M.A. Weigand

Viscoelastic and aggregometric point-of-care testing in patients with septic shock – cross-links between inflammation and haemostasis

In the pathogenesis of sepsis, inflammation‐induced changes in coagulation play a pivotal role.

Next-generation sequencing diagnostics of bacteremia in septic patients

BackgroundBloodstream infections remain one of the major challenges in intensive care units, leading to sepsis or even septic shock in many cases. Due to the lack of timely diagnostic approaches with sufficient sensitivity, mortality rates of sepsis are still unacceptably high. However a prompt diagnosis of the causative microorganism is critical to significantly improve outcome of bloodstream infections. Although various targeted molecular tests for blood samples are available, time-consuming blood culture-based approaches still represent the standard of care for the identification of bacteria.MethodsHere we describe the establishment of a complete diagnostic workflow for the identification of infectious microorganisms from seven septic patients based on unbiased sequence analyses of free circulating DNA from plasma by next-generation sequencing.ResultsWe found significant levels of DNA fragments derived from pathogenic bacteria in samples from septic patients. Quantitative evaluation of normalized read counts and introduction of a sepsis indicating quantifier (SIQ) score allowed for an unambiguous identification of Gram-positive as well as Gram-negative bacteria that exactly matched with blood cultures from corresponding patient samples. In addition, we also identified species from samples where blood cultures were negative. Reads of non-human origin also comprised fragments derived from antimicrobial resistance genes, showing that, in principle, prediction of specific types of resistance might be possible.ConclusionsThe complete workflow from sample preparation to species identification report could be accomplished in roughly 30xa0h, thus making this approach a promising diagnostic platform for critically ill patients suffering from bloodstream infections.

Sepsis-induced long-term immune paralysis – results of a descriptive, explorative study

BackgroundLong-lasting impairment of the immune system is believed to be the underlying reason for delayed deaths after surviving sepsis. We tested the hypothesis of persisting changes to the immune system in survivors of sepsis for the first time.MethodsIn our prospective, cross-sectional pilot study, eight former patients who survived catecholamine-dependent sepsis and eight control individuals matched for age, sex, diabetes and renal insufficiency were enrolled. Each participant completed a questionnaire concerning morbidities, medications and infection history. Peripheral blood was collected for determination of i) immune cell subsets (CD4+, CD8+ T cells; CD25+ CD127- regulatory T cells; CD14+ monocytes), ii) cell surface receptor expression (PD-1, BTLA, TLR2, TLR4, TLR5, Dectin-1, PD-1xa0L), iii) HLA-DR expression, and iv) cytokine secretion (IL-6, IL10, TNF-α, IFN-γ) of whole blood stimulated with either α-CD3/28, LPS or zymosan.ResultsAfter surviving sepsis, former patients presented with increased numbers of clinical apparent infections, including those typically associated with an impaired immune system. Standard inflammatory markers indicated a low-level inflammatory situation in former sepsis patients. CD8+ cell surface receptor as well as monocytic HLA-DR density measurements showed no major differences between the groups, while CD4+ T cells tended towards two opposed mechanisms of negative immune cell regulation via PD-1 and BTLA. Moreover, the post-sepsis group showed alterations in monocyte surface expression of distinct pattern recognition receptors; most pronouncedly seen in a decrease of TLR5 expression. Cytokine secretion in response to important activators of both the innate (LPS, zymosan) and the adaptive immune system (α-CD3/28) seemed to be weakened in former septic patients.ConclusionsCytokine secretion as a reaction to different activators of the immune system seemed to be comprehensively impaired in survivors of sepsis. Among others, this could be based on trends in the downregulation of distinct cell surface receptors. Based on our results, the conduct of larger validation studies seems feasible, aiming to characterize alterations and to find potential therapeutic targets to engage.

