Decreased protein binding of moxifloxacin in patients with sepsis?

The mean (SD) unbound fraction of moxifloxacin in plasma from patients with severe sepsis or septic shock was determined by ultrafiltration to 85.5±3.0% (range 81.9 and 91.6%) indicating a decreased protein binding of moxifloxacin in this population compared with the value of 58–60% provided in the Summary of Product Characteristics. However, previous investigations neglected the influence of pH and temperature on the protein binding of moxifloxacin. Maintaining physiological conditions (pH 7.4, 37°C) – as in the present study – the unbound fraction of moxifloxacin in plasma from healthy volunteers was 84%. In contrast, the unbound fraction of moxifloxacin was 77% at 4°C and 66–68% in unbuffered plasma or at pH 8.5 in fair agreement with previously published data. PK/PD parameters e.g. fAUC/MIC or ratios between interstitial fluid and free plasma concentrations, which were obtained assuming a protein binding rate of moxifloxacin of 40% or more, should be revised

Effizienz des "Anaesthetic conserving device" (AnaConDa®\circledR)

Desfluran hat sehr kurze An- und Abflutzeiten mit geringer Metabolisierung. Für inhalative Sedierung auf Intensivstationen ist es daher hochinteressant. Ziel dieser Arbeit ist die Untersuchung der Eigenschaften des "Anaesthetic conserving device" (AnaConDa$\circledR$) (ACD) bei Verwendung mit Desfluran. Dazu wurde in zwei Versuchsteilen die Effizienz des Reflektors des ACD in einem Modellversuch bestimmt. Bei Verwendung des ACD mit Desfluran zeigt sich eine vergleichbare Effizienz im Bezug auf Isofluran und Sevofluran. Einige Applikationsschwierigkeiten verbieten jedoch zum aktuellen Zeitpunkt eine klinische Anwendung

The aquaporin 5 -1364A/C promoter polymorphism impacts on resolution of acute kidney injury in pneumonia evoked ARDS.

BackgroundAquaporin 5 (AQP5) expression impacts on cellular water transport, renal function but also on key mechanisms of inflammation and immune cell migration that prevail in sepsis and ARDS. Thus, the functionally relevant AQP5 -1364A/C promoter single nucleotide polymorphism could impact on the development and resolution of acute kidney injury (AKI). Accordingly, we tested the hypothesis that the AQP5 promoter -1364A/C polymorphism is associated with AKI in patients suffering from pneumonia evoked ARDS.MethodsThis prospective study included 136 adult patients of Caucasian ethnicity with bacterially evoked pneumonia resulting in ARDS. Blood sampling was performed within 24 hours of ICU admission and patients were genotyped for the AQP5 promoter -1364A/C single nucleotide polymorphism. The development of an AKI and the cumulative net fluid balance was described over a 30-day observation period and compared between the AA and AC/CC genotypes, and between survivors and non-survivors.ResultsIncidence of an AKI upon admission did not differ in AA (58%) and AC/CC genotype carriers (60%; p = 0.791). However, on day 30, homozygous AA genotypes (57%) showed an increased prevalence of AKI compared to AC/CC genotypes (24%; p = 0.001). Furthermore, the AA genotype proved to be a strong, independent risk factor for predicting AKI persistence (odds-ratio: 3.35; 95%-CI: 1.2-9.0; p = 0.017). While a negative cumulative fluid balance was associated with increased survival (p = 0.001) the AQP5 promoter polymorphism had no impact on net fluid balance (p = 0.96).ConclusionsIn pneumonia evoked ARDS, the AA genotype of the AQP5 promoter polymorphism is associated with a decreased recovery rate from AKI and this is independent of fluid balance. Consequently, the role of AQP5 in influencing AKI likely rests in factors other than fluid balance

Major Adverse Kidney Events Are Associated with the Aquaporin 5 -1364A/C Promoter Polymorphism in Sepsis: A Prospective Validation Study

