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ZusammenfassungDieses zweite Positionspapier der Sektion Metabolismus und Ernährung der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI) gibt Empfehlungen zum laborchemischen Monitoring der Makro- und Mikronährstoffzufuhr sowie zum Einsatz der indirekten Kalorimetrie im Rahmen der medizinischen Ernährungstherapie erwachsener Intensivpatient:innen. Zusätzlich werden Empfehlungen zur krankheitsbezogenen bzw. individuellen (Spiegelbestimmung) Substitution und (Hochdosis‑)Pharmakotherapie von Vitaminen und Spurenelementen vorgenommen.

Background: Recirculation during veno-venous extracorporeal membrane oxygenation reduces extracorporeal oxygen exchange and patient oxygenation. To minimize recirculation and maximize oxygen delivery (DO2) the interaction of cannulation, ECMO flow and cardiac output requires careful consideration. We investigated this interaction in an observational trial. Methods: In 19 patients with acute respiratory distress syndrome and ECMO, we measured recirculation with the ultrasound dilution technique and calculated extracorporeal oxygen transfer (VO2), extracorporeal oxygen delivery (DO2) and patient oxygenation. To assess the impact of cardiac output (CO), we included CO measurement through pulse contour analysis. Results: In all patients, there was a median recirculation rate of approximately 14–16%, with a maximum rate of 58%. Recirculation rates >35% occurred in 13–14% of all cases. In contrast to decreasing extracorporeal gas exchange with increasing ECMO flow and recirculation, patient oxygenation increased with greater ECMO flows. High CO diminished recirculation by between 5–20%. Conclusions: Extracorporeal gas exchange masks the importance of DO2 and its effects on patients. We assume that increasing DO2 is more important than reduced VO2. A negative correlation of recirculation to CO adds to the complexity of this phenomenon. Patient oxygenation may be optimized with the direct measurement of recirculation.

Correction to J. Clin. Med. 2020, 9(9), 2695. Excerpt Note: In lieu of an abstract, this is an excerpt from the first page. In the original article, there were errors in Figure 1D (panel CD8-Control) [...]

Die Internistische Intensivmedizin ist fur die intensivmedizinische Diagnostik, Uberwachung, Therapie, Pflege und Nachsorge von Patienten mit schweren, potenziell lebensbedrohlichen Erkrankungen aus dem gesamten Bereich der Inneren Medizin verantwortlich. Die Qualifikation in Internistischer Intensivmedizin erfordert breite Kenntnisse und praktische Fahigkeiten, zum einen im gesamten Fach Innere Medizin und zum anderen in der konservativen (Internistischen) Intensivmedizin einschlieslich der Einbeziehung spezieller Diagnostik- und Therapieoptionen der angrenzenden Fachgebiete. Die Patientenbetreuung darf sich deshalb nicht nur auf lebenserhaltende Masnahmen beschranken, sondern muss wahrend der intensivmedizinischen Behandlungsphase auch die zugrunde liegenden internistischen Erkrankungen in bestmoglicher Weise einschliesen. Das Fundament der Internistischen Intensivmedizin beinhaltet theoretische Kenntnisse, praktische Fahigkeiten (Kompetenzlevel I–III) und eine adaquate beruflich-professionelle Einstellung. Fur die Zusatz-Weiterbildung (ZWB) (Internistische) Intensivmedizin der Bundesarztekammer soll dieses Curriculum der Deutschen Gesellschaft fur Internistische Intensivmedizin und Notfallmedizin (DGIIN) dem intensivmedizinisch weiterzubildenden Internisten die Moglichkeit geben, seine Weiterbildungszeit so effizient wie moglich zu strukturieren, sich gut auf die Prufung vorzubereiten und das Erlernte anschliesend im Sinne eines „berufslebenslangen“ Qualifizierens zu bewahren. Das Curriculum mochte aber auch die Weiterbilder und Weiterbildungsausschusse der Arztekammern erreichen und aufzeigen, welche Kenntnisse und Fertigkeiten nach Ansicht der DGIIN in der ZWB zum Internistischen Intensivmediziner vermittelt werden sollen.

Background ω‐3 Fatty acid (FA)–containing parenteral nutrition (PN) is associated with improvements in patient outcomes and with reductions in hospital length of stay (HLOS) vs standard PN regimens (containing non–ω‐3 FA lipid emulsions). We present a cost‐effectiveness analysis of ω‐3 FA–containing PN vs standard PN in 5 European countries (France, Germany, Italy, Spain, UK) and the US. Methods This pharmacoeconomic model was based on estimates of ω‐3 efficacy reported in a recent meta‐analysis and data from country‐specific sources. It utilized a probabilistic discrete event simulation model to compare ω‐3 FA–containing PN with standard PN in a population of critically ill and general ward patients. The influence of model parameters was evaluated using probabilistic and deterministic sensitivity analyses. Results Overall costs were reduced with ω‐3 FA–containing PN in all 6 countries compared with standard PN, ranging from €1741 (±€1284) in Italy to €5576 (±€4193) in the US. Expenses for infections and HLOS were lower in all countries for ω‐3 FA–containing PN vs standard PN, with the largest cost differences for both in the US (infection: €825 ± €4001; HLOS: €4879 ± €1208) and the smallest savings in the UK for infections and in Spain for HLOS (€63 ± €426 and €1636 ± €372, respectively). Conclusion This cost‐effectiveness analysis in 6 countries demonstrates that the superior clinical efficacy of ω‐3 FA–containing PN translates into significant decreases in mean treatment cost, rendering it an attractive cost‐saving alternative to standard PN across different healthcare systems.