Diagnostics, therapy and outcome prediction in abdominal sepsis: current standards and future perspectives

PurposeIn the perioperative phase, sepsis and sepsis-associated death are the most important problems for both the surgeon and the intensivist. Critically ill patients profit from an early identification and implementation of an interdisciplinary therapy. The purpose of this review on septic peritonitis is to give an update on the diagnosis and its evidence-based treatment.ResultsRapid diagnosis of sepsis is essential for patient´s survival. A bundle of studies was performed on early recognition and on new diagnostic tools for abdominal sepsis. Although surgical intervention is considered as an essential therapeutic step in sepsis therapy the time-point of source control is still controversially discussed in the literature. Furthermore, the Surviving Sepsis Campaign (SSC) guidelines were updated in 2012 to facilitate evidence-based medicine for septic patients.ConclusionDespite many efforts, the mortality of surgical septic patients remains unacceptably high. Permanent clinical education and further surgical trials are necessary to improve the outcome of critically ill patients.

Why mothers die

ZusammenfassungTäglich sterben weltweit über 800 Frauen an schwangerschafts- oder geburtsassoziierten Komplikationen. In denn Confidential Enquiry of Maternal Deaths Reports (CEMD) wird seit 1952 die Müttersterblichkeit im Vereinigten Königreich Großbritannien und Irland erfasst und aufgearbeitet. Die vorliegende Arbeit analysiert die CEMD der Jahre 1985–2013 hinsichtlich anästhesie- und analgesiebedingter mütterlicher Todesursachen in der Schwangerschaft, peripartal und im Wochenbett. Im untersuchten Zeitraum zeichnete sich eine Abnahme direkt anästhesiebedingter mütterlicher Sterbefälle auf aktuell 4,3u2009% ab. Jedoch kam es zu einer Zunahme anästhesieassoziierter mütterlicher Sterbefälle. Die Rate an tödlichen Komplikationen im Rahmen einer geburtshilflichen Regionalanästhesie hat sich in den letzten Jahren verdoppelt, während das Risiko im Rahmen einer geburtshilflichen Vollnarkose zu sterben rückläufig ist.Viele der geschilderten mütterlichen Sterbefälle wären möglicherweise vermeidbar gewesen. Jeder geburtshilflich tätige Anästhesist sollte sich mit dem schwangerschaftsspezifischen Vorgehen, peripartal und auch im Wochenbett vertraut machen, bestenfalls mithilfe der geforderten Simulationsübungen. Das Monitoring von Patientinnen nach geburtshilflichen Eingriffen muss dem nicht geburtshilflicher Patienten entsprechen, sogenannte Modified Early Obstetric Warning Scores sollten hierbei zur Anwendung kommen. Im Rahmen der Regionalanästhesie sind aktuelle Hygienestandards strikt einzuhalten und Postpunktionskontrollen durchzuführen. Interdisziplinäre Kommunikation und Zusammenarbeit sind essenziell, jedoch weiterhin verbesserungswürdig. Für Risikopatientinnen sollte bereits im Schwangerschaftsverlauf ein interdisziplinärer Geburtsplan erarbeitet werden.AbstractEvery day, more than 800 women die from causes related to pregnancy or childbirth. Since 1952 the Confidential Enquiry of Maternal Deaths Reports (CEMD) have collected and analysed data on maternal mortality in the United Kingdom and Northern Ireland. This publication analyses the CEMD from 1985–2013 regarding anaesthesia- and analgesia related maternal deaths during pregnancy or peripartum. During this period, there has been axa0reduction in directly anaesthesia-related maternal deaths to 4.3u2009%. Yet, an increase in anaesthesia-associated maternal deaths has been recorded. The rate of fatal complications during obstetric regional anaesthesia doubled in recent years, while the fatality risk for obstetric general anaesthesia has decreased.xa0Many of the reported maternal deaths could presumably have been avoided. The anaesthesiologist has to be familiar with state-of-the-art, guideline-based concepts for anaesthesia during pregnancy, childbirth or post partum, especially using tools like simulation. Vital sign monitoring after obstetric anaesthesia has to be identical to other postoperative monitoring, and Modified Early Warning Scores should be used for this purpose. In regional anaesthesia, current standards for hygiene have to be adhered to and patients have to be visited after spinal/epidural anaesthesia. Interdisciplinary communication and collaboration still have to be improved; careful interdisciplinary planning of childbirth in high-risk obstetric patients is strongly advised.

