; 95% confidence interval (CI) 2.95-7.62, p < 0.0001). Patients with NRBC values below the threshold of 500/µl had a significant survival advantage over those above the threshold (median survival 32 [95% CI 8.7-43.3] vs. 21 days [95% CI 18.2-23.8], log-rank test, p < 0.05). Patients who once reached the NRBC threshold of ≥ 500/µl during their ICU stay had a significantly increased long-term mortality (median survival 489 days, log-rank test, p = 0.0029, hazard ratio (HR) 3.2, 95% CI 1.2-8.5). CONCLUSIONS: NRBCs predict mortality in critically ill patients with SARS-CoV-2-induced ARDS with high prognostic power. Further studies are required to confirm the clinical impact of NRBCs to eventually enhance decision making.

[Influence of anesthesia on surgical site infections]. / Einfluss der Anästhesie auf chirurgische Wundinfektionen.

Surgical site infections (SSI) are the most frequent cause of impaired perioperative wound healing, lead to increased postoperative morbidity, mortality and length of hospital stay and are therefore a relevant perioperative complication. In addition to numerous measures taken by the surgical departments, there are anesthesiological options that can help to reduce the risk of SSI. In addition to heat, volume and transfusion management these include, for example, the use of antibiotics and the choice of the anesthesia procedure. This article is intended to provide fundamental knowledge on SSI, shows various options for reducing them in the context of anesthesia and evaluates their effectiveness and evidence based on the current state of knowledge.

[Ventilation concepts under extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome (ARDS)]. / Beatmungskonzepte unter extrakorporaler Membranoxygenierung bei akutem Lungenversagen.

Extracorporeal membrane oxygenation (ECMO) is often the last resort for escalation of treatment in patients with severe acute respiratory distress syndrome (ARDS). The success of treatment is mainly determined by patient-specific factors, such as age, comorbidities, duration and invasiveness of the pre-existing ventilation treatment as well as the expertise of the treating ECMO center. In particular, the adjustment of mechanical ventilation during ongoing ECMO treatment remains controversial. Although a reduction of invasiveness of mechanical ventilation seems to be reasonable due to physiological considerations, no improvement in outcome has been demonstrated so far for the use of ultraprotective ventilation regimens.

[Extracorporeal cardiopulmonary resuscitation-An orientation]. / Extrakorporale kardiopulmonale Reanimation ­ eine Standortbestimmung.

Both in-hospital and out-of-hospital cardiac arrests are associated with a high mortality. In the past survival advantages for patients could be achieved by optimizing the chain of rescue and postresuscitation treatment; however, for patients with refractory cardiac arrest, there have so far been few promising treatment options. For selected patients with refractory cardiac arrest who do not achieve return of spontaneous circulation with conventional cardiopulmonary resuscitation (CPR), extracorporeal (e)CPR using venoarterial extracorporeal membrane oxygenation is an option to improve the probability of survival. This article describes the technical features, important aspects of treatment, and the current data situation on eCPR in patients with in-hospital or out-of-hospital cardiac arrest.

A contemporary training concept in critical care cardiology.

Critical care cardiology (CCC) in the modern era is shaped by a multitude of innovative treatment options and an increasingly complex, ageing patient population. Generating high-quality evidence for novel interventions and devices in an intensive care setting is exceptionally challenging. As a result, formulating the best possible therapeutic approach continues to rely predominantly on expert opinion and local standard operating procedures. Fostering the full potential of CCC and the maturation of the next generation of decision-makers in this field calls for an updated training concept, that encompasses the extensive knowledge and skills required to care for critically ill cardiac patients while remaining adaptable to the trainee's individual career planning and existing educational programs. In the present manuscript, we suggest a standardized training phase in preparation of the first ICU rotation, propose a modular CCC core curriculum, and outline how training components could be conceptualized within three sub-specialization tracks for aspiring cardiac intensivists.

Monitoring of Argatroban in Critically Ill Patients: A Prospective Study Comparing Activated Partial Thromboplastin Time, Point-of-Care Viscoelastic Testing with Ecarin Clotting Time and Diluted Thrombin Time to Mass Spectrometry.