At the time of admission to an intensive or intermediate care unit, assessment of the patients' nutritional status may have both prognostic and therapeutic relevance with regard to the planning of individualized medical nutrition therapy (MNT). MNT has definitely no priority in the initial treatment of a critically ill patient, but is often also neglected during the course of the disease. Especially with prolonged length of stay, there is an increasing risk of malnutrition with considerable prognostic macro- and/or micronutrient deficit. So far, there are no structured, evidence-based recommendations for assessing nutritional status in intensive or intermediate care patients. This position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive and Emergency Medicine (DIVI) presents consensus-based recommendations for the assessment and technical monitoring of nutritional status of patients in intensive and intermediate care units. These recommendations supplement the current S2k guideline "Clinical Nutrition in Intensive Care Medicine" of the German Society for Nutritional Medicine (DGEM) and the DIVI.Die Erhebung des Ernährungsstatus zum Zeitpunkt der Aufnahme im Intensiv- oder Intermediate Care Bereich hat sowohl prognostische als auch therapeutische Relevanz im Hinblick auf die Planung einer individualisierten medizinischen Ernährungstherapie (engl. „medical nutrition therapy“, MNT). Diese Planung wird im Rahmen der Erstversorgung eines vital bedrohlichen Krankheitsbilds nachvollziehbar nicht priorisiert, jedoch im weiteren Verlauf häufig auch oft nicht mehr angemessen durchgeführt. Vor allem bei längerer Verweildauer besteht das Risiko einer Mangelernährung mit Aufbau eines kumulativen, prognoserelevanten Makro- und/oder Mikronährstoffdefizits. Bisher gibt es für Patient*innen auf Intensiv- und Intermediate Care Einheiten keine strukturierten Empfehlungen zur Erhebung des Ernährungsstatus. Das vorliegende Positionspapier der Sektion Metabolismus und Ernährung der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI) beinhaltet konsensbasierte Empfehlungen zur Erfassung und zum apparativen Monitoring des Ernährungsstatus von Patient*innen auf Intensiv- und Intermediate Care Stationen. Diese Empfehlungen ergänzen die aktuelle S2k-Leitlinie „Klinische Ernährung in der Intensivmedizin“ der Deutschen Gesellschaft für Ernährungsmedizin (DGEM) und der DIVI.

Summary Purpose Enteral and parenteral nutrition of adult critically ill patients varies in terms of the route of nutrient delivery, the amount and composition of macro- and micronutrients, and the choice of specific, immune-modulating substrates. Variations of clinical nutrition may affect clinical outcomes. The present guideline provides clinicians with updated consensus-based recommendations for clinical nutrition in adult critically ill patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g., mechanical ventilation) to maintain organ function. Methods The former guidelines of the German Society for Nutritional Medicine (DGEM) were updated according to the current instructions of the Association of the Scientific Medical Societies in Germany (AWMF) valid for a S2k-guideline. According to the S2k-guideline classification, no systematic review of the available evidence was required to make recommendations, which, therefore, do not state evidence- or recommendation grades. Nevertheless, we considered and commented the evidence from randomized-controlled trials, meta-analyses and observational studies with adequate sample size and high methodological quality (until May 2018) as well as from currently valid guidelines of other societies. The liability of each recommendation was described linguistically. Each recommendation was finally validated and consented through a Delphi process. Results In the introduction the guideline describes a) the pathophysiological consequences of critical illness possibly affecting metabolism and nutrition of critically ill patients, b) potential definitions for different disease phases during the course of illness, and c) methodological shortcomings of clinical trials on nutrition. Then, we make 69 consented recommendations for essential, practice-relevant elements of clinical nutrition in critically ill patients. Among others, recommendations include the assessment of nutrition status, the indication for clinical nutrition, the timing and route of nutrient delivery, and the amount and composition of substrates (macro- and micronutrients); furthermore, we discuss distinctive aspects of nutrition therapy in obese critically ill patients and those treated with extracorporeal support devices. Conclusion The current guideline provides clinicians with up-to-date recommendations for enteral and parenteral nutrition of adult critically ill patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g., mechanical ventilation) to maintain organ function. The period of validity of the guideline is approximately fixed at five years (2018–2023).

Згідно з новими стандартними операційними процедурами ESPEN були оновлені попередні рекомендації щодо забезпечення найкращого медичного нутритивного забезпечення для критично хворих пацієнтів. Дані рекомендації визначають, хто є пацієнтами в групі ризику, як оцінити нутритивний статус пацієнта ВІТ, як визначити кількість енергії, яку необхідно забезпечити, який обрати шлях для нутритивного забезпечення та як адаптувати пацієнта у відповідності до різних клінічних умов. Також описано, коли слід розпочати і як просуватися в управлінні процесом адекватного забезпечення поживними речовинами. Запропоновано найкраще визначення кількості та походження вуглеводів, жирів і білків. Особлива увага приділяється глутаміну і омега-3 жирним кислотам. Обговорюються конкретні стани, що часто спостерігаються в інтенсивній терапії, такі як пацієнти з дисфагією, виснажені пацієнти, пацієнти з множинними травмами, абдомінальна хірургія, сепсис і ожиріння, з метою ознайомлення практикуючого лікаря з найкращою доказовою терапією. Моніторинг цієї нутритивної терапії обговорюється в окремому документі.

PURPOSE OF REVIEW Lipid emulsions are an integral part of parenteral nutrition. Enteral nutrition is the preferred route to feed critically ill patients and parenteral nutrition is used in case of contraindications or when enteral nutrition does not reach the nutritional goals. n-3 Lipids are included into some newer lipid emulsions including fish oil or may be added by a fish oil-based lipid emulsion to lipid emulsion without fish oil. This review focuses on recent clinical trials, metaanalyses, and guidelines of parenteral nutrition with n-3 lipids in critically ill patients. RECENT FINDINGS Two single-center studies report a mortality benefit of adding fish oil-based lipid emulsions to the parenteral nutrition. Metaanalyses performed without these two studies had demonstrated beneficial effects of n-3 lipids regarding infections, length of stay, and time of mechanical ventilation but not on mortality. However, all metaanalyses judged the database derived from the underlying studies as not sufficient for a firm recommendation. Consecutively, guidelines and expert groups issue very cautious recommendations for the use of n-3 lipids in parenteral nutrition. SUMMARY Beneficial effects of n-3 lipids in trials and metaanalyses became available; however, high-quality multicenter randomized controlled trials are needed before more endorsing recommendation will be available.

Following the new ESPEN Standard Operating Procedures, the previous guidelines to provide best medical nutritional therapy to critically ill patients have been updated. These guidelines define who are the patients at risk, how to assess nutritional status of an ICU patient, how to define the amount of energy to provide, the route to choose and how to adapt according to various clinical conditions. When to start and how to progress in the administration of adequate provision of nutrients is also described. The best determination of amount and nature of carbohydrates, fat and protein are suggested. Special attention is given to glutamine and omega-3 fatty acids. Particular conditions frequently observed in intensive care such as patients with dysphagia, frail patients, multiple trauma patients, abdominal surgery, sepsis, and obesity are discussed to guide the practitioner toward the best evidence based therapy. Monitoring of this nutritional therapy is discussed in a separate document.

