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Bakgrund: Varje år drabbas uppskattningsvis 31,4 miljoner människor i världenav sepsis och dödssiffran beräknas vara kring 5,3 miljoner. Tidig identifikation aven begynnande sepsis kan vara avgörande för utvecklingen av patientens tillstånd.Eftersom sjuksköterskan arbetar nära patienten är det hen som har möjlighet attidentifiera sepsis på ett tidigt stadium. Det finns olika bedömningsinstrument somsjuksköterskan kan använda som hjälpmedel för identifiering.Syfte: Studien syftade till att undersöka vilka bedömningsinstrumentallmänsjuksköterskan kan använda för att identifiera sepsis och vilken evidens detfinns för de olika instrumentenMetod: Kvantitativ litteraturstudie där tio vetenskapliga studier publicerade 2012-2017 granskades, sammanställdes och evidensgraderades.Resultat: Fyra bedömningsinstrument identifierades: SIRS (eng. systemicinflammatory response syndrome), Elektroniska bedömningsinstrument, qSOFA(eng. quick sequential organ failure assessment) och PRESS (eng. prehospitalrecognition of severe sepsis) score. Evidensgraderingen visade på otillräckligevidens för samtliga bedömningsinstrument, till stor del på grund av begränsadurvalsstorlek.Konklusion: Studien visade att det finns olika bedömningsinstrument som kanvara hjälpmedel för att identifiera sepsis dock utan att ge en definitiv diagnos. Dekan användas för att identifiera symtom som vanligen uppstår vid ett systemisktsvar på infektion men ett holistiskt synsätt som omfattar hela patientenssymtombild krävs för att identifiera sepsis. Enligt internationella riktlinjer skaqSOFA användas inom allmänsjukvården, men SFAI (Svensk förening föranestesi och intensivvård) anser att eftersom NEWS (eng. national early warningscore) och MEWS (eng. modified early warning score) redan är etableradebedömningsinstrument ska dessa användas i Sverige. / Background: Approximately 31.4 million people worldwide develop sepsisannually with mortality rates around 5.3 million. Early identification of thesymptoms of sepsis is essential for the patient’s chances of recovery. The nurseworks closely with the patient and is therefore best equipped to identify sepsis atan early stage. There are different tools available to assist the nurse in identifyingsepsis.Aim: The aim of this study was to investigate which tools the general nurse canuse to identify sepsis and what evidence support them.Method: A quantitative literature review of ten scientific studies published 2012-2017 were reviewed, compiled and graded for evidence.Result: Four tools were identified: SIRS (systemic inflammatory responsesyndrome), Electronic Medical Record alert system, qSOFA (quick sequentialorgan failure assessment) and PRESS (prehospital recognition of severe sepsis)score. The evidence review indicated very low evidence for all tools, largely dueto limited sample size.Conclusion: The study showed that there are different tools that may be useful toidentify sepsis but not to give a definitive diagnosis. The tools can be used toidentify the symptoms typically exhibited in a systemic response to infection.However a holistic stance that takes into consideration all of the symptomspresented by the patient is needed to identify actual sepsis. The internationalguidelines recommend using qSOFA outside of intensive care but SFAI (swe.Svensk förening för anestesi och intensivvård) recommend adhering to NEWS(national early warning score) and MEWS (modified early warning score) inSweden as these are already established tools.

Abstract from the original paper: Aims: The study investigated a putative association between early-onset-sepsis (EOS) and poor neurodevelopmental outcomes at 2 years corrected age in very low birth weight infants. Methods: This was a single-center cohort study on infants weighing less than 1500g with a gestational age below 35 weeks at birth born between 2008 and 2011. Neurodevelopmental outcomes were assessed at follow-up with the Bayley Scales of Infant Development-II. EOS was defined as either culture-proven EOS or clinical EOS using blood culture, CrP levels, and clinical symptoms and treatment. Neurodevelopmental impairment (NDI) was defined as one or more of the following: Mental Developmental Index (MDI) and/or Psychomotor Developmental Index (PDI) scores lower than 70; presence of cerebral palsy. Results: Of 405 eligible newborns in the study period 166 were included. Two had culture-proven and 29 clinical EOS. Median MDI scores in patients with EOS were 96 (IQR: 86–106) and in the control group 94 (84–106, p=0.77). PDI scores in patients with EOS were 96 (86–106) and in the control group 99,5 (92–103, p=0.03). Of infected patients 7/31 (24%) showed NDI as defined, whereas only 11/135 (8%) showed NDI in the control group (OR 3.3, p=0.03). Multiple regression analyses identified chorioamnionitis and poor CRIB-Scores as individual risk factors for MDI or PDI values <70. Conclusion: In our study, EOS among VLBW-infants significantly impaired the neurodevelopment at two years corrected age. As shown in previous reports infection continues to be a problem and strategies for a reduction need further improvement.:Table of contents I. PRELIMINARY REMARKS 1 i. Tables and Figures 2 a. Figures and subtitles 2 b. Tables and titles 2 ii. Abbreviations 3 iii. Bibliographic Summary 4 1 Introduction 5 1.1. Early-onset-sepsis 5 1.1.1 Epidemiology 5 1.1.2 Pathogenesis 7 1.1.3 Pathogens causing EOS 7 1.1.4 Risk factors of EOS 8 1.1.5 Diagnosis of EOS 9 1.1.6 Treatment of EOS 10 1.2 Intrauterine infection 11 1.3 Neurodevelopment of neonates and brain injury 12 1.4 Rationale and objectives of our study 14 2 Original Publication 16 3 Summary 30 4 References 34 5 German Supplement 39 5.1. Darstellung des eigenen Beitrages 39 5.2. Erklärung über die eigenständige Abfassung der Arbeit 40 5.3. Curriculum vitae 41 5.4. Danksagung 42

