Background: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection1. One of the most commonly affected organ is the brain, leading to sepsis-associated encephalopathy (SAE). The prevalence of SAE widely varies between studies, between 10 to 75% of septic patients. It is characterized by a diffuse cerebral dysfunction ranging from delirium to coma, in the absence of direct brain damage or another cause of encephalopathy3–5. Despite improvements in critical care, SAE remains associated with increased mortality and cognitive disability. Sepsis is also associated with long term cognitive sequelae such as memory, attentional and executive functions deficits.Methods: Single-center prospective observational study of adult’s patients with sepsis without acute or chronic neuropsychiatric disorders and co-existing causes of encephalopathy between January 1, 2016, and August 30, 2020. During acute phase, we assessed the severity of sepsis, consciousness and arousal using four clinical scales (CAM-ICU, CRS-R, GCS and FOUR) and electroencephalography. Survivors underwent a cognitive assessment before hospital discharge with brief screening tools (MoCA and FAB scores) and a comprehensive neuropsychological assessment at 6 and 12 months after discharge.Results: We enrolled 109 patients, of which 61% had SAE during the first 48-h of the ICU stay. The most frequent clinical manifestation was fluctuation of arousal. Ten of the 52 ICU survivors that could be assessed showed persistent cognitive dysfunction at hospital discharge. Only the presence of SAE was associated with persistent cognitive dysfunction, in the whole cohort as well as in the subgroup of patients not receiving continuous sedation. At 6 months after discharge, 84% of survivors presented diffuse cognitive impairment (memory, attention, and executive functions were impaired), and high depression score. Cognitive deficit at 6 month was associated with cognitive disability at discharge, and severity of illness during ICU stay, but not with SAE. After 12 months, 82% of survivors presented cognitive difficulties in the same cognitive domains as at the 6-month follow-up. Presence of SAE or any other ICU associated variables were not associated with the severity of cognitive impairment. We found an evolution compared to middle-term assessment in broad cognition, but individual cognitive profiles were mixed.Conclusion: SAE occurs in most patients with sepsis, even in the absence of prior or concomitant causes of encephalopathy. Its detection requires testing patients for fluctuation in arousal. Also, long-term cognitive impairment and depression are observed in survivors. Therapeutics interventions to improve cognitive deficits are thus desirable, and it is also crucial to consider psychological health in those patients. / Doctorat en Sciences psychologiques et de l'éducation / info:eu-repo/semantics/nonPublished

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Bakgrund: Sepsis och septisk chock är ett akut livshotande tillstånd där en tidig behandlingär livsavgörande. Många människor drabbas och fler människor överlever idag jämfört medför några år sedan. Detta leder till fler komplikationer och konsekvenser som kan påverkamänniskans vardagliga liv exempelvis nedsatt ADL. Vid akut sjukdom genomgår människanen traumatisk upplevelse som kan påverka hälsa, välbefinnande och livskvalitet.Syfte: Syftet med denna studie är att, ur ett patientperspektiv, beskriva upplevelser av hurlivet påverkas efter sepsis eller septisk chock.Metod: Studien är en kvalitativ innebördsanalys. Informanter kontaktades viaFacebookgruppen, Sepsisforum. Informanterna beskrev hur deras liv påverkades efter sepsisoch septisk chock. Analysen framställde fyra teman vilket lade grund till resultatet i studien.Resultat: Resultatet belyser fyra teman; oro och rädsla hos personer skapar lidande, enobeskrivlig trötthet, att inte klara av vardagen och uppnå hälsa, bristande eftervård ochvårdpersonalens ansvar.Konklusion: Komplikationerna som kan uppstå efter sepsis eller septisk chock är mångaoch kan vara livslånga. Detta påverkar personen på olika sätt såsom livskvalité och hälsa.Vården har ett stort ansvar och eftervården behöver utvecklas.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Jaroslav Jenčo Supervisor: prof. MUDr. Jaroslav Dršata, CSc. Consultant: Ing. Jana Netriová, PhD. Title of diploma thesis: Determination of biochemical parameters and their diagnostic and prognostic value in sepsis Sepsis is a relatively common complication that may be signed by the increased mortality of patients. It affects all ages, regardless of gender. Occurrence is more frequent in polymorbid and immunosuppressed patients. The most effective method to prevent the development of septic complications is quick and accurate diagnosis. In the period from 1.6.2012 to 01.4.2014, we observed 697 patients hospitalized due to the development of septic complications and we analyzed statistically tracked markers: presepsin, procalcitonin, C - reactive protein, interleukin - 6, lactate, D - dimer, fibrinogen and quantity of leukocytes to determine their predictive and diagnostic value. Largest correlation was observed between comparison of presepsin with procalcitonin and presepsin with C - reactive protein, which reflected rapidly changing status of patients. Moderate correlation was observed in lactate, interleukin - 6, D - dimer concentration and leukocyte count. Between the development...