Mitochondrial dysfunction is regarded as one key factor involved in the pathogenesis of septic disorders, leading to a decline in energy supply. The influence of short- and medium-chain fatty acids (SCFA/MCFA) on mitochondrial respiration under inflammatory conditions has thus far not been investigated. In the following protocol, we describe the assessment of mitochondrial respiration using high-resolution respirometry under inflammatory and baseline conditions. For this approach, human endothelial cells and monocytes were pretreated with TNF-α to mimic inflammation followed by incubation with SCFA/MCFA and then subjected to high-resolution respirometry. Mitochondrial DNA content was assessed by PCR.

Chronic Lung Allograft Dysfunction (CLAD) is a life-threatening complication that limits the long-term survival of lung transplantation patients. Early diagnosis remains the basis of efficient management of CLAD, making the need for distinctive biomarkers critical. This explorative study aimed to investigate the predictive power of mitochondrial DNA (mtDNA) derived from bronchoalveolar lavages (BAL) to detect CLAD. The study included 106 lung transplant recipients and analyzed 286 BAL samples for cell count, cell differentiation, and inflammatory and mitochondrial biomarkers, including mtDNA. A receiver operating curve analysis of mtDNA levels was used to assess its ability to detect CLAD. The results revealed a discriminatory pro-inflammatory cytokine profile in the BAL fluid of CLAD patients. The concentration of mtDNA increased in step with each CLAD stage, reaching its highest concentration in stage 4, and correlated significantly with decreasing FEV1. The receiver operating curve analysis of mtDNA in BAL revealed a moderate prediction of CLAD when all stages were grouped together (AUROC 0.75, p-value < 0.0001). This study has found the concentration mtDNA in BAL to be a potential predictor for the early detection of CLAD and the differentiation of different CLAD stages, independent of the underlying pathology.

Background Immunosuppression including high-dose calcineurin inhibitors (CNI) is essential after lung transplantation. Dosing is usually guided by therapeutic drug monitoring adjusted to target trough levels of CNIs to keep the balance between over-dose causing severe toxicity and increased risk of infections or under-dose with a risk of graft injury. Adaptation of CNI-based immunosuppression by monitoring of torque teno virus (TTV), a latent nonpathogenic DNA virus, measured in the whole blood in addition to conventional therapeutic drug monitoring may reduce the toxicity of immunosuppression with similar efficacy. Methods/design An open-label, randomized, controlled, parallel-group, multicenter trial in lung transplant recipients will be conducted to investigate the safety and efficacy of immunosuppression guided by TTV monitoring as an add-on to conventional therapeutic drug monitoring. Adult lung transplant recipients 21 to 42 days after transplantation are eligible to participate. Patients (N = 144) will be randomized 1:1 to the experimental intervention (arm 1: immunosuppression guided by TTV monitoring in addition to conventional therapeutic drug monitoring of tacrolimus trough levels) and control intervention (arm 2: conventional therapeutic drug monitoring). Outcomes will be assessed 12 months after randomization with the change in glomerular filtration rate as the primary endpoint. Secondary endpoints will be additional measurements of renal function, allograft function, incidence of acute rejections, incidence of chronic lung allograft dysfunction, graft loss, and infections. Discussion The results of this randomized controlled trial may reduce the toxicity of immunosuppression after lung transplantation while maintaining the efficacy of immunosuppression. Study results are transferable to all other solid organ transplantations. Trial registration ClinicalTrials.gov NCT04198506. Registered on 12 December 2019

Mitochondrial dysfunction is regarded as one key factor involved in the pathogenesis of septic disorders, leading to a decline in energy supply. The influence of short- and medium-chain fatty acids (SCFA/MCFA) on mitochondrial respiration under inflammatory conditions has thus far not been investigated. In the following protocol, we describe the assessment of mitochondrial respiration using high-resolution respirometry under inflammatory and baseline conditions. For this approach, human endothelial cells and monocytes were pretreated with TNF-α to mimic inflammation followed by incubation with SCFA/MCFA and then subjected to high-resolution respirometry. Mitochondrial DNA content was assessed by PCR.

Background:Immunosuppression including high dose calcineurin-inhibitors (CNI) is essential after lung transplantation. Dosing is usually guided by therapeutic drug monitoring adjusted to target trough levels of CNIs to keep the balance between over-dose causing severe toxicity and increased risk of infections or under-dose with risk of graft-injury.Adaptation of CNI-based immunosuppression by monitoring of Torque-Teno-Virus (TTV) – a latent nonpathogenic DNA virus, measured in whole blood in addition to conventional therapeutic drug monitoring may reduce toxicity of immunosuppression with similar efficacy.Methods/Design:An open-label, randomized, controlled, parallel-group, multicenter trial in lung transplant recipients will be conducted to investigate the safety and efficacy of immunosuppression guided by TTV monitoring as add-on to conventional therapeutic drug monitoring. Adult lung transplant recipients 21 - 42 days after transplantation are eligible to participate. Patients (N = 144) will be randomized 1:1 to the experimental intervention (Arm 1: Immunosuppression guided by TTV monitoring in addition to conventional therapeutic drug monitoring of tacrolimus trough levels) and control intervention (Arm 2: conventional therapeutic drug monitoring). Outcomes will be assessed 12 months after randomization with the change in glomerular filtration rate as the primary endpoint. Secondary endpoints will be additional measurements on renal function, allograft function, incidence of acute rejections, incidence of chronic lung allograft dysfunction, graft loss and infections.Discussion:The results of this randomized controlled trial may reduce toxicity of immunosuppression after lung transplantation while maintaining efficacy of immunosuppression. Study results are transferable to all other solid organ transplantations.Trial registration: ClinicalTrials.gov, NCT04198506. Registered 12 December 2019, https://www.clinicaltrials.gov/show/NCT04198506

