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

The protein interaction of mitochondrial transcription factors A and B2 is associated with 30-day survival in critical COVID-19

IntroductionRepair of mitochondrial damage seems pivotal for clinical recovery and determining outcome in patients with critical COVID-19. However, reliable biomarkers for non-invasively assessing mitochondrial repair in peripheral blood of critically ill COVID-19 patients are currently lacking. Accordingly, we sought to assess different surrogates of mitochondrial repair in peripheral blood and correlate these measurements with clinical outcome in patients with critical COVID-19.MethodsIn this prospective multicentric cohort study, 88 critically ill COVID-19 patients were enrolled across three German intensive care units. Gene products of mitochondrial quality control (MFN2, PINK, TFAM, TFB2M) and the mtDNA copy number were measured in peripheral blood mononuclear cells. Furthermore, the protein interactions between TFAM and TFB2M were quantified. Patients were stratified regarding 30-day mortality. ResultsTranscript levels of the assessed mRNA markers of mitochondrial quality control were not associated with clinical outcome. In contrast, more than 10.7 protein interactions per cell were associated with a 74% 30-day survival (37 out of 50), while 10.7 or fewer protein interactions per cell were associated with a 32% 30-day survival (12 out of 38; p < 0.001). Furthermore, multivariable Cox regression analysis revealed TFAM-TFB2M protein interaction as an independent predictor for 30-day survival (HR: 3.2; 95% CI: 1.6 to 6.5; p < 0.001). DiscussionOur findings indicate that TFAM-TFB2M protein interactions, identified as a novel biomarker, are strongly and independently associated with 30-day survival in critical COVID-19. Therefore, our data suggest a significant impact of mitochondrial repair and quality control on clinical outcome in critical COVID-19

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

Präoperative Hypertonie – Muss der Elektiveingriff verschoben werden?

ZusammenfassungLeitlinien zur Klassifikation und Therapie der Volkskrankheit „essenzielle Hypertonie“ sind über nationale 1 und internationale Fachgesellschaften verfügbar und unterliegen einem regelmäßigen Review- und Novellierungsprozess. Eine spezifische Leitlinie zum Management von hypertensiven Patienten in der perioperativen Sondersituation stellt ein Novum dar und richtet sich an alle im perioperativen Setting beteiligten Fachdisziplinen 3.</jats:p

Kasuistik: ECMO-Einsatz bei hyperkapnischer Hirndruckkrise

ZusammenfassungUnter der Geburt trübte sich bei einer 29-jährigen Patientin die Vigilanz progredient bis zum Koma. Grund war eine schwere Hirnblutung als Komplikation eines bis dahin nicht erkennbaren HELLP-Syndroms. Nach der zerebralen OP entwickelte die Patientin aggravierend ein schweres ARDS mit Hyperkapnie und kritischem Anstieg des intrakraniellen Druckes. Trotz Kontraindikation war eine ECMO-Therapie für insgesamt 31 Tage letztlich erfolgreich.</jats:p

Evaluation of inhaled salbutamol effectiveness under supportive use of electrical impedance tomography in ventilated ICU patients: study protocol for a randomised controlled clinical trial

IntroductionThe 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.Methods and analysisThis 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.Ethics and disseminationThe 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.Trial registration numberDRKS00014706; Pre-results.</jats:sec

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

The Actual Clinical Situation Ruthlessly Exposes the Challenge of Rational Care for Nosocomial and Community-Acquired Infections and Requires Even More Efforts for Satisfactory Antibiotic Stewardship

Background: Antimicrobial resistance is one of the 10 most pressing health problems worldwide. Methods: First steps toward harnessing the complex dynamics of antibiotic resistance are presented. To accomplish this, we first shift down a gear and try to understand the actual driving dynamics behind the development of resistance in a specific clinical department. Analyses are based on the clinical and microbiological data of a German hospital over an observation period of more than 7 years, which we evaluate descriptively and semi-quantitatively in order to obtain a basis for informed and intelligent action in terms of antibiotic stewardship. Results: The specific results include the observed increase in the resistance rate with increasing overall consumption, while increases over time independent of consumption are fairly moderate. Vancocymin and refoximin are an exception in the development of resistance, as resistance to these substances appears to decrease with increasing consumption. However, there have been substantial dose adjustments for these substances, which are likely to be decisive here. An intra-host increase in resistance due to treatment time on the one hand and repeated treatments on the other is observed. Within the sub-cohort of ineffectively treated patients, i.e., with resistance to the antibiotic, mortality increases on average, but with ampicillin/sulbactam as a striking exception. Patients with infections caused by ampicillin-resistant bacteria have a lower mortality rate. The observed resistance rates of the eight most frequently administered antibiotics show a temporal variability that includes random fluctuations as well as decidedly regular cycles. The time series associated with the various antibiotics show pairwise time lag correlations, which indicates the existence of retardedly mediated cross-resistance. Conclusions: We conclude with an outlook on upcoming further analyses and a draft action plan on how to control and harness the complex dynamics observed by means of successful, informed, and intelligent antibiotic stewardship

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 &ndash;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&ndash;0.62; p &lt; 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