Background: The trajectory of recovery after sepsis varies. Survivors may have considerable ongoing limitations, requiring a caregiver for a prolonged period. Objectives: To learn about experiences, quality of life, coping, resilience, and social support of caregiver caring for survivors of sepsis. Methods: We conducted a convergent mixed-methods study, recruiting informal caregivers of patients who had survived sepsis in the past year and were readmitted to the intensive care unit with sepsis. Individual face-to-face, semistructured interviews and validated surveys on quality of life, coping, caregiver burden, resilience, and social support were administered to caregivers. Interview transcripts were analyzed using content analysis. Surveys were scored and summarized using descriptive statistics. Results: Caregivers were primarily middle-aged, White, and female. Half were spouses of their care recipient. Caregivers reported some deficits in mobility, pain, and anxiety/depression. Coping styles varied, with engaged coping being more prevalent. Most caregivers reported mild to moderate burden, all reported either normal or high resilience levels, and types of social support were similar. However, interviews and survey findings were not always consistent. Major themes that emerged from the analysis included (1) advocating for and protecting their loved one, (2) coping with caregiving, (3) uncertain future, (4) rewards of caregiving, and (5) need to optimize communication with family. Discussion: Caregivers of sepsis survivors are protective of their care recipient and use a variety of strategies to advocate for their loved one and to cope with the uncertainty involved in a new intensive care unit admission. More advocacy and support are needed for this population.

The overuse of antibiotics is a large problem in healthcare today, accelerating the development of microbial resistance to antibiotics. Antibiotic stewardship campaigns have been implemented to help clinicians curb their use. Procalcitonin is a serum peptide and marker of inflammation secreted in response to microbial toxins. For this reason it is more specific to bacterial infections than other markers of general inflammation , like Creactive protein. The population of patients with sepsis in the Intensive Care Unit is one in which extended durations of antibiotics are used. The FDA has approved use of procalcitonin to guide de-escalation of antibiotic therapy in critically ill patients with sepsis to avoid both antibiotic overuse and antibiotic related side effects. Review of current literature shows that procalcitonin is efficacious in reducing duration of antibiotic therapy in patients with sepsis in the ICU setting. This result, however, is not being observed in clinical practice. This discrepancy is due to the inappropriate use of procalcitonin that does not align with use outlined in randomized control trials. We propose a study to determine how procalcitonin is being used in clinical practice in four Boston area hospital Intensive Care Units. Through chart review, we will identify patients in the Intensive Care Unit with sepsis from 2013-2018 recording patient demographic information and patient characteristics. We will determine whether they had PCT measured during their stay, and if they did, whether or not discontinuation of antibiotics was in accordance with FDA’s proposed algorithm. We will aim to compare whether discontinuing antibiotic therapy in accordance with the FDA’s procalcitonin deescalation algorithm is associated with reduced duration of antibiotic therapy or incidence of Clostridium Difficile infection. In conducting this study, we hope to identify patterns of procalcitonin use in clinical practice and provide further evidence that using the algorithm to guide therapy can serve as an effective tool in reducing exposure to unnecessary antibiotics and the complications from their use.