Background: Prolonged immunosuppression and hypoinflammation, termed compensatory anti-inflammatory response syndrome (CARS), contribute to high morbidity and mortality in the late phase of sepsis. Although apoptosis is a well-known cause of lymphopenia in sepsis, the contribution of thymic output to immune alterations in sepsis and potential compensatory mechanisms are largely unknown. Methods: We investigate the release of CD4+ T cells from the thymus and their peripheral proliferation by evaluating T-cell receptor excision circles (TREC) and the expression of CD31 as markers for recent thymic emigrants (RTE) and their proliferative offspring in septic patients with relevant lymphopenia in the CARS phase. Moreover, we determine the aging of T cells by measuring telomere characteristics. Results: In septic patients, we found decreased CD4+ T-helper cell numbers, while CD8+ T cell numbers were unchanged. As a possible cause, we detected increased apoptosis of CD4+ T-helper cells and decreased levels of IL-7, which promotes the maturation of T cells in the thymus. Accordingly, the relative number of mature CD4+ T cells, TREC-containing CD4+ T cells, and CD31+ RTEs (characteristic of thymic output) was decreased, while the relative number of CD31-T cells (peripherally expanded naïve T cells) was increased. Furthermore, the telomere length decreased, although telomerase activity and markers for the shelterin complex were increased specifically in CD4+ but not in CD8+ T cells. Conclusion: We thus conclude that, in addition to T-cell apoptosis, decreased thymic output and increased aging of CD4+ T cells may contribute to lymphopenia and immunosuppression in sepsis. Increased proliferation of peripheral T cells cannot compensate for these effects.

Background: Acute respiratory distress syndrome (ARDS) is associated with both high morbidity and mortality in intensive care units worldwide. Patients with ARDS often require parenteral nutrition with lipid emulsions as essential components. In the present study, we assessed the immunomodulatory and apoptotic effects of a modern, n-6-reduced lipid emulsion mixture in murine ARDS. Methods: Mice received an infusion of either normal saline solution, pure long-chain triglyceride (LCT) emulsion, or SMOF (soybean oil, medium-chain triglycerides, olive oil, and fish oil) before a lipopolysaccharide (LPS) challenge. Mice were sacrificed at different time points (0, 24, or 72 h) after ARDS induction, and an analysis of inflammatory cytokines, protein concentrations, and the cellular composition of the alveolar and interstitial compartments was performed with special focus on alveolar apoptosis and necrosis. Results: Mice infused with SMOF showed decreased leukocyte invasion, protein leakage, myeloperoxidase activity, and cytokine production in alveolar spaces after LPS challenge compared to animals that received LCT. There were fewer cells in the lung interstitium of the SMOF group compared to the LCT group. Both lipid emulsions exerted pro-apoptotic and pro-necrotic properties on alveolar immune cells, with significantly increased necrosis in mice infused with LCT compared to SMOF. Conclusion: SMOF has both anti-inflammatory and pro-resolving influences in murine ARDS. Partial replacement of n-6 fatty acids with n-3/n-9 fatty acids may therefore benefit critically ill patients at risk for ARDS who require parenteral nutrition.

Severe inflammatory disorders such as sepsis are a major cause of morbidity and mortality worldwide. Mitochondrial dysfunction is regarded as a key feature involved in inflammation pathogenesis. In the present study, we investigated the impact of the omega-3 fatty acid-derived lipid mediator Resolvin E1 (RvE1) on mitochondrial function in experimental pulmonary inflammation. RvE1 was found to exert anti-inflammatory properties in human alveolar epithelial cells during severe inflammation. RvE1 is capable of restoring inflammation-induced mitochondrial dysfunction and the impaired imbalance of mitochondrial fission and fusion. Experimental inhibition of mitochondrial fission with Mdivi-1 in our model is associated with a significantly reduced inflammatory response and improved mitochondrial function. These findings suggest a novel functional mechanism for the beneficial effects of RvE1 in experimental pulmonary inflammatory reactions.

Zusammenfassung Fragestellung Variationen in der klinischen Ernährungstherapie können die Prognose kritisch kranker Patienten beeinflussen. Hier präsentieren wir die Kurzversion der aktualisierten, konsensbasierten S2k-Leitlinie „Klinische Ernährung in der Intensivmedizin“ der Deutschen Gesellschaft für Ernährungsmedizin (DGEM) in Kooperation mit 7 anderen nationalen Fachgesellschaften. Als Zielpopulation der Leitlinie wurden kritisch kranke, erwachsene Patienten, die an mindestens einer akuten, medikamentös und/oder mechanisch unterstützungspflichtigen Organdysfunktion leiden, definiert. Methodik Die früheren Leitlinien der DGEM wurden in Einklang mit den aktuellen Richtlinien der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF) als S2k-Leitlinie aktualisiert. Als Grundlage für die Empfehlungen wurde die Evidenz von randomisiert-kontrollierten Studien, Metaanalysen und Beobachtungsstudien mit angemessener Fallzahl und hoher methodologischer Qualität (bis Mai 2018) sowie aktuell gültige Leitlinien internationaler Fachgesellschaften herangezogen und kommentiert. Die Empfehlungsstärke ist rein sprachlich beschrieben. Jede Empfehlung wurde mittels Delphi-Verfahren abschließend bewertet und konsentiert. Ergebnisse In der vorliegenden Kurzversion werden alle 69 Empfehlungen für essenzielle, praxisrelevante Bestandteile der klinischen Ernährung der Zielpopulation zusammenfassend dargestellt. Ein spezifischer Fokus ist die Adjustierung der Ernährung gemäß den Phasen der kritischen Erkrankung sowie gemäß der individuellen Toleranz gegenüber exogener Substratzufuhr. Unter anderem werden Empfehlungen zur Beurteilung des Ernährungszustandes, zur Indikation für eine klinische Ernährungstherapie, zum Zeitpunkt des Beginns, zum Applikationsweg, zur Menge und Zusammensetzung der Ernährungssubstrate (Makro- und Mikronährstoffe) sowie zu speziellen Aspekten der Ernährung bei adipösen kritisch kranken Patienten und Patienten mit extrakorporalen Unterstützungsverfahren gegeben. Schlussfolgerung Die Kurzversion der Leitlinie gibt eine prägnante Übersicht über alle 69 aktualisierten Handlungsempfehlungen zur enteralen und parenteralen Ernährung erwachsener kritisch kranker Patienten, die an mind. einer akuten, medikamentös und/oder mechanisch unterstützungspflichtigen Organdysfunktion leiden. Die Gültigkeit der Leitlinie beträgt voraussichtlich 5 Jahre (2018 – 2023).