Proteomics is the large-scale study of proteins, particularly their structures and functions. Proteomics has been utilized in medicine for investigation of disease mechanisms and biomarker discovery. Instrumental methods cover sample preparation, protein and peptide separation and mass spectrometry. At present, there is no proteomic method that can be used as universal for every sample. Analytical methods need to be adapted and optimized for certain samples. The aim of this work was to create methodic procedures and to interpret results of experimental and clinical research. The first part of the thesis includes experiments utilizing proteomics to study changes in the plasma proteome clinically relevant porcine model of sepsis-induced peritonitis. Proteomic analyzes were also starting methodological strategies in experiments aimed at kidney physiology and pathophysiology of acute kidney injury during sepsis. Renal biopsies were analyzed in order to study the time course of proteome changes caused by sepsis and surgery. The second part of the thesis contains experiments studying biocompatibility. A method for elution of proteins interacting with adsorbents used in extracorporeal liver support system and with hemodialyzer capillaries was prepared. Analysis of proteins adsorbed to polysulfone...

This study is a part of a project at Q-linea that aims to present a rapid diagnostic instrument to speed up the process of identification of pathogens and determination of MIC-values (Minimal Inhibitory Concentration) of antibiotic needed to treat patients with sepsis. Specifically, this report is aimed to describe the development and implementation of algorithms that examine susceptibility profiles ofsepsis related pathogens where the bacteria have been exposed to different antibiotics and by different lapse of concentrations. The developed algorithms are based on a clustering technique that identify inhibited growth and present the lowest concentration needed to slow down the growth of the pathogen. The implemented solution was tested on sepsis related pathogens and the determined MIC values were compared to MIC values generated with a method commonly used in healthcare today. Approximately 90% of instances were correctly classified based on data from six hours long tests which is significantly faster than the reference method which takes 16-24 hours to complete. Furthermore, each result comes with a set of quality measures for validation of the algorithm results. Although, further studies are necessary to increase the performance at the four-hour target time, and more data is needed to validate the developed quality measures.

Myeloid-derived suppressor cells (MDSC) expand during sepsis, suppress both innate and adaptive immunity, and promote chronic immunosuppression, which characterizes the late/chronic phase of sepsis. We previously reported that the transcription factors Stat3 and C/EBPb synergize to induces the expression of microRNA (miR)-21 and miR-181b to promote MDSC expansion in a mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive stage. We also showed that Gr1+CD11b+ cells, the precursors of MDSCs, from mice genetically deficient in the inflammatory protein S100A9 lack miR-21 or miR-181b in late sepsis, and are not immunosuppressive. In the present study, we show that S100A9 induces miR-21 and miR-181b during the late sepsis phase. We find that S100A9 associates with and stabilizes the Stat3-C/EBPb protein complex that activates the miRNA promoters. Reconstituting Gr1+CD11b+ cells from the S100A9 knockout mice with late sepsis with S100A9 protein restores the Stat3-C/EBPb protein complex and miRNA expressions, and switches the Gr1+CD11b+ cells into the immunosuppressive, MDSC phenotype. Importantly, we find that this process requires IL-10 mediated signaling, which induces S100A9 translocation from the cytosol to the nucleus. These results demonstrate that S100A9 promotes MDSC expansion and immunosuppression in late/chronic sepsis by inducing the expression of miR-21 and miR-181b.

