Cette thèse s’inscrit dans le cadre du projet « NanoFret », financé par L’Agence Nationale de Recherche (ANR). Elle visait à développer de nouveaux complexes luminescents de lanthanides dans le but de les utiliser dans le diagnostic du choc septique. Le complexe idéal devait posséder une longueur d’onde d’excitation élevée, un temps de vie de luminescence long et une brillance élevée. Nos complexes devaient présenter un nombre important de groupements chromophoriques. Nous avons travaillé sur plusieurs types de ligands afin d’améliorer ces propriétés. La recherche sur les ligands dérivés du cyanophénol a permis d’obtenir un ligand qui est utilisé comme sensibilisateur des nanoparticules « ultra-brillantes ». Les ligands poly-picolinates sont des ligands très intéressants mais nécessite encore d’être perfectionnés afin d’obtenir la géométrie de complexation souhaitée. Les complexes des ligands benzyle-cyclène et pyridine-bispyrazole sont de bonnes plateformes pour la synthèse de complexes luminescents de lanthanides. Les perspectives de ces travaux concernent l’optimisation des chromophores afin d’atteindre des longueurs d’ondes d’excitation supérieures. / This work is part of the "NanoFret" project, funded by the “Agence National de Recherche” (ANR). It aimed to develop new luminescent lanthanide complexes for their use in the diagnosis of septic shock. The ideal complex should have a high excitation wavelength, a long luminescence lifetime and high brightness. The complexes should then present a significant number of chromophoric groups. We worked on several types of ligands to improve these properties. Research on derivatives of cyanophenol ligands allowed to get a ligand used as a sensitizer for "ultra-bright" Ln(III) nanoparticles. Poly-picolinates ligands are very interesting ligands but still needs to be improved in order to obtain the desired complexing geometry. Complexes of benzyl-cyclen ligands and pyridine-bispyrazole ligands are good platforms for the synthesis of luminescent lanthanide complexes. The perspectives of these works concern the optimization of chromophores to achieve higher excitation wavelengths.

Peu de données sont disponibles sur le devenir à long terme après un choc septique. De plus le foie, organe clé dans la réponse de l’hôte à l’agression pourrait jouer un rôle important concernant le devenir à long terme. Dans une cohorte de patients chirurgicaux en choc septique, nous avons observé une mortalité élevée à 6 mois et une altération de la qualité de vie parmi les survivants par rapport à la population générale. Toutefois, celle-ci tend à s’améliorer au cours du temps. Dans un second travail, nous avons observé que la dysfonction hépatique précoce évaluée par le score SOFA dans les 24 heures qui suivait l’introduction des vasopresseurs n’avait pas d’impact sur la mortalité et la qualité de vie à long terme dans une cohorte multicentrique de patients médico-chirurgicaux en choc septique. Au contraire, l’apparition secondaire ou l’aggravation d’une dysfonction hépatique était associée à une surmortalité jusque 6 mois après l’épisode de choc septique. Afin d’approfondir par une approche expérimentale les mécanismes impliqués dans la dysfonction septique hépatique, nous avons mis au point un modèle in vitro de co-cultures hépatocytes-macrophages soumis au LPS. A partir de ce modèle, nous avons montré qu’une catécholamine telle que l’adrénaline, jouait un rôle dans la pérennisation d’une inflammation péri hépatique locale par un mécanisme AMPc dépendant mais epac/PKa indépendant. / Knowledge regarding long-term outcome after septic shock is limited. Additionally, the liver, which plays a key role during the septic illness, could significantly impact the long term outcome. First, in a surgical cohort of septic shock patients, we found that the 6-month mortality rate remained high. Baseline health-related quality of life (HRQOL) was found to be lower than in the general population and although HRQOL improved 6 months after the onset of septic shock, HRQOL remained lower than in the general population. In a second work including a large multicenter cohort of septic patients, we found a significant relationship between the occurrence or the worsening of liver dysfunction during the course of septic shock and mortality at 6 months; however, this relationship was not found in the patients with baseline liver dysfunction. At last, experimentally, we established a hepatocyte-macrophage co-culture model and septic shock was mimicked by lipopolysaccharide (LPS) treatment. We found that a catecholamine frequently used in septic shock such as epinephrine was able to shift the innate immune response toward a pro-inflammatory environment even when a low anti-inflammatory response was observed in macrophages and these effects were cAMP dependent but PKA/epac independent.