Background The 2018 Lipids in Parenteral Nutrition summit involved a panel of experts in clinical nutrition, lipid metabolism, and pharmacology, to assess the current state of knowledge and develop expert consensus statements regarding the use of intravenous lipid emulsions in various patient populations and clinical settings. The main purpose of the consensus statements is to assist healthcare professionals by providing practical guidance on common clinical questions related to the provision of lipid emulsions as part of parenteral nutrition (PN). Methods The summit was designed to allow interactive discussion and consensus development. The resulting consensus statements represent the collective opinion of the members of the expert panel, which was informed and supported by scientific evidence and clinical experience. Results The current article summarizes the key discussion topics from the summit and provides a set of consensus statements designed to complement existing evidence-based guidelines. Lipid emulsions are a major component of PN, serving as a condensed source of energy and essential fatty acids. In addition, lipids modulate a variety of biologic functions, including inflammatory and immune responses, coagulation, and cell signaling. A growing body of evidence suggests that lipid emulsions containing ω-3 fatty acids from fish oil confer important clinical benefits via suppression of inflammatory mediators and activation of pathways involved in the resolution of inflammation. Conclusions This article provides a set of expert consensus statements to complement formal PN guideline recommendations.

In hospitalized patients, lipid emulsions are an integral part of balanced parenteral nutrition. Traditionally, a single lipid source, soybean oil, has been given to patients and was usually regarded as just a source of energy and to prevent essential fatty-acid deficiency. However, mixtures of different lipid emulsions have now become widely available, including mixtures of soybean oil, medium-chain triglycerides, olive oil, and fish oil. Fish oil is high in the ω-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). There is a growing body of evidence that these ω-3 fatty acids can exert beneficial immunomodulatory, anti-inflammatory, and inflammation-resolution effects across a wide range of patient groups including surgical, cancer, and critically ill patients. At least in part, these effects are realized via potent specialized pro-resolution mediators (SPMs). Moreover, parenteral nutrition including ω-3 fatty acids can result in additional clinical benefits over the use of standard lipid emulsions, such as reductions in infection rates and length of hospital and intensive care unit stay. Clinical and experimental evidence is reviewed regarding lipid emulsion use in a variety of hospitalized patient groups, including surgical, critically ill, sepsis, trauma, and acute pancreatitis patients. Practical aspects of lipid emulsion use in critically ill patients are also considered, such as how to determine and fulfill energy expenditure, how and when to consider parenteral nutrition, duration of infusion, and safety monitoring.

There is currently much interest in understanding the mechanisms of normal and aberrant lung alveolarization, particularly in the context of bronchopulmonary dysplasia, a common complication of preterm birth where alveolarization is impeded. To this end, the parenteral administration of pharmacological agents that modulate biochemical pathways, or facilitate modulation of gene expression in transgenic animals, has facilitated the discovery and validation of mechanisms that direct lung development. Such studies include control interventions, where the solvent vehicle, perhaps containing an inactive form of the agent applied, is administered; thereby providing a well-controlled point of reference for the analysis of the partner experiment. In the present study, the impact of several widely used control interventions in developing C57Bl/6J mouse pups was examined for effects on lung structure and the lung transcriptome. Parenteral administration of scrambled microRNA inhibitors (called antagomiRs) that are used to control in vivo microRNA neutralization studies, impacted lung volume, septal thickness, and the transcriptome of developing mouse lungs; with some effects dependent upon nucleotide sequence. Repeated intraperitoneal isotonic saline injections altered lung volume, with limited impact on the transcriptome. Parenteral administration of the tamoxifen solvent Miglyol accelerated mouse pup growth, and changed the abundance of 73 mRNA transcripts in the lung. Tamoxifen applied in Miglyol-in the absence of Cre recombinase-decreased pup growth, lung volume, and lung alveolarization and changed the abundance of 298 mRNA transcripts in the lung. These data demonstrate that widely used control interventions can directly impact lung alveolarization and the lung transcriptome in studies on lung development. Anat Rec, 302:346-363, 2019. © 2018 Wiley Periodicals, Inc.

Zusammenfassung Fragestellung Die enterale und parenterale Ernährungstherapie kritisch kranker Patienten kann u. a. durch den Zeitpunkt des Beginns, die Wahl des Applikationswegs, die Menge und Zusammensetzung der Makro- und Mikronährstoffzufuhr sowie der Wahl spezieller, immunmodulierender Nährsubstrate variieren. Die Durchführung der Ernährungstherapie nimmt Einfluss auf den klinischen Ausgang dieser Patienten. Ziel der vorliegenden Leitlinie ist es, aktualisierte konsensbasierte Empfehlungen zur klinischen Ernährung kritisch kranker, erwachsener Patienten, die an mindestens einer akuten, medikamentös und/oder mechanisch unterstützungspflichtigen Organdysfunktion leiden, zu geben. Methodik Die früheren Leitlinien der Deutschen Gesellschaft für Ernährungsmedizin (DGEM) wurden in Einklang mit den aktuellen Richtlinien der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF) als S2k-Leitlinie aktualisiert. Entsprechend der S2k-Klassifikation dieser Leitlinie enthalten die dargestellten Empfehlungen keine Angabe von Evidenz- und Empfehlungsgraden, da keine systematische Aufbereitung der Evidenz zugrunde gelegt wurde. Als Grundlage für die Empfehlungen wurden insbesondere die seit Erscheinen der letzten DGEM-Leitlinien Intensivmedizin publizierten randomisiert-kontrollierten Studien und Metaanalysen, Beobachtungsstudien mit angemessener Fallzahl und hoher methodologischer Qualität (bis Mai 2018) sowie aktuell gültige Leitlinien anderer Fachgesellschaften herangezogen und kommentiert. Die Empfehlungsstärke ist rein sprachlich beschrieben. Jede Empfehlung wurde mittels Delphi-Verfahren abschließend bewertet und konsentiert. Ergebnisse Die Leitlinie beschreibt einführend die pathophysiologischen Konsequenzen einer kritischen Erkrankung, welche den Metabolismus und die Ernährbarkeit der Patienten beeinflussen können, ferner die Definitionen unterschiedlicher Erkrankungsphasen im Krankheitsverlauf und sie diskutiert methodologische Aspekte zu ernährungsmedizinischen Studien. In der Folge werden 69 konsentierte Empfehlungen zu wesentlichen, praxisrelevanten Elementen der klinischen Ernährung kritisch kranker Patienten gegeben, darunter die Beurteilung des Ernährungszustands, die Indikation für die klinische Ernährungstherapie, der Beginn und Applikationsweg der Nahrungszufuhr, die Menge und Art der zugeführten Substrate (Makro- und Mikronährstoffe) sowie ernährungstherapeutische Besonderheiten bei adipösen kritisch kranken Patienten und Patienten mit mechanischen Unterstützungssystemen. Schlussfolgerung Mit der Leitlinie werden aktuelle Handlungsempfehlungen zur enteralen und parenteralen Ernährung erwachsener Patienten geben, die an mindestens einer akuten, medikamentös und/oder mechanisch unterstützungspflichtigen Organdysfunktion leiden. Die Gültigkeit der Leitlinie beträgt voraussichtlich 5 Jahre (2018 – 2023).

