Sepsis is defined as a dysregulated immune response to infection causing organ dysfunction, and is a major area of unmet clinical need. Although conventionally considered a unified disease with a common pathway to organ failure and death, substantial clinical and molecular heterogeneity is seen, which has limited efforts to understand pathophysiology and improve therapeutic strategies. Sepsis is associated with global changes in gene expression, and genetic variants are known to affect the response to infection. This thesis therefore uses an integrated functional genomics approach to investigate disease mechanisms and variation in the sepsis response. Data are presented for 551 patients admitted to intensive care with sepsis due to community acquired pneumonia (CAP) or faecal peritonitis (FP). The sepsis response is explored using genome-wide gene expression and proteomics data, and molecular quantitative trait loci (QTL) are mapped in the context of disease. Comparisons with cardiac surgery patients are performed to identify shared and specific aspects of the host response. The host transcriptomic response was largely shared across sources of sepsis, although some specificity relating to viral infection and interferon signalling was observed and validated in prospectively recruited patients. Expression-based sepsis response signature (SRS) subgroups previously described in CAP were validated, and were additionally observed in FP. SRS1 is associated with higher early mortality, and shows enrichment of pathways relating to T cell exhaustion, cell death, and endotoxin tolerance. Differences between SRS groups were also observed in the FP plasma proteome. Serial sampling enabled the investigation of temporal changes in gene expression and protein abundance within patients. Lastly, disease-relevant expression QTL were identified, and interactions with source of sepsis and SRS determined, highlighting the potential impact of regulatory variation on the sepsis response. This thesis demonstrates the benefit of an integrative functional genomics approach to explore heterogeneity in sepsis, and highlights opportunities for patient stratification and personalised medicine.

Die Sepsis ist ein häufiges, komplexes Krankheitsbild und oft mit einer hohen Letalität verbunden. Um das Outcome der betroffenen Patienten zu verbessern, ist eine schnelle adäquate Therapie notwendig. Durch den schnellen Erregernachweis ist eine gezielte Antibiotikatherapie möglich. In der vorliegenden Arbeit wurden 57 Patienten der IMPACT-Sepsis Studie, die bereits antibiotisch vorbehandelt waren, hinsichtlich der Erregerdiagnostik mit dem aktuellen Goldstandard, der Blutkulturdiagnostik, und der VYOO®-Multiplex-PCR untersucht. Das Patientenkollektiv war epidemiologisch vergleichbar mit dem anderer Studien, nur lag der Anteil an immunsupprimierten Patienten höher, was a. e. auf das Patientenkollektiv einer Universitätsklinik zurückzuführen ist. Insgesamt konnten bei den Patienten 21 Erreger diagnostiziert werden. 10 Erreger wurden nur in der VYOO®-Multiplex-PCR, nur 3 in der Blutkulturdiagnostik und 4 Erreger in beiden Methoden nachgewiesen. Dies entspricht einer Nachweisquote pro Patient von 21,4% für die VYOO®-Multiplex-PCR und 12,5% für die Blutkulturdiagnostik. Es zeigte sich somit eine tendenziell bessere Detektionsrate bei der VYOO®-Multiplex-PCR. Verglichen mit Blutkulturdiagnostik gab es jedoch keine statistisch signifikante Verbesserung der Erregerdiagnostik mit der VYOO®-Multiplex-PCR. Dies ist a.e. auf eine kleine Studiengröße zurückzuführen. Wird die aktuelle Studienlage betrachtet, so bleibt die Blutkulturdiagnostik bei septischen Patienten weiterhin der Goldstandard, was sich auch in den aktuellen Leitlinien von 2016 widerspiegelt. Ob molekulardiagnostische Verfahren, wie die PCR, die Blutkulturdiagnostik ablösen oder routinemäßig ergänzen werden, müssen weitere Studien zeigen. Auch der gesundheits-ökonomische Nutzen durch Verkürzung der intensivmedizinischen Behandlung und Reduktion des Antibiotikaverbrauchs bedarf prospektiver Untersuchungen eines großen Patientenkollektivs. / Sepsis is a common, complex clinical picture and often associated with a high mortality rate. In order to improve the outcome of the affected patients, a fast adequate therapy is necessary. The rapid detection of the pathogen makes targeted antibiotic therapy possible. In the present study, 57 patients of the IMPACT-Sepsis study who had already undergone antibiotic pre-treatment were examined with regard to pathogen diagnostics using the current gold standard, blood culture diagnostics, and VYOO® multiplex PCR. The patient population was epidemiologically comparable to other studies, only the proportion of immunocompromised patients was higher, which a. e. is due to the patient population of a university hospital. A total of 21 pathogens were diagnosed in the patients. 10 pathogens were only detected in VYOO® multiplex PCR, only 3 in blood culture diagnostics and 4 pathogens in both methods. This corresponds to a detection rate of 21.4% per patient for VYOO® multiplex PCR and 12.5% for blood culture diagnostics. Thus, the detection rate of VYOO® multiplex PCR tended to be better. However, compared to blood culture diagnostics, there was no statistically significant improvement in pathogen diagnostics with VYOO® multiplex PCR. This is a.e. due to a small study size. If the current study situation is considered, blood culture diagnostics in septic patients remains the gold standard, which is also reflected in the current guidelines of 2016. Further studies will have to show whether molecular diagnostic methods, such as PCR, will replace blood culture diagnostics or routinely supplement them. The health-economic benefits of shortening intensive medical treatment and reducing the consumption of antibiotics also require prospective examinations by a large group of patients.

