Despite its fundamental role in providing an extensive surface for gas exchange, the alveolar epithelium (AE) serves as an immunological barrier through, e.g., the release of proinflammatory cytokines and secretion of surfactant to prevent alveolar collapse. Thus, AE is important for sustaining lung homeostasis. Extracellular ATP secreted by alveolar epithelial cells (AECs) is involved in physiological and pathological conditions and acts mainly through the activation of purine receptors (P2Rs). When studying P2R-mediated processes, primary isolated type II AECs (piAECs) still represent the gold standard in in vitro research, although their preparation is time-consuming and requires the sacrifice of many animals. Hence, cultivated immortalized and tumor-derived AEC lines may constitute a valuable alternative. In this work, we examined P2R expression and functionality in piAECs, in immortalized and tumor-derived AEC lines with the purpose of gaining a better understanding of purinergic signaling in different cell systems and assisting researchers in the choice of a suitable cell line with a certain P2R in demand. We combined mRNA and protein analysis to evaluate the expression of P2R. For pharmacological testing, we conducted calcium ([Ca2+]) measurements and siRNA receptor knockdown. Interestingly, the mRNA and protein levels of P2Y2, P2Y6, and P2X4 were detected on all cell lines. Concerning functionality, P2XR could be narrowed to L2 and piAECs while P2YR were active in all cell lines.

Objectives Perioperative cardiovascular events remain an important factor that affects surgery outcome. We assessed if asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, predicts perioperative risk, and if pre-operative supplementation with L-arginine/L-citrulline improves the plasma L-arginine/ADMA ratio. Methods In this prospective study, planned thoracic and/or abdominal surgery patients were randomized to receive L-arginine/L-citrulline (5 g/day) or placebo 1 to 5 days before surgery. We measured perioperative plasma ADMA and L-arginine levels. The primary outcome was a 30-day combined cardiovascular endpoint. Results Among 269 patients, 23 (8.6%) experienced a major adverse cardiovascular event. ADMA and C-reactive protein were significantly associated with the incidence of cardiovascular complications in the multivariable-adjusted analysis. The L-arginine plasma concentration was significantly higher on the day of surgery with L-arginine/L-citrulline supplementation compared with placebo. In patients with high pre-operative ADMA, there was a non-significant trend towards reduced incidence of the primary endpoint with L-arginine/L-citrulline supplementation (six vs. nine events). Conclusions ADMA is a predictor of major adverse cardiovascular complications in the perioperative period for patients who are undergoing major abdominal and/or thoracic surgery. Supplementation with L-arginine/L-citrulline increased the L-arginine plasma concentration, enhanced the L-arginine/ADMA ratio, and induced a trend towards fewer perioperative events.

Background In acute respiratory distress syndrome (ARDS), pulmonary perfusion failure increases physiologic dead space ventilation (V-D/V-T), leading to a decline of the alveolar CO2 concentration [CO2](iA). Although it has been shown that alveolar hypocapnia contributes to formation of atelectasis and surfactant depletion, a typical complication in ARDS, the underlying mechanism has not been elucidated so far. Methods In isolated perfused rat lungs, cytosolic or mitochondrial Ca2+ concentrations ([Ca2+](cyt) or [Ca2+](mito), respectively) of alveolar epithelial cells (AECs), surfactant secretion and the projected area of alveoli were quantified by real-time fluorescence or bright-field imaging (n=3-7 per group). In ventilated White New Zealand rabbits, the left pulmonary artery was ligated and the size of subpleural alveoli was measured by intravital microscopy (n=4 per group). Surfactant secretion was determined in the bronchoalveolar lavage (BAL) by western blot. Results Low [CO2](iA) decreased [Ca2+](cyt) and increased [Ca2+](mito) in AECs, leading to reduction of Ca2+-dependent surfactant secretion, and alveolar ventilation in situ. Mitochondrial inhibition by ruthenium red or rotenone blocked these responses indicating that mitochondria are key players in CO2 sensing. Furthermore, ligature of the pulmonary artery of rabbits decreased alveolar ventilation, surfactant secretion and lung compliance in vivo. Addition of 5% CO2 to the inspiratory gas inhibited these responses. Conclusions A ccordingly, we provide evidence that alveolar hypocapnia leads to a Ca2+ shift from the cytosol into mitochondria. The subsequent decline of [Ca2+](cyt) reduces surfactant secretion and thus regional ventilation in lung regions with high V-D/V-T. Additionally, the regional hypoventilation provoked by perfusion failure can be inhibited by inspiratory CO2 application.