Sepsis Induces Specific Changes in Histone Modification Patterns in Human Monocytes

Background Sepsis is a global burden and the primary cause of death in intensive care units worldwide. The pathophysiological changes induced by the host’s systemic inflammatory response to infection are not yet fully understood. During sepsis, the immune system is confronted with a variety of factors, which are integrated within the individual cells and result in changes of their basal state of responsiveness. Epigenetic mechanisms like histone modifications are known to participate in the control of immune reactions, but so far the situation during sepsis is unknown. Methods and Findings In a pilot approach, we performed combined chromatin immunoprecipitation followed by high-throughput sequencing to assess the genome-wide distribution of the chromatin modifications histone 3 lysine 4 and 27 trimethylation and lysine 9 acetylation in monocytes isolated from healthy donors (n = 4) and patients with sepsis (n = 2). Despite different underlying causes for sepsis, a comparison over promoter regions shows a high correlation between the patients for all chromatin marks. These findings hold true also when comparing patients to healthy controls. Despite the global similarity, differential analysis reveals a set of distinct promoters with significant enrichment or depletion of histone marks. Further analysis of overrepresented GO terms show an enrichment of genes involved in immune function. To the most prominent ones belong different members of the HLA family located within the MHC cluster together with the gene coding for the major regulator of this locus—CIITA. Conclusions We are able to show for the first time that sepsis in humans induces selective and precise changes of chromatin modifications in distinct promoter regions of immunologically relevant genes, shedding light on basal regulatory mechanisms that might be contributing to the functional changes occurring in monocytes.

Developing the skill of laryngeal mask insertion: prospective single center study.

BackgroundLaryngeal mask insertion (LMI) represents a fundamental skill for anesthesiologists in routine management as well as in difficult airway situations. This study aimed to evaluate the time needed by first year anesthesiology residents to perform 40xa0LMIs and assessed the associated success rates and the number of attempts needed for successful LMI.MethodsThis prospective single center study evaluated the number of work days, the success rate and the attempts needed for successful LMI (LMA ProSeal™) in consecutive blocks of five LMI procedures and the related difficulties and complications.ResultsFrom 2007 to 2010 a total of 10 anesthesiology resident physicians were evaluated consecutively. These residents needed a mean of 18.3u2009±u20094.1 (mean ± standard deviation) working days to successfully perform 40xa0LMIs. The LMI success rate after the first 5xa0LMIs increased steadily up to the results after 40xa0LMIs per resident (LMI success rate within 1 attempt 72 versus 86u2009%, pu2009=u20090.09, LMI success rate within all LMI attempts 74 versus 96u2009%, pu2009=u20090.001). The mean number of attempts required until successful LMI decreased from 1.45u2009±u20090.82 after the first 5 LMIs to 1.16u2009±u20090.37 after 40xa0LMIs (pu2009=u20090.03). The most common difficulties associated with unsuccessful LMI by residents that led to handing over to an experienced colleague were small oral aperture (9.8u2009%), short thick neck, large tongue, blood/mucus in the mouth or throat (each 7.3u2009%) and retrognathy (4.9u2009%).ConclusionsThe increasing LMI success rate and the decreasing rate of LMI attempts for successful airway management correlated to a learning curve and development of LMI dexterity over time.ZusammenfassungHintergrundDie Insertion einer Larynxmaske (LMI) stellt eine fundamentale Fähigkeit des Anästhesisten sowohl im Routinemanagement als auch im Rahmen einer schwierigen Atemwegssituation dar. Ziel der vorliegenden Untersuchung war es, das von Erstjahresweiterbildungsassistenten benötigte Zeitintervall bis zu Durchführung von 40xa0LMI und die hiermit assoziierte Erfolgsrate sowie die Zahl der notwendigen Versuche bis zur erfolgreichen LMI zu evaluieren.MethodenIn der prospektiven monozentrischen Untersuchung wurden die Zahl der Arbeitstage, die Erfolgsraten und die zur erfolgreichen LMI (LMA ProSeal™) benötigten Versuche in konsekutiven Blocks von 5xa0LMI-Prozeduren ebenso wie die entstandenen Schwierigkeiten und Komplikationen erfasst.ErgebnisseVon 2007 bis 2010 wurden 10 anästhesiologische Erstjahresweiterbildungsassistenten konsekutiv evaluiert. Die Weiterbildungsassistenten benötigten durchschnittlich 18,3u2009±u20094,1 Arbeitstage (Mittelwert ± Standardabweichung) für 40xa0LMI. Die Erfolgsrate der LMI stieg nach den ersten 5xa0LMI stetig bis zu den 40xa0LMI/Weiterbildungsassistent an (Erfolgsrate der LMI im 1.xa0Versuch: 72 vs. 86u2009%, pu2009=u20090,09; Erfolgsrate der LMI bei allen Versuchen: 74 vs. 96u2009%, pu2009=u20090,001). Die Anzahl der benötigten Versuche bis zur erfolgreichen LMI verringerte sich von 1,45u2009±u20090,82 nach den ersten 5 LMI auf 1,16u2009±u20090,37 nach 40xa0LMI (pu2009=u20090,03). Die häufigsten Schwierigkeiten, die mit einer nichterfolgreichen LMI durch die Weiterbildungsassistenten einhergingen und zur Übergabe der LMI an einen erfahrenen Kollegen führten, waren schmale Mundöffnung (9,8u2009%), kurzer/dicker Hals, große Zunge, Blut/Sekret im Mund-Rachen-Raum (je 7,3u2009%) und Retrognathie (4,9u2009%).SchlussfolgerungDie ansteigende Erfolgsrate der LMI und die sinkende Anzahl an benötigten Versuchen bis zur erfolgreichen LMI korrelierten mit der Lernkurve und der entwickelten Sicherheit der LMI über die Zeit.