Impairment of the intestinal microcirculation (IMC) plays a critical role in the pathogenesis of sepsis. Consequently, the protection of the IMC represents a pivotal therapeutic target in severe sepsis. The aim of this study was to examine the effects of endocannabinoid system modulation on the IMC. Experimental animals groups were: control, endotoxemic animals (lipopolysaccharide; LPS), LPS + CB1R agonist, LPS + CB1R antagonist, LPS + CB1R agonist + CB1R antagonist, LPS + CB2R agonist, LPS + CB2R antagonist, LPS + CB2R agonist + CB2R antagonist, LPS + cannabinoid degradation enzyme inhibitor and LPS + enzyme inhibitor + CB2R antagonist. Endotoxemia significantly increased leukocyte adhesion in intestinal submucosal venules, and significantly reduced capillary perfusion of the muscular and mucosal layers of the intestinal wall. In acute experimental endotoxemia, IMC was significantly improved (by reducing leukocyte adhesion and increasing capillary perfusion) with CB1R inhibition or CB2R activation or inhibition of endocannabinoid degradation.

Sepsis-induced delayed gastric emptying is a significant clinical problem for patients in intensive care units worldwide. A series of studies were carried out to examine the nature and mechanisms of sepsis-induced delayed gastric emptying using a novel mouse model which used a standard food source and was devoid of upper gastrointestinal tract trauma and restraint. Using this model, lipopolysaccharide (LPS) injection produced a dose-dependent decrease in gastric emptying which onset by one hour. LPS produced an alteration in mouse behavior and piloerection at 30 minutes, increased resting respiratory rate at 3 hours, and did not impact body temperature. The onset of sepsis-induced delayed gastric emptying was closer to those centrally-mediated clinical signs of sepsis (altered behavior and piloerection) than to the peripherally-mediated clinical signs (respiratory rate) suggesting a central mechanism. C-Fos activation of the area postrema (AP), the nucleus of the solitary tract (NTS), and the dorsal motor nucleus of the vagus (DMV) was examined 30 minutes after LPS injection which is the onset time for sepsis-induced delayed gastric emptying. LPS exposure produced significantly more activated neurons in the AP and NTS, and less in the DMV. These results may suggest a central mechanism with the AP and NTS inhibiting the DMV. Examination of isolated strips of gastric antrum in a tissue bath showed a decreased contractile response to electrical field stimulation and carbachol after injection of LPS. This occurred at 18 hours post LPS injection, but not at 6 hours. Using the mouse model, sepsis-induced delayed gastric emptying was shown to be occurring at 6 hours when no difference in contractility was measurable suggesting intrinsic changes are not the cause. These studies suggest a new mechanistic paradigm for sepsis-induced delayed gastric emptying in which there is a biphasic response. This involves an initial rapid, centrally-mediated delay in gastric emptying occurring the first hour and followed by an intrinsic tissue-level response several hours later characterized by a decrease in gastric muscle contractility. / Thesis (Ph.D, Biology) -- Queen's University, 2012-05-02 16:17:55.564

No description available.

Bakgrund: Sepsis är kroppens svar på en bakteriell infektion. En patient med sepsis kan vara svår att upptäcka i tid då symtomen initialt kan vara mycket diffusa. Om patienten inte får behandling i tid är dödligheten mycket stor. En specialistutbildad ambulanssjuksköterska ska kunna bedöma patientens tillstånd, utföra åtgärder, utvärdera dessa och samtidigt se till att patienten blir behandlad under rätt vårdnivå. Samtidigt som sjuksköterskans anamnestagande är viktigt får sjuksköterskan inte glömma bort att arbeta patientsäkert och för patientens bästa. Syfte: Syftet var att följa upp det nationella kvalitetsregistret ”Svår sepsis på IVA inom 24t”.  Metod: Studien var en retrospektiv registerstudie där de inkluderade (n=110) var patienter som registrerats i det nationella kvalitetsregistret, ”Svår sepsis på IVA inom 24 t” under åren 2007-2014. Urvalet bestod av patienter behandlade på lokal nivå. Patienterna delades in i grupper beroende på ankomstsätt till sjukhus och data analyserades med hjälp av statistikprogram (SPSS). Resultat: En jämn fördelning avseende patienternas kön- och åldersgrupper påvisades. De som anlänt med ambulans utgjorde den största gruppen (66 %). Denna grupp fick i större utsträckning också sin antibiotikabehandling snabbare insatt (p= 0,032). Medelvärdet för populationens tid till första antibiotikabehandling var 1,35 timme. Ambulanstransporterade patienter visade över lag ett allvarligare sjukdomstillstånd än motsvarande grupp. Samtliga registrerade avlidna på sjukhus hade ankommit med ambulans. Konklusion: Kvalitetsregister kan vara effektivt för att utvärdera och utveckla vården. För att registret ska kunna nyttjas till fullo krävs att registret hålls uppdaterat och är korrekt ifyllt. Ett avsevärt bortfall av data på grund av felaktiga eller saknade registreringar gör denna studies resultat osäkert.

No description available.

Universiẗat, Diss., 2007--Giessen.

Universiẗat, Diss., 2007--Marburg.

Freie Universiẗat, Diss., 2001--Berlin. / Dateiformat: zip, Dateien im PDF-Format.