Background: Older patients are undergoing surgery in increasing numbers. Frailty is a key risk factor associated with higher rates of complications and mortality, longer hospital stays, and functional impairment. Methods: This review is based on pertinent publications retrieved by a selective search in PubMed, including guidelines from Germany and abroad. Results: Many studies have been published on the assessment of frailty and its consequences, but the scientific investigation of this topic and the clinical utility of the findings are made more difficult by the lack of a uniform definition and of uniform instruments for assessment. Some definitions of frailty include only physical aspects, while others encompass cognitive, emotional, and social factors as well. Despite this variability, the assessment of frailty enables better estimation of the perioperative risk so that the patient can be optimally prepared for the operation. Especially for frail elderly patients, an interdisciplinary approach is called for over the entire perioperative treatment period. Conclusion: In the future, the definition of frailty will need to be standardized so that this parameter can be properly assessed and investigated in comparative studies.

Introduction: The focus of public attention and health policy is increasingly being drawn to patient safety. According to studies, more than 30,000 patients die each year as a result of medical errors. To date, learning objectives such as patient safety have not played a role in the core curriculum for medical education in Germany. The National Competence-Based Catalogue of Learning Objectives for Undergraduate Medical Education contains a total of 13 learning objectives relating to this subject. Methods: In a descriptive study, learning content was implemented within the "Operative Medicine" study block offered by the Faculty of Medicine at Universität Hamburg. The definition and occurrence of errors as well as strategies for dealing with and avoiding errors were set as the learning objectives for an interactive lecture, problem-based learning (PBL) case as well as the bedside teaching on anaesthesiology. Students were able to evaluate the lecture directly. During the simulator session on anaesthesia, the safety-relevant information that students requested from patients was compared with the questions asked by a control group in the previous trimester. Results: The topic of patient safety could be integrated into the "Operative Medicine" curriculum through a number of minor changes to classes. The accounts of personal experiences and importance assigned to the subject were considered positive, while content perceived as redundant was criticised. In the simulator, the students appeared to request more comprehensive preoperative safety-relevant information than the control group. Conclusion: The subject's relevance, positive feedback and trend towards a change in behaviour in the simulator lead the authors to deem introduction of the topic of patient safety a success.

INTRODUCTION:Geriatric patients have a pronounced risk to suffer from postoperative complications. While effective risk-specific perioperative measures have been studied in controlled experimental settings, they are rarely found in routine healthcare. This study aims (1) to implement a multicomponent preoperative and intraoperative intervention, and investigate its feasibility, and (2) exploratorily assess the effectiveness of the intervention in routine healthcare.METHODS AND ANALYSIS:Feasibility and exploratory effectiveness of the intervention will be investigated in a monocentric, prospective, non-randomised, controlled trial. The intervention includes systematic information for patients and family about measures to prevent postoperative complications; preoperative screening for frailty, malnutrition, strength and mobility with nutrient supplementation and physical exercise (prehabilitation) as needed. Further components focus on potentially inadequate medication, patient blood-management and carbohydrate loading prior to surgery, retainment of orientation aids in the operating room and a geriatric anaesthesia concept. Data will successively be collected from control, implementation and intervention groups. Patients aged 65+ with impending surgery will be included. A sample size of 240, n=80 per group, is planned. Assessments will take place at inclusion and 2, 30 and 180 days after surgery. Mixed-methods analyses will be performed. Exploratory effectiveness will be assessed using mixed segmented regressions. The primary endpoint is functional status. Secondary endpoints include cognitive performance, health-related quality of life, length of inpatient stay and occurrence of postoperative complications. Feasibility will be assessed through semi-structured interviews with staff and patients and quantitative analyses of the data quality, focussing on practicability, acceptance, adoption and fidelity to protocol.ETHICS AND DISSEMINATION:The study will be carried out in accordance with the Helsinki Declaration and to principles of good scientific practice. The Ethics Committee of the Medical Association Hamburg, Germany, approved the protocol (study ID: PV5596). Results will be disseminated in scientific journals and healthcare conferences.TRIAL REGISTRATION NUMBER:ClinicalTrials.gov Identifier: NCT03325413.

Delayed cerebral ischemia (DCI) is the major cause of lethality and neuronal damage in patients who survived the primary subarachnoid hemorrhage (SAH). Asymmetric and symmetric dimethylarginines (ADMA and SDMA) inhibit nitric oxide production from l-arginine via distinct mechanisms. Elevated ADMA levels are associated with vasospasm after SAH. We aimed to study the time course of ADMA and SDMA in plasma and ventricular cerebrospinal fluid (CSF) and their associations with DCI and outcome.