Delir auf der Intensivstation

In recent years delirium in the intensive care unit (ICU) has internationally become a matter of rising concern for intensive care physicians. Due to the design of highly sophisticated ventilators the practice of deep sedation is nowadays mostly obsolete. To assess a ventilated ICU patient for delirium easy to handle bedside tests have been developed which permit a psychiatric scoring. The significance of ICU delirium is equivalent to organ failure and has been proven to be an independent prognostic factor for mortality and length of ICU and hospital stay. The pathophysiology and risk factors of ICU delirium are still insufficiently understood in detail. A certain constellation of pre-existing patient-related conditions, the current diagnosis and surgical procedure and administered medication entail a higher risk for the occurrence of ICU delirium. A favored hypothesis is that an imbalance of the neurotransmitters acetylcholine and dopamine serotonin results in an unpredictable neurotransmission. Currently, the administration of neuroleptics, enforced physiotherapy, re-orientation measures and appropriate pain treatment are the basis of the therapeutic approach.ZusammenfassungDas Intensivdelir bzw. das Delir des Intensivpatienten erfährt in den letzten Jahren international ein zunehmendes Interesse der Intensivmediziner. Auf deutschen Intensivstationen hingegen scheint dieses hoch komplexe Krankheitsbild weiterhin eine lästige Begleiterscheinung darzustellen, dessen Bedeutung verkannt wird. Das ist insofern erstaunlich, als dass dank der Entwicklung hoch differenzierter Beatmungsgeräte für die meisten Intensivpatienten eine tiefe Analgosedierung heute oftmals obsolet ist und leicht zu handhabende Bedside-Tests erarbeitet wurden, die ein neurologisches und kognitives „scoring“ des beatmeten Intensivpatienten ermöglichen. Die Inzidenz des Intensivdelirs erweist sich dabei als überraschend hoch. In seiner Bedeutung ist das Intensivdelir als ein Organversagen zu verstehen und gilt als unabhängiger prognostischer Faktor für die Letalität und die Krankenhausverweildauer. Sowohl die Pathophysiologie als auch die Risikofaktoren sind bisher noch unzureichend verstanden. Als gesichert gilt, dass bestimmte alterassoziierte Vorerkrankungen, allen voran die Demenz, die aktuelle Diagnose bzw. der erfolgte chirurgische Eingriff und viele „Standardmedikamente“ der anästhesiologischen Prämedikation sowie der Intensivtherapie ein deutlich höheres Risiko für die Entwicklung eines Intensivdelirs nach sich ziehen. Bezüglich der Pathophysiologie des Delirs wird eine Imbalance von Neurotransmittern, insbesondere zwischen Acetylcholin (ACh) und Dopamin/Serotonin vermutet. Die therapeutischen Möglichkeiten beschränken sich bislang auf die Anwendung von reorientierenden Begleitmaßnahmen, intensiver Physiotherapie, einer adäquaten Schmerztherapie und der Gabe von Neuroleptika.AbstractIn recent years delirium in the intensive care unit (ICU) has internationally become a matter of rising concern for intensive care physicians. Due to the design of highly sophisticated ventilators the practice of deep sedation is nowadays mostly obsolete. To assess a ventilated ICU patient for delirium