Inflammatory disorders such as sepsis are a major cause of morbidity and mortality. Mitochondrial dysfunction is considered a key factor in the pathogenesis of severe inflammation. In the present study, we aimed to investigate the impact of arachidonic acid, omega-3 (n-3) fatty acids, and n-3-derived lipid mediators 18R-HEPE and resolvin (Rv) E1 on mitochondrial function in experimental inflammation. The results revealed that, in contrast to n-6 and n-3 fatty acids, both 18R-HEPE and RvE1 possess anti-inflammatory and anti-apoptotic properties. Both mediators are able to restore inflammation-induced mitochondrial dysfunction, which is characterized by a decrease in mitochondrial respiration and membrane potential, as well as an imbalance of mitochondrial fission and fusion. Furthermore, inhibition of mitochondrial fission by Mdivi-1 and Dynasore reduces levels of the pro-inflammatory cytokines IL-6 and IL-8. These results suggest a novel functional mechanism for the beneficial effects of RvE1 in inflammatory reactions.

Trophic functions for macrophages are emerging as key mediators of developmental processes, including bone, vessel, and mammary gland development. Yolk sac-derived macrophages mature in the distal lung shortly after birth. Myeloid-lineage macrophages are recruited to the lung and are activated under pathological conditions. These pathological conditions include bronchopulmonary dysplasia (BPD), a common complication of preterm birth characterized by stunted lung development, where the formation of alveoli is blocked. No study has addressed causal roles for immune cells in lung alveolarization. We employed antibody-based and transgenic death receptor-based depletion approaches to deplete or prevent lung recruitment of immune cell populations in a hyperoxia-based mouse model of BPD. Neither neutrophils nor exudate macrophages (which might include lung interstitial macrophages) contributed to structural perturbations to the lung that were provoked by hyperoxia; however, cells of the Csf1r-expressing monocyte/macrophage lineage were implicated as causal mediators of stunted lung development. We propose that resident alveolar macrophages differentiate into a population of CD45+ CD11c+ SiglecF+ CD11b+ CD68+ MHCII+ cells, which are activated by hyperoxia, and contribute to disturbances to the structural development of the immature lung. This is the first report that causally implicates immune cells in pathological disturbances to postnatal lung organogenesis. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Community-acquired pneumonia (CAP) is a frequent and potentially fatal disorder. Due to the notably high mortality within the first days, the immediate initiation of rational diagnostic pathways and treatment is of tremendous prognostic impact. In this review article, the current German guideline on the diagnosis and therapy of CAP is presented. Special focus is put on structured patient management based on the individual risk for early identification of critically ill patients. In particular, risk assessment directly influences rational diagnostics and adequate therapy. New recommendations concerning preventive strategies are also discussed in this article.

The emergence of microRNA as regulators of organogenesis and tissue differentiation has stimulated interest in the ablation of microRNA expression and function during discrete periods of development. To this end, inducible, conditional modulation of microRNA expression with doxycycline-based tetracycline-controlled transactivator and tamoxifen-based estrogen receptor systems has found widespread use. However, the induction agents and components of genome recombination systems negatively impact pregnancy, parturition, and postnatal development; thereby limiting the use of these technologies between late gestation and the early postnatal period. MicroRNA inhibitor (antimiR) administration also represents a means of neutralizing microRNA function in vitro and in vivo. To date, these studies have used direct (parenteral) administration of antimiRs to experimental animals. As an extension of this approach, an alternative means of regulating microRNA expression and function is described here: the maternal–placental–fetal transmission of antimiRs. When administered to pregnant dams, antimiRs were detected in offspring and resulted in a pronounced and persistent reduction in detectable steady-state free microRNA levels in the heart, kidney, liver, lungs, and brain. This effect was comparable to direct injection of newborn mouse pups with antimiRs, although maternal delivery resulted in fewer off-target effects. Furthermore, depletion of steady-state microRNA levels via the maternal route resulted in concomitant increases in steady-state levels of selected microRNA targets. This novel methodology permits the temporal regulation of microRNA function during late gestation and in neonates, without recourse to conventional approaches that rely on doxycycline and tamoxifen, which may confound studies on developmental processes.

The quantitative assessment of the lung architecture forms the foundation of many studies on lung development and lung diseases, where parameters such as alveoli number, alveolar size, and septal thickness are quantitatively influenced by developmental or pathological processes. Given the pressing need for robust data that describe the lung structure, there is currently much enthusiasm for the development and refinement of methodological approaches for the unbiased assessment of lung structure with improved precision. The advent of stereological methods highlights one such approach. However, design‐based stereology is both expensive and time‐demanding. The objective of this study was to examine whether ‘limited’ stereological analysis, such as the stereological analysis of a single mouse lung lobe, may serve as a surrogate for studies on whole, intact mouse lungs; both in healthy lungs and in diseased lungs, using an experimental animal model of bronchopulmonary dysplasia (BPD). This served the dual‐function of exploring BPD pathobiology, asking whether there are regional (lobar) differences in the responses of developing mouse lungs to oxygen injury, by examining each mouse lung lobe separately in the BPD model. Hyperoxia exposure resulted in decreased alveolar density, alveoli number, and gas‐exchange surface area in all five mouse lung lobes, and increased the arithmetic mean septal thickness in all mouse lung lobes except the lobus cardialis. The data presented here suggest that – in healthy developing mice – a single mouse lung lobe might serve as a surrogate for studies on whole, intact mouse lungs. This is not the case for oxygen‐injured developing mouse lungs, where a single lobe would not be suitable as a surrogate for the whole, intact lung. Furthermore, as the total number of alveoli can only be determined by an analysis of the entire lung, and given regional differences in lung structure, particularly under pathological conditions, the stereological assessment of the whole, intact lung remains desirable.