Sepsis is defined as a life-threatening organ dysfunction that results in systemic activation of coagulation and inflammation in response to microbial infection. Neutrophil extracellular traps (NETs) have shown to be an important interface between innate immunity and coagulation in sepsis. The major structural components of NETs are nucleosomes (DNA-histone complexes). Although nucleosomes do not modulate coagulation, there are conditions where DNA and histones dissociate from each other in the circulation (e.g. in the presence of heparan sulfate or therapeutic heparin binding histones, or DNase digestion of DNA). In vitro, purified DNA was reported to activate coagulation, but this procoagulant activity has been questioned due to isolation methods that yield DNA that is contaminated with other procoagulant molecules. On the other hand, histones have been shown to not only activate coagulation but are cytotoxic to endothelial cells. However, their contribution to the pathogenesis of sepsis has yet to be determined in an in vivo model. Understanding the contribution of DNA, histones, and nucleosomes to the pathogenesis of sepsis may allow us to develop novel therapies that may prove targeting multiple components of NETs (i.e. DNA and histones) may be beneficial. Consequently, in this thesis, we (1) identified methods of DNA purification that produce DNA that is free of contamination and confirmed the procoagulant properties of the isolated DNA, (2) determined the harmful effects of DNA, histones, and nucleosomes cytotoxicity, coagulation, and inflammation in vitro and in vivo, (3) and then we explored the possibility of targeting both DNA and histones using a combination approach of DNase I and heparin in a mouse model of sepsis. Since heparin is administered to patients as a thromboprophylaxis and DNase I is a potential therapy in sepsis, it is important to understand any potential drug-drug interactions. / Thesis / Doctor of Philosophy (PhD) / Sepsis is a type of blood poisoning that occurs when the body has an over reactive response to an infection. This can lead to tissue damage, organ failure, and death. Sepsis is recognized as a global health priority. The death rate from sepsis is high between 15% to 30%, suggesting that an improved understanding of how sepsis leads to death may develop into new therapies. Recently, it was discovered that high levels of free-floating DNA and histones in the blood can predict death in sepsis. The DNA and histones are likely released by white blood cells in response to trying to fight off the infection. In test tubes, free-floating DNA can trigger clotting of blood. DNA often exists in blood together with histones. In test tubes, histones can kill blood vessels and make blood thicker. However, no one has confirmed that DNA and/or histones are harmful to mammals and contributes to death in sepsis. Some new studies show that getting rid of DNA with injections of DNase I minimally increases survival in mice. Other studies show that removing histones with a treatment called heparin shows a small increase in survival in mice. Heparin is also a blood thinner and decreases inflammation. No one knows if these drugs used together can improve sepsis survival. Because both drugs on their own show some survival improvement in sepsis, perhaps using them together will cure sepsis. This thesis has three objectives: (1) to confirm the clotting properties of free-floating DNA, (2) to find out if DNA and/or histones contributes to death in sepsis, and (3) if using a combination of DNase I and heparin can cure sepsis in a mouse model. Finding new therapies for sepsis can save millions of people's lives and decrease the financial burden on society and healthcare systems.

Early Goal Directed Therapy (EGDT) has been thoroughly researched and clinically supported to be effective at lowering morbidity and mortality associated with severe sepsis and septic shock. Due to the strengths of its efficacy, it has been integrated as an essential component of the Surviving Sepsis Campaign. However, very few studies have explored the barriers that affect compliance of the protocol in actual practice. The purpose of this study was to synthesize current research findings regarding nursing barriers associated with EGDT. This research was limited to studies performed in the United States between 2003-2012, with patients at least 18 years old, and with data obtained from studies conducted within emergency departments (EDs) only. These findings may serve to help increase the compliance rate with the protocol among nurses in the ED. Findings indicated that compliance rates were mostly affected by two major barriers: 1) Lack of knowledge regarding the presentation and management of sepsis and septic shock, and 2)Lack of resources in the ED to perform the protocol to its full potential. Limitations of the review noted were that most research studies used were in major academic hospitals which limited the generalizability of the findings to other hospital settings. Nursing education should emphasize early recognition and aggressive treatment of sepsis. Future research should focus on addressing the most efficient ways to educate nurses on sepsis presentation and management and the ways these can be implemented in practice.

Sepsis är ett livshotande tillstånd som kan drabba patienter inom hela sjukvården där sjuksköterskans arbete är av stor betydelse. Dödligheten vid sepsis är oroväckande hög och är därmed ett viktigt område att uppmärksamma. Syftet med litteraturöversikten var att belysa hur sjuksköterskan med hjälp av omvårdnadsinsatser kan identifiera patienter med sepsis på en somatisk vårdavdelning. Metod: en litteraturöversikt med systematisk ansats har genomförts i databaserna PubMed och Cinahl. Resultatet baseras på tio kvantitativa artiklar där fyra teman uppkommit som innefattade sjuksköterskans kompetens, utbildning, samverkan och fysiologiska parametrar och instrument. Den slutsats som framkom var att det krävs hög kompetens hos sjuksköterskan, god samverkan och tillgängliga instrument för att tidig identifiering av patienter med sepsis ska kunna vara möjligt. / Sepsis is one of the most life-threatening conditions that can affect patients in the whole healthcare sector. Therefore it is important to early identify the symptoms, where the nurse's work is of great importance. The mortality rate for sepsis is alarmingly high and is an important area to touch. The aim of this literature review was to highlight how nurses with nursing care can identify patients with sepsis in a somatic ward. Method: a literature review with a systematic approach has been implemented in the databases PubMed and Cinahl. The results are based on ten quantitative articles that four themes emerged as including nursing skills, education, collaboration and physiological parameters and tools. The conclusion that emerged was that it required great competence of the nurse; good interaction and available instruments for early identification of patients with sepsis should be possible.

A qualitative study with an aim to examine the experience and reaktions nurses had while caring for patients with sepsis. / En kvalitativ studie med syftet att undersöka vilka upplevelser och reaktioner sjuksköterskor hade i samband med vård av patienter med sepsis.