BACKGROUND: The direct thrombin inhibitor argatroban is indicated for the treatment of heparin-induced thrombocytopenia II, but it is also used off-label to treat critically ill patients presenting with heparin resistance, severe antithrombin deficiency, or hypercoagulability. Direct drug monitoring is not routinely available, and argatroban dosing is mainly based on global coagulation assays such as activated partial thromboplastin time (PTT) or diluted thrombin time (TT), both of which have limitations in patients with hypercoagulability. METHODS: Blood samples were obtained from critically ill patients treated with argatroban. Activated PTT and diluted TT were measured with a STA R Max3 analyzer (STAGO Deutschland GmbH, Germany) using an argatroban-calibrated kit. Ecarin clotting time was measured using a point-of-care viscoelastic test device. Liquid chromatography with tandem mass spectrometry was performed using a reversed-phase column, a solvent gradient, and an API4000 mass spectrometer with electrospray. Correlation was described using Pearson correlation coefficient r and Bayesian multilevel regression to estimate relationships between outcomes and covariates. RESULTS: From June 2021 to March 2022, 205 blood samples from 22 patients were analyzed, allowing for 195 activated PTT-liquid chromatography with tandem mass spectrometry comparisons, 153 ecarin clotting time-liquid chromatography with tandem mass spectrometry comparison, and 105 diluted TT-liquid chromatography with tandem mass spectrometry comparisons. Compared to liquid chromatography with tandem mass spectrometry, performance of argatroban quantification was best for diluted TT (r = 0.91), followed by ecarin clotting time (r = 0.58) and activated PTT (r = 0.48). Regression analysis revealed that patients with sepsis were more prone to argatroban overdosing (coefficient, 4.194; 95% credible interval, 2.220 to 6.792). CONCLUSIONS: Although activated PTT monitoring of argatroban is the most commonly used test, in critically ill patients, diluted TT provides more precise measurements. Alternately, point-of-care viscoelastic ecarin clotting time also provides guidance for argatroban dosing to identify overdosing if available. The data also suggested that patients with sepsis are at greater risk for argatroban overdosing.

[Extracorporeal cardiopulmonary resuscitation-An orientation]. / Extrakorporale kardiopulmonale Reanimation ­ eine Standortbestimmung.

Both in-hospital and out-of-hospital cardiac arrests are associated with a high mortality. In the past survival advantages for patients could be achieved by optimizing the chain of rescue and postresuscitation treatment; however, for patients with refractory cardiac arrest, there have so far been few promising treatment options. For selected patients with refractory cardiac arrest who do not achieve return of spontaneous circulation with conventional cardiopulmonary resuscitation (CPR), extracorporeal (e)CPR using venoarterial extracorporeal membrane oxygenation is an option to improve the probability of survival. This article describes the technical features, important aspects of treatment, and the current data situation on eCPR in patients with in-hospital or out-of-hospital cardiac arrest.

Outcome of Emergency Pulmonary Lobectomy under ECMO Support in Patients with COVID-19.

BACKGROUND: Not much is known about the results of nonelective anatomical lung resections in coronavirus disease 2019 (COVID-19) patients put on extracorporeal membrane oxygenation (ECMO). The aim of this study was to analyze the outcome of lobectomy under ECMO support in patients with acute respiratory failure due to severe COVID-19. METHODS: All COVID-19 patients undergoing anatomical lung resection with ECMO support at a German university hospital were included into a prospective database. Study period was April 1, 2020, to April 30, 2021 (first, second, and third waves in Germany). RESULTS: A total of nine patients (median age 61 years, interquartile range 10 years) were included. There was virtually no preexisting comorbidity (median Charlson score of comorbidity 0.2). The mean interval between first positive COVID-19 test and surgery was 21.9 days. Clinical symptoms at the time of surgery were sepsis (nine of nine), respiratory failure (nine of nine), acute renal failure (five of nine), pleural empyema (five of nine), lung artery embolism (four of nine), and pneumothorax (two of nine). Mean intensive care unit (ICU) and ECMO days before surgery were 15.4 and 6, respectively. Indications for surgery were bacterial superinfection with lung abscess formation and progressive septic shock (seven of nine) and abscess formation with massive pulmonary hemorrhage into the abscess cavity (two of nine). All patients were under venovenous ECMO with femoral-jugular configuration. Operative procedures were lobectomy (eight) and pneumonectomy (one). Weaning from ECMO was successful in four of nine. In-hospital mortality was five of nine. Mean total ECMO days were 10.3 ± 6.2 and mean total ICU days were 27.7 ± 9.9. Mean length of stay was 28.7 ± 8.8 days. CONCLUSION: Emergency surgery under ECMO support seems to open up a perspective for surgical source control in COVID-19 patients with bacterial superinfection and localized pulmonary abscess.