Die Lungenembolie stellt eine relativ haufige und potenziell todliche Erkrankung dar. Vor dem Hintergrund der hohen klinischen Relevanz sind eine rasche und zielfuhrende Risikostratifizierung, Diagnostik und Therapie von entscheidender Bedeutung. Die aktuelle europaische Leitlinie zur Diagnostik und Therapie der akuten Lungenembolie bietet zu diesem Thema eine wertvolle und praxisnahe Unterstutzung und bildet die Grundlage des vorliegenden Artikels. Besonderer thematischer Schwerpunkt dieser Ubersichtsarbeit soll auf dem Einsatz neuer oraler Antikoagulanzien in der Therapie akuter Lungenembolien liegen.

Lysyl oxidases are credited with pathogenic roles in lung diseases, including cancer, fibrosis, pulmonary hypertension, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). Lysyl oxidases facilitate the covalent intra- and intermolecular cross-linking of collagen and elastin fibers, thereby imparting tensile strength to the extracellular matrix (ECM). Alternative ECM-independent roles have recently been proposed for lysyl oxidases, including regulation of growth factor signaling, chromatin remodeling, and transcriptional regulation, all of which impact cell phenotype. We demonstrate here that three of the five lysyl oxidase family members, Lox, Loxl1, and Loxl2, are highly expressed in primary mouse lung fibroblasts compared with other constituent cell types of the lung. Microarray analyses revealed that small interfering RNA knockdown of Lox, Loxl1, and Loxl2 was associated with apparent changes in the expression of 134, 3,761, and 3,554 genes, respectively, in primary mouse lung fibroblasts. The impact of lysyl oxidase expression on steady-state Mmp3, Mmp9, Eln, Rarres1, Gdf10, Ifnb1, Csf2, and Cxcl9 mRNA levels was validated, which is interesting, since the corresponding gene products are relevant to lung development and BPD, where lysyl oxidases play a functional role. In vivo, the expression of these genes broadly correlated with Lox, Loxl1, and Loxl2 expression in a mouse model of BPD. Furthermore, β-aminopropionitrile (BAPN), a selective lysyl oxidase inhibitor, did not affect the steady-state mRNA levels of lysyl oxidase target genes, in vitro in lung fibroblasts or in vivo in BAPN-treated mice. This study is the first to report that lysyl oxidases broadly influence the cell transcriptome.

OBJECTIVES To reduce the shortage of organs for transplantation by expanding organ selection criteria as a means to increase the pool of potential lung donors. In this study, we sought to investigate the impact of using lungs from very old donors aged >70 years on outcomes after lung transplantation. METHODS Between January 2010 and November 2016, 96 patients with end-stage lung disease underwent lung transplantation in our centres. Lung donors were divided into 3 groups according to age (donor aged

Persistent air leaks (PALs) are regarded as a frequent complication after thoracic surgery resulting in prolonged hospitalization and increased morbidity. Several more or less invasive therapeutic approaches are available for treatment of PAL with varying degrees of success. The endoscopic placement of one-way intrabronchial valves in the segment(s) in which the air leak has been located offers a highly effective and well-tolerated minimal invasive option for patients with PAL.

Postnatal lung maturation generates a large number of small alveoli, with concomitant thinning of alveolar septal walls, generating a large gas exchange surface area but minimizing the distance traversed by the gases. This demand for a large and thin gas exchange surface area is not met in disorders of lung development, such as bronchopulmonary dysplasia (BPD) histopathologically characterized by fewer, larger alveoli and thickened alveolar septal walls. Diseases such as BPD are often modeled in the laboratory mouse to better understand disease pathogenesis or to develop new interventional approaches. To date, there have been no stereology-based longitudinal studies on postnatal mouse lung development that report dynamic changes in alveoli number or alveolar septal wall thickness during lung maturation. To this end, changes in lung structure were quantified over the first 22 mo of postnatal life of C57BL/6J mice. Alveolar density peaked at postnatal day (P)39 and remained unchanged at 9 mo (P274) but was reduced by 22 mo (P669). Alveoli continued to be generated, initially at an accelerated rate between P5 and P14, and at a slower rate thereafter. Between P274 and P669, loss of alveoli was noted, without any reduction in lung volume. A progressive thinning of the alveolar septal wall was noted between P5 and P28. Pronounced sex differences were observed in alveoli number in adult (but not juvenile) mice, when comparing male and female mouse lungs. This sex difference was attributed exclusively to the larger volume of male mouse lungs.

Polymorphonuclear granulocytes (PMN) are activated in inflammatory reactions. Intestinal epithelial cells are relevant for maintaining the intestinal barrier. We examined interactions of PMN and intestinal epithelial cell-like CaCo-2 cells to elucidate their regulation of inflammatory signalling and the impact of cyclooxygenase (COX), nitric oxide (NO) and platelet-activating factor (PAF). Human PMN and CaCo-2 cells, separately and in co-incubation, were stimulated with the calcium ionophore A23187 or with N-Formyl-methionyl-leucyl-phenylalanin (fMLP) that activates PMN only. Human neutrophil elastase (HNE) and respiratory Burst were measured. To evaluate the modulation of inflammatory crosstalk we applied inhibitors of COX (acetyl salicylic acid; ASA), NO-synthase (N-monomethyl-L-arginin; L-NMMA), and the PAF-receptor (WEB2086). Unstimulated, co-incubation of CaCo-2 cells and PMN led to significantly reduced Burst and elevated HNE as compared to PMN. After stimulation with A23187, co-incubation resulted in an inhibition of Burst and HNE. Using fMLP co-incubation failed to modulate Burst but increased HNE. Without stimulation, all three inhibitors abolished the effect of co-incubation on Burst but did not change HNE. ASA partly prevented modulation of Burst L-NMMA and WEB2086 did not change Burst but abolished mitigation of HNE. Without stimulation, co-incubation reduced Burst and elevated HNE. Activation of PMN and CaCo-2 cells by fMLP as compared to A23187 resulted in a completely different pattern of Burst and HNE, possibly due to single vs. dual cell activation. Anti-inflammatory effect of co-incubation might in part be due to due to COX-signalling governing Burst whereas NO- and PAF-dependent signalling seemed to control HNE release.