easy to handle bedside tests have been developed which permit a psychiatric scoring. The significance of ICU delirium is equivalent to organ failure and has been proven to be an independent prognostic factor for mortality and length of ICU and hospital stay. The pathophysiology and risk factors of ICU delirium are still insufficiently understood in detail. A certain constellation of pre-existing patient-related conditions, the current diagnosis and surgical procedure and administered medication entail a higher risk for the occurrence of ICU delirium. A favored hypothesis is that an imbalance of the neurotransmitters acetylcholine and dopamine serotonin results in an unpredictable neurotransmission. Currently, the administration of neuroleptics, enforced physiotherapy, re-orientation measures and appropriate pain treatment are the basis of the therapeutic approach.

Relevance of Candida and other mycoses for morbidity and mortality in severe sepsis and septic shock due to peritonitis.

This single‐centre retrospective cohort study evaluated the incidence and outcome of mycoses in critical ill patients (n = 283) with sepsis due to peritonitis. Overall mortality was 41.3%, and the 28‐day mortality was 29.3%. Fungal pathogens were found in 51.9%. The common first location was the respiratory tract (66.6%), followed by the abdominal site (19.7%). Candida colonisation was found in 64.6%, and invasive Candida infection in 34.0%. Identified fungi were Candida spp. in 98.6% and Aspergillus spp. in 6.1%. Patients with fungal pathogens showed a higher rate of postoperative peritonitis, APACHE II and tracheotomy. In comparison to patients without fungal pathogens, these patients showed a longer duration on mechanical ventilation, and a higher overall mortality. Patients with Candida‐positive swabs from abdominal sites had more fascia dehiscence and anastomosis leakage. Seventy‐two patients (48.9%) received antifungal therapy, 26 patients were treated empirically. Antifungal therapy was not associated with a decrease in mortality. Age and renal replacement therapy were associated with mortality. In conclusion, fungi are common pathogens in critically ill patients with peritonitis, and detection of fungi is associated with an increase in overall mortality. Particularly, Candida‐positive abdominal swabs are associated with an increase in morbidity. However, we were not able to demonstrate a survival benefit for antifungal therapy in peritonitis patients.

Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study

Abstract Objectives: The impact of TREM-1-mediated inflammation was investigated in different inflammatory settings. Methods: Secondary analyses of an observational clinical pilot study, including 60 patients with septic shock, 30 postoperative controls and 30 healthy volunteers. Results: Plasma levels of sTREM-1 were found to identify patients with septic shock more effectively than procalcitonin and C-reactive protein. Moreover, sTREM-1 was identified to be an early predictor for survival in patients with septic shock. Conclusion: Due to its diagnostic as well as prognostic value in sepsis syndrome, implementation of sTREM-1 measurements in routine diagnostics should be taken into account.