AIM:Sepsis is a serious complication following surgery and identification of patients at risk is of high importance. Syndecan-1 (sSDC1) levels are known to be elevated during sepsis.MATERIALS & METHODS:Fifty-five patients scheduled for major abdominal surgery were prospectively included and sSDC1 concentrations were measured during hospital stay.RESULTS:Patients with postoperative sepsis showed a continued increase of sSDC1 levels and exhibited higher median sSDC1 concentrations at day 1 compared with nonseptic patients 90.3 versus 16.5 ng/ml. A significant association of sSDC1 levels with the incidence of sepsis and death was demonstrated.CONCLUSION:This study identifies sSDC1 as potential biomarker for sepsis and survival after abdominal surgery.

The problem of high rates of false alarms in patient monitoring in anesthesiology and intensive care medicine is well known but remains unsolved. False alarms desensitize the medical staff, leading to ignored true alarms and reduced quality of patient care. A database of intra-operative monitoring data was analyzed to find characteristic alarm patterns. The original data were re-evaluated to find relevant events and to rate the severity of these events. Based on this analysis an adaptive time delay was developed that individually delays the alarms depending on the grade of threshold deviation. The conventional threshold algorithm led to 4893 alarms. 3515 (71.84 %) of these alarms were annotated as clinically irrelevant. In total 81.0 % of all clinically irrelevant alarms were caused by only mild and/or brief threshold violations. We implemented the new algorithm for selected parameters. These parameters equipped with adaptive validation delays led to 1729 alarms. 931 (53.85 %) alarms were annotated as clinically irrelevant. 632 alarms indicated the 645 clinically relevant events. The positive predictive value of occurring alarms improved from 28.16 % (conventional algorithm) to 46.15 % (new algorithm). 13 events were missed. The false positive alarm reduction rate of the algorithm ranged from 33 to 86.75 %. The overall reduction was 73.51 %. The implementation of this algorithm may be able to suppress a large percentage of false alarms. The effect of this approach has not been demonstrated but shows promise for reducing alarm fatigue. Its safety needs to be proven in a prospective study.

In adult respiratory distress syndrome (ARDS) pulmonary perfusion failure increases physiologic dead-space (VD/VT) correlating with mortality. High VD/VT results in alveolar hypocapnia, which has been demonstrated to cause edema formation, atelectasis, and surfactant depletion, evoked, at least in part, by apoptosis of alveolar epithelial cells (AEC). However, the mechanism underlying the hypocapnia-induced AEC apoptosis is unknown. Here, using fluorescent live-cell imaging of cultured AEC type 2 we could show that in terms of CO2 sensing the tricarboxylic acid cycle enzyme isocitrate dehydrogenase (IDH) 3 seems to be an important player because hypocapnia resulted independently from pH in an elevation of IDH3 activity and subsequently in an increase of NADH, the substrate of the respiratory chain. As a consequence, the mitochondrial transmembrane potential (ΔΨ) rose causing a Ca2+ shift from cytosol into mitochondria, whereas the IDH3 knockdown inhibited these responses. Furthermore, the hypocapnia-induced mitochondrial Ca2+ uptake resulted in reactive oxygen species (ROS) production, and both the mitochondrial Ca2+ uptake and ROS production induced apoptosis. Accordingly, we provide evidence that in AEC type 2 hypocapnia induces elevation of IDH3 activity leading to apoptosis. This finding might give new insight into the pathogenesis of ARDS and may help to develop novel strategies to reduce tissue injury in ARDS.

The effects of inhaled and intravenous application of a guanylate cyclase stimulator (BAY 41-8543) on pulmonary vascular resistance (PVR) and cardiac output (CO) were investigated in an experimental model of septic shock. Following induction of septic shock, anaesthetized pigs (n=31) were randomly place into two groups receiving different interventions. Animals in the first group received intravenous BAY 41-8543 (0.6 mg), inhalative BAY 41-8543 (6 mg) or a placebo. In the second group, the dosage of BAY 41-8543 was increased two-fold or combined with inhalation of nitric oxide (iNO). Intravenous and inhaled administration of BAY 41-8543 resulted in a significantly (P<0.05) reduced PVR and increased CO compared with the placebo. Increasing the dosage of BAY 41-8543 or combining it with iNO did not further decrease PVR. The results of the present study indicate that BAY 41-8543 effectively reduces PVR and increases CO in septic shock, through inhaled or intravenous routes of administration.

Nitric oxide (NO) regulates processes involved in sepsis progression, including vascular function and pathogen defense. Direct NO measurement in patients is unfeasible because of its short half-life. Surrogate markers for NO bioavailability are substrates of NO generating synthase (NOS): L-arginine (lArg) and homoarginine (hArg) together with the inhibitory competitive substrate asymmetric dimethylarginine (ADMA). In immune cells ADMA is cleaved by dimethylarginine-dimethylaminohydrolase-2 (DDAH2). The aim of this study was to investigate whether concentrations of surrogate markers for NO bioavailability are associated with sepsis severity.