Hemostatic disorders associated with extracorporeal membrane oxygenation.

Hemostatic disorders are common during extracorporeal membrane oxygenation (ECMO)-therapy. This includes both bleeding and thrombotic complications. Particularly bleeding is often associated with fatal outcome. The early identification of hemorrhagic diathesis and the diagnosis of the underlying pathology are essential. A distinction into device-, disease-, and drug-related disorders appears reasonable. However, both correct diagnosis and therapy can be challenging and sometimes counterintuitive. Since bleeding seems to be more frequent and dangerous compared to thrombosis, the understanding of coagulation disorders and minimizing anticoagulation has been focused in recent years. Due to progress in membrane coating and configuration of modern ECMO circuits it is even possible to perform ECMO without any anticoagulation in well selected cases. It became apparent that routine laboratory tests are likely to miss severe coagulation disorders during ECMO-therapy. Better understanding can also help to individualize anticoagulation in patients and hence preventing complications. Acquired von Willebrand syndrome, platelet dysfunction, waste coagulopathy as well as silent hemolysis should be taken into account when bleeding or thromboembolic complications appear. Recognizing impaired intrinsic fibrinolysis may favour intensified anticoagulation even in patients exhibiting signs of bleeding. Drug monitoring with standard coagulation tests, viscoelastic tests and anti-Xa-levels as wells as screening for disorders of primary hemostasis should be implemented in clinical routine to guide physicians through complex anticoagulative therapy. The patient's coagulative status should be interpreted taking the underlying disease and current therapy into account in order to enable a personalized approach to hemostasis in patients treated with ECMO.

A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2's known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.

Bleeding management in patients with direct oral anticoagulants.

Bleeding events in patients under direct oral anticoagulation (DOAC) can be life-threating but are commonly not related to drug overdose. However, a relevant DOAC plasma concentration impairs the hemostasis and should therefore be ruled out immediately after hospital admission. The effect of DOAC is typically not visible in standard coagulation tests such as activated partial thrombin time or thromboplastin time. Specific anti-Xa or anti-IIa assays allow a specific drug monitoring, but they are too time-consuming in critical bleeding events and typically not available 24 h/7 d in routine care. Recent advantages in point-of-care (POC) testing might improve patient care by early exclusion of relevant DOAC levels, but sufficient validation is still lacking. POC urine analysis help to exclude DOAC in emergency patients, but does not provide a quantitative information about plasma concentration. POC viscoelastic testing (VET) can determine the DOAC effect on clotting time and helps further to reveal other concomitant bleeding disorders in emergency, e.g., factor deficiency or hyperfibrinolysis. If a relevant plasma concentration of the DOAC is assumed or was proven by either laboratory assays or POC testing, restoration of factor IIa or factor IIa activity is key for effective hemostasis. Limited evidence suggests that specific reversals for DOAC, e.g., idarucizumab for dabigatran and andexanet alfa for apixaban or rivaroxaban, might be superior to increasing thrombin generation by administration of prothrombin complex concentrates. To determinate, if DOAC reversal is indicated or not, time from last intake, anti-Xa/dTT values or results from POC tests can be considered. This experts' opinion provides a feasible decision algorithm for clinical practice.

Treatment of Acquired von Willebrand Disease due to Extracorporeal Membrane Oxygenation in a Pediatric COVID-19 Patient with Vonicog Alfa: A Case Report and Literature Review.

Acquired von Willebrand disease (aVWD) is frequently observed in patients with the need for extracorporeal membrane oxygenation (ECMO). aVWD can be treated by plasma-derived concentrates containing factor VIII (FVIII) and/or von Willebrand factor (VWF) and recombinant VWF concentrate as well as adjuvant therapies such as tranexamic acid and desmopressin. However, all of these therapeutic options possibly cause thromboembolism. Therefore, the optimal treatment remains uncertain. This report presents a case of a 16-year-old patient suffering from severe acute respiratory distress syndrome due to coronavirus disease 2019 with the need of ECMO support. Our patient developed aVWD under ECMO therapy characterized by loss of high-molecular-weight multimers (HMWM) and severe bleeding symptoms following endoscopic papillotomy due to sclerosing cholangitis. At the same time standard laboratory parameters showed hypercoagulability with increased fibrinogen level and platelet count. The patient was successfully treated with recombinant VWF concentrate (rVWF; vonicog alfa; Veyvondi) combined with topic tranexamic acid application and cortisone therapy. rVWF concentrate vonicog alfa is characterized by ultra-large multimers and absence of FVIII. Patient could be successfully weaned from ECMO support after 72 days. Multimer analysis 1 week after ECMO decannulation showed an adequate reappearance of HMWM.

mRNA Levels of Epithelial and Mesenchymal Markers in Lung Epithelial Cell Lines.