Lipidomics, a rapidly developing field of study, focuses on the classification and quantitation of lipid species. Lipidomics has emerged in the forefront of scientific research due to the key roles that lipids play in metabolism, cancer, and disease. Using mass spectrometry as a tool for analysis, understanding the role eicosanoids and sphingolipids play has advanced rapidly. Being able to observe these small molecules in vivo has led to better understanding of several lipid-driven mechanisms and identification of eicosanoid and sphingolipid biomarkers in neurodegenerative disease, cancer, sepsis, wound healing, and pre-eclampsia. In the studies herein, we developed targeted mass spectrometric methods to identify lipids of interest in inflammatory disease signaling. We further used lipidomics to identify biomarkers in a clinical trial involving patients diagnosed with pre-eclampsia, discovering that ceramide-1-phosphate, a lipid involved in the initiation of inflammation, was significantly decreased in the plasma of patients who developed pre-eclampsia. Additionally, lipidomic studies were used to elucidate the mechanism of the cPLA2α/C1P interaction, in which the binding of C1P to of cPLA2α was ablated (cPLA2α KI) resulting in resistance to sepsis and increased wound closure rate of cPLA2α KI mice. These studies show how useful lipidomics coupled with mass spectrometry can be in studying inflammatory diseases regulated by lipid signaling.

Cardiosurgery is a potent activator of the immune response similar to sepsis in critically ill patients. Therefore the differential diagnostics of infectious and non-infectious etiology plays an important role. The aim of the study was to compare the biomarkers in the diagnostics of patients after cardiosurgery and in septic patients. 24 patients fulfilling criteria of sepsis and 8 patients after cardio surgery were involved in the study. We demonstrated higher specificity and sensitivity of PCT in comparison with CRP at diagnostics of sepsis. sTREM-1, expression of TREM-1 on monocytes, TREM-1 on granulocytes and the number of FoxP3+T regulatory lymphocytes do not provide a reliable differential diagnostics of infectious and non-infectious etiology of examined group of the patients. The number of lymphocytes in patients with sepsis is a useful parameter at this diagnostics. Cardiosurgery represent a significant impulse for the evocation of the systemic inflammatory response of non-infectious etiology.

The microcirculation system is crucial for the function of delivering biological markers such as oxygen and removing carbon dioxide from all the cells forming the complex ma- trix of tissue in the body. To keep up with the demands of each and every cell, there is a response from the microvasculature - resulting from for instance changes in blood flow to the tissue area. Infections cause disturbances in this important system, which increases the risk of development into one of the world’s most common syndrome - sepsis. This con- dition can be explained as a biological response affecting each and every vital organ, and can as a result of the dysfunction be life threatening. Studies have shown when monitoring pulse and respiratory rate the response is not visually quick enough to be able to determine the gravity in the state of the patient. The primarily chosen biological markers were oxy- genated hemoglobin and deoxygenated hemoglobin present in blood, respectively melanin in the skin. This was performed using the optical instrument Spatial Frequency Domain Imaging in combination with a Tissue Viability Imager respectively an Enhanced Perfusion and Oxygen Saturation-equipment. The formulated aim for this thesis was separated into an optical part and a mathematical modeling part. Regarding the optical section the aim was to understand if there were any optical methods more preferable to detect changes in the microcirculation, whilst the modeling section aimed to understand how to construct the best adjusted model for the changes in the biological markers and how these could be related to sepsis. Spatial Frequency Domain Imaging is an optical technique able to generate two- dimensional maps of the absorption coefficient and the reduced scattering coefficient of a biological tissue surface. The skin of healthy subjects were illuminated with RGB-LEDs to detect the chromophores of interest. The data obtained from the experimental sessions was then collected to work as a base for building a mathematical model. The experimental session was performed with a total of six healthy subjects and the data was collected dur- ing a control-measurement and a simulated sepsis-measurement using a pressure chamber and applying negative pressure to the lower part of the body. The mathematical model was based on theory regarding the biological events of sepsis in the microcirculation and was described by ordinary differential equations. The results were presented in graphs and the resulting model likewise, with an addi- tional figure to describe the source of associated equations written to describe the events. An observation of a distinct difference in the deoxygenated, respectively oxygenated hemoglobin could be observed and did show in general more changes during the measure- ments using a lower body negative pressure chamber. The chosen optical approach was the Spatial Frequency Domain Imaging equipment along with the mathematical model named as the Macro-Micro model due to its more realistic design. Future improvements were dis- cussed and summarized as a repetition of the experimental sessions and including more parameters and relationships between the biological markers and the model. This would contribute to more robust results.