Bariatric surgery has proven a successful approach in the treatment of morbid obesity and its concomitant diseases such as diabetes mellitus and arterial hypertension. Aiming for optimal management of this challenging patient cohort, tailored concepts directly guided by individual patient physiology may outperform standardized care. Implying esophageal pressure measurement and electrical impedance tomography—increasingly applied monitoring approaches to individually adjust mechanical ventilation in challenging circumstances like acute respiratory distress syndrome (ARDS) and intraabdominal hypertension—we compared our institutions standard ventilator regimen with an individually adjusted positive end expiratory pressure (PEEP) level aiming for a positive transpulmonary pressure (P L) throughout the respiratory cycle.

ZusammenfassungHintergrund und Fragestellung | Das hepatorenale Syndrom (HRS) ist eine schwere, potenziell reversible Komplikation bei Patienten mit Leberzirrhose. Unbehandelt ist die Prognose sehr schlecht. Fur eine Behandlung mit Terlipressin in Kombination mit Humanalbumin wurde in mehreren randomisiert-kontrollierten Studien eine Verbesserung der Nierenfunktion demonstriert, der Einfluss dieser Therapie auf die Gesamtprognose bleibt allerdings unklar. Im Rahmen der vorliegenden Observations-Studie sollte der Effekt einer Terlipressin-Behandlung bei HRS auf Nierenfunktion, Gesamtuberleben sowie dialyse- und transplantationsfreiem uberleben untersucht werden.Patienten und Methodik | uber einen Zeitraum von 12 Monaten wurden in unserem Zentrum alle Patienten mit HRS und Terlipressin-Therapie prospektiv erfasst. Klinisch relevante Parameter, Therapiecharakteristika, Ansprechen, Gesamtuberleben, Dialyseeinleitung und Lebertransplantation (LTx) wurden ausgewertet.Ergebnisse | Insgesamt wurden 57 Patienten uber einen medianen Zeitraum von 65 Tagen prospektiv beobachtet. Bei der Mehrzahl der Patienten lag ein fortgeschrittenes Zirrhose-Stadium vor (Child-Pugh C: 46; 81%). Die kumulative Terlipressin-Dosis bzw. -Behandlungsdauer betrug im Median 20mg bzw. 5 Tage. Ein komplettes oder partielles Ansprechen auf Terlipressin im Sinne einer HRS-Ruckbildung wurde in 29 bzw. 3 von 57 Patienten beobachtet (51%; 5%). Patienten mit Terlipressin-Ansprechen zeigten mit einem medianen Gesamtuberleben von 167 vs. 27 Tagen bzw. einem dialyse- und LTx-freiem uberleben von 81 vs. 4 Tagen eine signifikant bessere Gesamtprognose als Patienten mit Nicht-Ansprechen. In einer uni- und multivariaten Analyse war eine hohe Ausgangs-Serum-Bilirubin-Konzentration mit dem Nicht-Ansprechen assoziiert.Folgerung | Terlipressin in Kombination mit Humanalbumin ist eine effektive Therapie beim HRS. Das Terlipressin-Ansprechen ist dabei mit einem signifikanten uberlebensvorteil assoziiert.AbstractBackground and aim | Hepatorenal syndrome (HRS) is a severe but potentially reversible complication in patients with cirrhosis. Untreated it is associated with a poor prognosis. Several randomized controlled trials (RCT) demonstrated that treatment with terlipressin and albumin improves renal function. However the effect on overall survival is unclear. Aim of the study was to gain further insight into the effect of terlipressin treatment in patients with HRS on renal function, overall survival and survival without liver transplantation or renal replacementMethods | All patients presenting with HRS and treated with terlipressin in our tertiary referral liver and transplantation center between April 2013 and April 2014 were included. Clinically relevant parameters such as response to therapy, overall survival and transplant- and renal-replacement-free-survival were prospectively investigated.Results | Overall 57 patients were prospectively followed over a median of 65 days. In the majority of patients cirrhosis was in an advanced stage (Child-Pugh C: 46; 81%). Median cumulative terlipressin dosage and treatment duration were 20mg and 5 days, respectively. Complete or partial response to terlipressin with recovery from HRS was observed in 20 and 3 out of 57 patients (51%; 5%). Median overall survival was significantly better in patients with response to terlipressin than in patients with non-response (167 vs. 27 days; p>0.0001), as well as median survival free of liver transplantation and renal-replacement-therapy (81 vs. 4 days; p>0.0001). In uni- and multivariate analysis, non-response was associated with a high baseline serum-bilirubin-concentration.Conclusion | Terlipressin in combination with albumin is effective in the majority of patients with HRS. Response to therapy is associated with improved survival.