Background: Epithelial-mesenchymal transition (EMT) is an important physiologic process that determines the outcome of lung tissue healing after injury. Stimuli and molecular cascades inducing EMT lead to up-regulation of the mesenchymal-specific genes in the alveolar epithelial cells and to down-regulation of the genes coding for epithelial markers. Alveolar epithelial cell lines are commonly used as in vitro models to study processes occurring in the lung tissue. The aim of this study is to quantify and compare mRNA expression levels of epithelial and mesenchymal markers in a number of lung epithelial cell lines. Methods: Lung epithelial cell lines L2, R3/1 and RLE-6TN were cultured. Repeated mRNA isolation, reverse transcription, and quantitative PCR with primers to epithelial (E-cadherin, occludin, and ZO-2) and mesenchymal (α-SMA, collagen III, and vimentin) markers were performed. Results: First, our study revealed a higher level of epithelial transcripts in the RLE-6TN cell line compared to L2 and R3/1 cells. Secondly, we have found simultaneous mRNA expression of both epithelial (E-cadherin, occludin and ZO-2) and mesenchymal (α-SMA, collagen III and vimentin) markers in all cell lines studied. Conclusions: Our data indicate that at the transcriptional level the L2, R3/1, and RLE-6TN cell lines are at one of the intermediate stages of EMT, which opens new possibilities for the study of EMT on cell lines. Determination of the direction of changes in epithelial and mesenchymal markers will make it possible to establish the factors responsible for both EMT and reverse mesenchymal-epithelial transition.

Extreme obesity is a strong predictor for in-hospital mortality and the prevalence of long-COVID in severe COVID-19 patients with acute respiratory distress syndrome.

Acute Respiratory Distress Syndrome (ARDS) is common in COVID-19 patients and is associated with high mortality. The aim of this observational study was to describe patients' characteristics and outcome, identifying potential risk factors for in-hospital mortality and for developing Long-COVID symptoms. This retrospective study included all patients with COVID-19 associated ARDS (cARDS) in the period from March 2020 to March 2021 who were invasively ventilated at the intensive care unit (ICU) of the University Hospital Dresden, Germany. Between October 2021 and December 2021 patients discharged alive (at minimum 6 months after hospital discharge-midterm survival) were contacted and interviewed about persistent symptoms possibly associated with COVID-19 as well as the quality of their lives using the EQ-5D-5L-questionnaire. Long-COVID was defined as the occurrence of one of the symptoms at least 6 months after discharge. Risk factors for mortality were assessed with Cox regression models and risk factors for developing Long-COVID symptoms by using relative risk (RR) regression. 184 Patients were included in this study (male: n = 134 (73%), median age 67 (range 25-92). All patients were diagnosed with ARDS according to the Berlin Definition. 89% of patients (n = 164) had severe ARDS (Horovitz-index < 100 mmHg). In 27% (n = 49) extracorporeal membrane oxygenation was necessary to maintain gas exchange. The median length of in-hospital stay was 19 days (range 1-60). ICU mortality was 51%, hospital mortality 59%. Midterm survival (median 11 months) was 83% (n = 55) and 78% (n = 43) of these patients presented Long-COVID symptoms with fatigue as the most common symptom (70%). Extreme obesity (BMI > 40 kg/m2) was the strongest predictor for in-hospital mortality (hazard ratio: 3.147, confidence interval 1.000-9.897) and for developing Long-COVID symptoms (RR 1.61, confidence interval 1.26-2.06). In-hospital mortality in severe cARDS patients was high, but > 80% of patients discharged alive survived the midterm observation period. Nonetheless, most patients developed Long-COVID symptoms. Extreme obesity with BMI > 40 kg/m2 was identified as independent risk factor for in-hospital mortality and for developing Long-COVID symptoms.Trial registration DRKS-ID DRKS00027856.