Background Omega-3 (ω-3) fatty acid (FA)-containing parenteral nutrition (PN) is associated with significant improvements in patient outcomes compared with standard PN regimens without ω-3 FA lipid emulsions. Here, we evaluate the impact of ω-3 FA-containing PN versus standard PN on clinical outcomes and costs in adult intensive care unit (ICU) patients using a meta-analysis and subsequent cost-effectiveness analysis from the perspective of a hospital operating in five European countries (France, Germany, Italy, Spain, UK) and the US. Methods We present a pharmacoeconomic simulation based on a systematic literature review with meta-analysis. Clinical outcomes and costs comparing ω-3 FA-containing PN with standard PN were evaluated in adult ICU patients eligible to receive PN covering at least 70% of their total energy requirements and in the subgroup of critically ill ICU patients (mean ICU stay > 48 h). The meta-analysis with the co-primary outcomes of infection rate and mortality rate was based on randomized controlled trial data retrieved via a systematic literature review; resulting efficacy data were subsequently employed in country-specific cost-effectiveness analyses. Results In adult ICU patients, ω-3 FA-containing PN versus standard PN was associated with significant reductions in the relative risk (RR) of infection (RR 0.62; 95% CI 0.45, 0.86; p = 0.004), hospital length of stay (HLOS) (− 3.05 days; 95% CI − 5.03, − 1.07; p = 0.003) and ICU length of stay (LOS) (− 1.89 days; 95% CI − 3.33, − 0.45; p = 0.01). In critically ill ICU patients, ω-3 FA-containing PN was associated with similar reductions in infection rates (RR 0.65; 95% CI 0.46, 0.94; p = 0.02), HLOS (− 3.98 days; 95% CI − 6.90, − 1.06; p = 0.008) and ICU LOS (− 2.14 days; 95% CI − 3.89, − 0.40; p = 0.02). Overall hospital episode costs were reduced in all six countries using ω-3 FA-containing PN compared to standard PN, ranging from €-3156 ± 1404 in Spain to €-9586 ± 4157 in the US. Conclusion These analyses demonstrate that ω-3 FA-containing PN is associated with statistically and clinically significant improvement in patient outcomes. Its use is also predicted to yield cost savings compared to standard PN, rendering ω-3 FA-containing PN an attractive cost-saving alternative across different health care systems. Study registration PROSPERO CRD42019129311.

Human cytomegalovirus (HCMV) infections and reactivations are common after lung transplantation and are associated with the development of bronchiolitis obliterans syndrome. Against this background, temporary HCMV prophylaxis is an established standard regimen after lung transplantation in most centers. However, the optimal duration of prophylaxis is unclear. We conducted a retrospective two-center study to determine the efficacy of indefinite lifelong HCMV prophylaxis with oral valganciclovir in a cohort of 133 lung transplant recipients with a mean follow-up time of approximately 5 years. During the follow-up period, HCMV DNA was detected in 22 recipients (16.5%). In one case, HCMV pneumonitis developed after prophylaxis had been terminated. We observed a beneficial safety profile and tolerability in our cohort, as the majority of patients still received valganciclovir after a 1- and 3-year observation period, respectively. Compared to the literature, these data indicate a beneficial effect of extended valganciclovir prophylaxis with an acceptable safety profile.

Linked content: : This article is related to a Review Article by Abbasoglu et al. (https://onlinelibrary.wiley.com/doi/10.1177/0148607117721907) and a Letter to the Editor by Abbasoglu et al. (https://onlinelibrary.wiley.com/doi/10.1002/jpen.1046)Based upon the ESPEN Workshop “Lipids in the ICU” held in Tel Aviv, Israel, on 23 and 24 November 2014.

This systematic review and meta‐analysis investigated ω‐3 fatty‐acid enriched parenteral nutrition (PN) vs standard (non‐ω‐3 fatty‐acid enriched) PN in adult hospitalized patients (PROSPERO 2018 CRD42018110179). We included 49 randomized controlled trials (RCTs) with intervention and control groups given ω‐3 fatty acids and standard lipid emulsions, respectively, as part of PN covering ≥70% energy provision. The relative risk (RR) of infection (primary outcome; 24 RCTs) was 40% lower with ω‐3 fatty‐acid enriched PN than standard PN (RR 0.60, 95% confidence interval [CI] 0.49‐0.72; P < 0.00001). Patients given ω‐3 fatty‐acid enriched PN had reduced mean length of intensive care unit (ICU) stay (10 RCTs; 1.95 days, 95% CI 0.42‐3.49; P = 0.01) and reduced length of hospital stay (26 RCTs; 2.14 days, 95% CI 1.36‐2.93; P < 0.00001). Risk of sepsis (9 RCTs) was reduced by 56% in those given ω‐3 fatty‐acid enriched PN (RR 0.44, 95% CI 0.28‐0.70; P = 0.0004). Mortality rate (co‐primary outcome; 20 RCTs) showed a nonsignificant 16% reduction (RR 0.84, 95% CI 0.65‐1.07; P = 0.15) for the ω‐3 fatty‐acid enriched group. In summary, ω‐3 fatty‐acid enriched PN is beneficial, reducing risk of infection and sepsis by 40% and 56%, respectively, and length of both ICU and hospital stay by about 2 days. Provision of ω‐3‐enriched lipid emulsions should be preferred over standard lipid emulsions in patients with an indication for PN.

Acute respiratory distress syndrome (ARDS) is still regarded as an enormous medical challenge due to its complexity and poor prognosis. In spite of progress in research and therapy lethality remains unacceptably high. Besides established interventiotnal treatment options, numerous pharmacological approaches have been investigated in the past decades.