Sepsis is a relatively unknown, but common, condition with high mortality. Sepsis is defined as life-threatening organ dysfunction caused by an excessive immune response in the host as a result of an infection. Sepsis can be caused by many different pathogens, giving a varying symptomatic profile and arise via many different routes of exposure. The pathogenesis of sepsis is very complex and not yet fully understood, but hyperactivation of mainly the innate immune system with consequences such as complement activation, cytokine storm, secretion of reactive oxygen species and endothelial influence are considered central mechanisms that further lead to organ dysfunction with septic shock and possible death. The cause of infection in sepsis can often be treated with early-acting broad-spectrum antibiotics, but there is a lack of treatment for the host response and the hyperactivation of the immune system.  Oxytocin is an endogenous neuropeptide that acts on receptors throughout the body including the nervous system and in certain immune cells. Oxytocin has long been known for its role in childbirth and breastfeeding, where it is also used clinically, and for its importance in behavioral functions such as learning and bonding. Recent research has shown a broader effect of oxytocin such as antioxidant and anti-inflammatory substance. These findings have opened up a new perspective on oxytocin and its potential uses, where treatment for sepsis-induced hyperactivation of the immune system is a suggestion.  The aim of this work is to evaluate, based on the published studies, whether exogenous oxytocin can be used therapeutically in sepsis to limit hyperactivation of the immune system and reduce the risk of organ dysfunction with septic shock and possible death.  The method used in the work is literature search via the database PubMed and further analysis and discussion of six preclinical research articles. All analyzed studies were sepsis induced in rodents, and oxytocin was administered as potential treatment.     The results showed exogenous administration of oxytocin in rodents had the effect of antioxidant, anti-inflammatory substance, tissue protective peptide and that via vagal cholinergic stimulation it can to some extent restore physical parameters affected by sepsis induction such as heart rate, heart rate variation and respiration. Oxytocin also had positive effects on the general condition in these preclinical studies. In conclusion, exogenous administration of oxytocin in sepsis seems to have beneficial effects that can reduce the hyperactivation of the immune system in sepsis and contribute to reduced mortality in the same. / Sepsis är en sjukdom som har skördat oändligt många liv historiskt och gör så än idag. Sjukdomens patofysiologi har två komponenter; infektion och överdrivet inflammatoriskt värdsvar vilket orsakar organdysfunktion. I dagsläget kan infektionen oftast behandlas med antibiotika men det saknas medicinsk behandling mot den inflammatoriska responsen. Världshälsoorganisationen gjorde 2017 sepsis till en global hälsoprioritet och betonade då att det behövs nya behandlingsalternativ. Oxytocin är en endogen neuropeptid med komplex verkan i kroppen. Forskningen har sedan länge bekräftat dess betydelse vid förlossning och amning där den också används kliniskt. På senare tid har forskningen börjat intressera sig för oxytocins övriga fysiologiska effekter. Studier visar på att oxytocin har egenskaper som kan påverka immunologiska reaktioner vilket skulle kunna vara av intresse vid behandling av sepsis. Syftet med detta arbete var att utifrån publicerade studier utvärdera om exogent oxytocin kan användas terapeutiskt vid sepsis för att begränsa hyperaktivering av immunförsvaret och reducera risken för organskador med septisk chock och eventuell död som följd. Metoden som användes i arbetet var litteratursökning via databasen PubMed och vidare analys och diskussion av sex prekliniska forskningsartiklar. Alla studier som analyserades använde exogen administrering av oxytocin i en gnagarmodell. Resultaten visade sammantaget att exogen administrering av oxytocin hos gnagare hade effekt som antioxidant, antiinflammatorisk substans, vävnadsskyddande peptid och att oxytocin till viss del kan återställa fysiska parametrar som påverkas av sepsisinduktion såsom hjärtfrekvensvariation, andning och temperatur. Arbetets slutsats blev att exogen administrering av oxytocin vid sepsis har positiva effekter som kan minska hyperaktivering av immunsystemet och bidra till minskad dödlighet vid densamma.