Since the functionally important AQP5 -1364A/C single nucleotide promoter polymorphism alters key mechanisms of inflammation and survival in sepsis, it may affect the risk of an acute kidney injury. Accordingly, we tested the hypothesis in septic patients that this AQP5 polymorphism is associated with major adverse kidney events and also validated its impact on 90-day survival. In this prospective observational monocentric genetic association study 282 septic patients were included and genotyped for the AQP5 –1364A/C polymorphism (rs3759129). The primary endpoint was the development of major adverse kidney events within 30 days. In AC/CC genotypes, major adverse kidney events were less frequent (41.7%) than in AA genotypes (74.3%; OR:0.34; 95%-CI: 0.18–0.62; p < 0.001). Ninety-day survival was also associated with the AQP5 polymorphism (p = 0.004), with 94/167 deaths (56.3%) in AA genotypes, but only 46/115 deaths (40.0%) in C-allele carriers. Multiple proportional hazard analysis revealed AC/CC genotypes to be at significantly lower risk for death within 90 days (HR: 0.60; 95%-CI: 0.42-0.86; p = 0.006). These findings confirm the important role of the AQP5 -1364A/C polymorphism as an independent prognostic factor in sepsis. Furthermore, we demonstrate a strong association between this AQP5 polymorphism and susceptibility for major adverse kidney events suggesting a promising characteristic in terms of precision medicine

Proximale osteosynthetisch versorgte Femurfrakturen: der Versorgungszeitpunkt verzögert sich bei vorbestehender Antikoagulation

$\textbf {Hintergrund und Fragestellung}$ Proximale Femurfrakturen stellen mit ca. 100.000 Betroffenen/Jahr in Deutschland ein häufiges Krankheitsbild dar. Durch eine zeitnahe Versorgung (<24 h) konnte die Mortalität erheblich gesenkt werden. Ziele der Arbeit waren, die Prävalenz der Antikoagulation und hiermit assoziierte Komplikationen bei osteosynthetisch versorgter, proximaler Femurfraktur und deren Impact auf die präoperative Verweildauer zu analysieren und Potenziale zum optimalen perioperativen Gerinnungsmanagements aufzuzeigen. $\textbf {Material und Methoden}$ Die Daten der externen vergleichenden Qualitätssicherung Nordrhein-Westfalen für die Jahre 2015 und 2016 wurden ausgewertet. Dabei wurden ausschließlich Fälle analysiert, bei denen eine hüftgelenknahe Femurfraktur osteosynthetisch versorgt wurde. Insgesamt wurden 24.786 Fälle hüftgelenknaher Femurfrakturen in die Studie eingeschlossen. $\bf Ergebnisse$ Von den Patienten mit einer antithrombotischen Dauertherapie (ATDT) wurden in der größten Subgruppe mit ASS-Medikation ($\it n$ = 4005) 17 %, in der zweitgrößten Gruppe mit Vitamin-K-Antagonisten-Einnahme ($\it n$ = 2157) 44,6 % und in der drittgrößten Gruppe mit Einnahme von direkten oralen Antikoagulanzien (DOAKs, $\it n$ = 994) 18,2 % verzögert operiert. $\bf Schlussfolgerungen$ Das größte Potenzial zur Verkürzung der präoperativen Verweildauer ergibt sich in der Gruppe der Patienten, die ASS (17 % auffällig) oder einen Vitamin-K-Antagonisten (VKA, 44,6 % auffällig) einnehmen. Eine Antagonisierung der Wirkung von VKA lässt sich innerhalb kurzer Zeit durch die Gabe von Prothrombinkomplex (PPSB) erreichen. Auch unter der Einnahme von DOAKs muss das noch gängige Prozedere einer verzögerten operativen Versorgung kritisch hinterfragt werden. Die Etablierung eines Gerinnungsmanagements ist zu fordern. Neben der medizinischen Intervention (Gabe von Antidota) müssen Strukturen geschaffen werden, die eine zeitnahe Versorgung ermöglichen.$\textbf {Background and objective}$ Proximal femoral fractures are common in Germany with approximately 100,000 affected patients per year. The mortality could be considerably reduced by timely treatment (<24 h). The objectives of this work were to demonstrate the prevalence of anticoagulation and associated complications in osteosynthetically treated proximal femoral fractures, the impact of anticoagulation on the preoperative period and potential optimization of perioperative anticoagulation management. $\textbf {Material and methods}$ External quality control data for North Rhine-Westphalia for the years 2015–2016 were evaluated. Only cases in which a femoral fracture near the hip joint was treated osteosynthetically were analyzed. A total of 24,786 cases of femoral fractures near the hip joint were included in the study. $\bf Results$ In the largest subgroup with acetylsalicylic acid (ASS) medication (n = 4005) 17% underwent delayed surgery, in the second largest group with vitamin K antagonists (VKA, n = 2157) 44.6% underwent delayed surgery and in the third largest group with direct oral anticoagulant (DOACs) medication (n = 994) 18.2% underwent delayed surgery. $\bf Conclusion$ The biggest potential of shortening the preoperative period can be found in the ASS and vitamin K antagonist subgroups (17% and 44.6% delayed surgery, respectively). The antagonization of the effect of VKA can be achieved within a short time by the administration of prothrombin complex (PPSB). Even when taking DOACs, the current common procedure of delayed surgical treatment must be critically questioned. A coagulation management should be established in the SOP. In addition to medical interventions (administration of antidotes), structures must be created that enable prompt care

Long-term mortality and outcome in hospital survivors of septic shock, sepsis, and severe infections: The importance of aftercare.

Patients with severe infections and especially sepsis have a high in-hospital mortality, but even hospital survivors face long-term sequelae, decreased health-related quality of life, and high risk of death, suggesting a great need for specialized aftercare. However, data regarding a potential benefit of post-discharge rehabilitation in these patients are scarce. In this retrospective matched cohort study the claim data of a large German statutory health care insurer was analyzed. 83,974 hospital survivors having suffered from septic shock, sepsis, and severe infections within the years 2009-2016 were identified using an ICD abstraction strategy closely matched to the current Sepsis-3 definition. Cases were analyzed and compared with their matched pairs to determine their 5-year mortality and the impact of post-discharge rehabilitation. Five years after hospital discharge, mortality of initial hospital survivors were still increased after septic shock (HRadj 2.03, 95%-CI 1.87 to 2.19; P<0.001), sepsis (HRadj 1.73, 95%-CI 1.71 to 1.76; P<0.001), and also in survivors of severe infections without organ dysfunction (HRadj 1.70, 95%-CI 1.65 to 1.74; P<0.001) compared to matched controls without infectious diseases. Strikingly, patients treated in rehabilitation facilities showed a significantly improved 5-year survival after suffering from sepsis or septic shock (HRadj 0.81, 95%-CI 0.77 to 0.85; P<0.001) as well as severe infections without organ dysfunction (HRadj 0.81, 95%-CI 0.73 to 0.90; P<0.001) compared to matched patients discharged to home or self-care. Long-term mortality and morbidity of hospital survivors are markedly increased after septic shock, sepsis and severe infections without organ dysfunction, but best 5-year survival was recorded in patients discharged to a rehabilitation facility in all three groups. Thus, our data suggest that specialized aftercare programs may help to improve long-term outcome in these patients and warrants more vigilance in future investigations

Repeated determination of moxifloxacin concentrations in interstitial space fluid of muscle and subcutis in septic patients

Background: For an effective antimicrobial treatment, it is crucial that antibiotics reach sufficient concentrations in plasma and tissue. Currently no data exist regarding moxifloxacin plasma concentrations and exposure levels in tissue under septic conditions. Objectives: To determine the pharmacokinetics of moxifloxacin in plasma and interstitial space fluid over a prolonged period. Patients and methods: Ten septic patients were treated with 400 mg of moxifloxacin once a day; on days 1, 3 and 5 of treatment plasma sampling and microdialysis in the subcutis and muscle of the upper thigh were performed to determine concentrations of moxifloxacin in different compartments. This trial was registered in the German Clinical Trials Register (DRKS, register number DRKS00012985). Results: Mean unbound fraction of moxifloxacin in plasma was 85.5 +/- 3.4%. On day 1, C-max in subcutis and muscle was 2.8 +/- 1.8 and 2.5 +/- 1.3 mg/L, respectively, AUC was 24.8 +/- 15.1 and 21.3 +/- 10.5 mgh/L, respectively, and fAUC(0-24)/MIC was 100.9 +/- 62.9 and 86.5 +/- 38.3 h, respectively. C-max for unbound moxifloxacin in plasma was 3.5 +/- 0.9 mg/L, AUC was 23.5 +/- 7.5 mg.h/L and fAUC(0-24)/MIC was 91.6 +/- 24.8 h. Key pharmacokinetic parameters on days 3 and 5 showed no significant differences. Clearance was higher than in healthy adults, but tissue concentrations were comparable, most likely due to a lower protein binding. Conclusions: Surprisingly, the first dose already achieved exposure comparable to steady-state conditions. The approved daily dose of 400 mg was adequate in our patient population. Thus, it seems that in septic patients a loading dose on the first day of treatment with moxifloxacin is not required

LPS-Induced Endotoxemia Evokes Epigenetic Alterations in Mitochondrial DNA That Impacts Inflammatory Response

Mitochondrial DNA (mtDNA) plays a vital role as a damage-associated molecular pattern in sepsis being able to shape the immune response. Since pathogen recognition receptors of innate immune cells are activated by demethylated DNA only, we set out to investigate the amount of DNA methyltransferase 1 (DNMT1) in mitochondria and the extent of mtDNA methylation in a human endotoxin model. Peripheral blood mononuclear cells of 20 healthy individuals were isolated from whole blood and stimulated with lipopolysaccharide (LPS) for 48 h. Subsequently, DNMT1 protein abundance was assessed in whole cells and a mitochondrial fraction. At the same time, methylation levels of mtDNA were quantified, and cytokine expression in the supernatant was measured. Despite increased cellular expression of DNMT1 after LPS stimulation, the degree of mtDNA methylation slightly decreased. Strikingly the mitochondrial protein abundance of DNMT1 was reduced by 50% in line with the lower degree of mtDNA methylation. Although only modest alterations were seen in the degree of mtDNA methylation, these strongly correlated with IL-6 and IL-10 expression. Our data may hint at a protein import problem for DNMT1 into the mitochondria under LPS stimulation and suggest a role of demethylated mtDNA in the regulation of the inflammatory immune response

Evaluation of inhaled salbutamol effectiveness under supportive use of electrical impedance tomography in ventilated ICU patients

$\bf Introduction$ The inhalative administration of drugs is a non-invasive application form that is regularly used in the treatment of ventilated patients in critical care setting. However, assessment of effectiveness or distribution of nebulised drugs is one of the lacking cornerstones of modern intensive care monitoring. Electrical impedance tomography (EIT) may provide a promising new monitoring and guiding tool for an adequate optimisation of mechanical ventilation in critically ill patients. EIT may assist in defining mechanical ventilation settings, assess distribution of tidal volume and evaluate associated pathologies at bedside. This study aims to elucidate the extent to which the effectiveness of inhaled salbutamol can be increased by the additional use of EIT for optimisation of respirator settings. $\textbf {Methods and analysis}$ This study is a randomised, open-label, superiority trial conducted on an intensive care unit of a German university hospital, comparing two groups of mechanically ventilated patients with an acute or chronic bronchial airway obstruction according to the effectiveness of inhaled salbutamol with (intervention) or without (control) additional use of EIT for optimising ventilator settings. The primary outcome is change in airway resistance 30 min after salbutamol inhalation. $\textbf {Ethics and dissemination}$ The study has received approval from the Ethics Committee of the Medical Faculty of Ruhr-University Bochum (17-6306). The results will be made available to critical care survivors, their caregivers, the funders, the critical care societies and other researchers by publication in a peer-reviewed journal

Legionella contamination of a cold-water supplying system in a German university hospital – assessment of the superheat and flush method for disinfection: Heat and flush disinfection for legionella contamination

Introduction: Legionella spp. is a potential pneumonia causing pathogen, which can be transmitted to humans from water-supplying systems. Immunocompromised but also healthy individuals can be vitally threatened. Both, hot and cold-water supplying systems must be considered as transmission sources and therefore a periodic surveillance has to be performed in public buildings according to local legislations. During a routine surveillance, a hazardous colonization was detected within the cold-water supplying system at University Hospital Knappschaftskrankenhaus Bochum, Germany. Applied architectural measures remained unsatisfying in the reduction of legionella contamination of the cold-water distributing system. Methods: Adapted to an analysis of risks, effort and benefit, the superheat and flush procedure was applied twice with a time interval of 6 months. Results were evaluated concerning the efficiency and the sustainability and statistically analyzed. Results: While 33 out of 70 samples had a higher legionella count than the legal threshold of 100 CFU/100 mL (CFU - Colony Forming Units) before the first disinfection was carried out, this number could be reduced to 1 out of 202 samples after the first intervention. Additionally, in contrast to previously published studies, the effect was long-lasting, as no relevant limit exceedance occurred during the following observation period of more than two years. Conclusion: The superheat and flush disinfection can provide an economic and highly effective measure in case of legionella contamination and should be shortlisted for an eradication attempt of affected water-supplying systems in hospitals