Le pronostic à court terme des patients d'oncohématologie admis en réanimation s'est notablement amélioré au cours des deux dernières décennies. Ces progrès sont le fait d'une diversification importante de l'arsenal thérapeutique relatif à l'oncologie et l'hématologie mais aussi d'une meilleure prise en charge de ces patients au sein des réanimations. Notre travail de recherche s'est centré sur la devenir de ces malades et les facteurs associés à celui-ci.Dans ce cadre, nous avons conduit plusieurs études observationnelles pronostiques portant sur des patients neutropéniques admis en réanimation. Nous avons montré que les facteurs indépendamment associés à la mortalité hospitalière étaient une allogreffe de moelle, le recours à la ventilation mécanique invasive, le recours à l'épuration extra-rénale ainsi qu'une documentation microbiologique positive. De plus, chez les patients neutropéniques admis en réanimation pour sepsis sévère/choc septique, les facteurs indépendamment associés à la mortalité en réanimation étaient une antibiothérapie initiale inappropriée, un délai d'initiation de l'antibiothérapie en réanimation > 1h, une documentation microbiologique positive à bacille gram négatif non fermentant et à un score SOFA élevé dès l'admission en réanimation. La désescalade du traitement antibiotique initial, réalisable dans 44% des cas,était sans répercussion significative sur le pronostic à court et long-terme. Enfin, chez les patients neutropéniques admis en réanimation pour détresse respiratoire aiguë, le seul facteur indépendant associé à la mortalité hospitalière était le recours à la ventilation mécanique alors que l'utilisation de corticostéroïdes les jours précédant l'admission en réanimation et l'une admission dans un contexte de sortie d'aplasie étaient protecteurs.Finalement, nous avons montré dans une récente revue de la littérature que le pronostic du patient d'oncohématologie admis en réanimation s'était amélioré au cours du temps et que la neutropénie ne semblait pas être un facteur pronostique dans ce contexte.En conclusion, nous avons montré que le patient neutropénique est à haut risque de complications sévères infectieuses, respiratoires et immunologiques. Ces complications impactent le pronostic des patients de manière significative. Nos résultats vont donner lieu à plusieurs essais randomisés chez le patient neutropénique admis en réanimation notamment autour de la désescalade antibiotique au cours du sepsis et des stratégies d'oxygénothérapie en cas de détresse respiratoire. / The short-term prognosis of patients with onco-hematological diseases and neutropenia admitted to intensive care has significantly improved over the last two decades. This progress is the fact of a significant diversification of the armamentarium on oncology and hematology but also a better management of these patients in the ICUs. Our research has focused on the outcome of these patients and its prognostic factors. In this context, we have conducted several prognostic observational studies of neutropenic patients admitted to intensive care units. We showed that factors independently associated with hospital mortality were the bone marrow transplantation, the use of invasive mechanical ventilation, the use of renal replacement therapy and a positive microbiological documentation. Moreover, in neutropenic patients admitted to intensive care for severe sepsis / septic shock, factors independently associated with ICU mortality were inappropriate initial antibiotic therapy, a delay of antibiotic treatment > 1h, a positive microbiological documentation with non-fermenting gram negative bacilli, a high SOFA score on admission in ICU. The de-escalation of initial antibiotic treatment feasible in 44% of cases had no significant impact on the short and long-term outcomes. Otherwise, in neutropenic patients admitted to intensive care for acute respiratory failure, the only independent factor associated with hospital mortality was the need for mechanical ventilation, while the use of corticosteroids in the days before ICU admission and a admission during neutropenia recovery period were protective. Finally, we have shown in a recent review of the literature that the outcome of hematology-oncology patient admitted to intensive care had improved over time and that neutropenia did not seem to be a prognostic factor in this context. In conclusion, we have shown that the neutropenic patient is at high risk of severe infectious,respiratory and immunological complications. These complications significantly impact the outcome of these patients. Our results could lead to the planning of several randomized trials in neutropenic patients admitted to intensive care in particular about the escalation antibiotic in sepsis and oxygentherapy strategies for respiratory distress.

Myocardial dysfunction is an important manifestation of sepsis/septic shock. Activation of Phosphatidylinositol 3-kinase(PI3K)/protein kinase B (Akt) signaling pathway has been shown to improve cardiac performance during sepsis/septic shock. We have reported previously that α-lipoic acid (LA) activates PI3K/Akt pathway in neuronal cells. It is possible, therefore, that treatment with LA will attenuate cardiac dysfunction during sepsis/septic shock through a PI3K/Akt-dependent mechanism. To test this possibility, we treated mice with LA prior to lipopolysaccharide (LPS) challenge. Cardiac function was analyzed by echocardiography 6 h after LPS challenge. LPS significantly suppressed cardiac function as evidenced by decreases in EF% and FS% in mice. However, LA pretreatment significantly attenuated cardiac dysfunction following LPS challenge. LA pretreatment also improved survival in LPS-challenged mice. Furthermore, LA markedly attenuated the LPS-induced inflammatory response in myocardium, as evidenced by decreases in the upregulation of VCAM-1, ICAM-1 and iNOS, as well as myocardial leucocytes infiltration. Moreover, LPS challenge significantly decreased the phosphorylation levels of Akt and Gsk-3β, which was prevented by LA pretreatment. More importantly, inhibition of PI3K/Akt signaling by Wortmannin (WM) completely abrogated the LA-induced protection in cardiac dysfunction following LPS challenge. Collectively, our results demonstrated that LA improved cardiac function during endotoxemia. The mechanism was through, at least in part, preserved activation of the PI3K/Akt signaling.

Myocardial dysfunction is an important manifestation of sepsis/septic shock. Activation of Phosphatidylinositol 3-kinase(PI3K)/protein kinase B (Akt) signaling pathway has been shown to improve cardiac performance during sepsis/septic shock. We have reported previously that α-lipoic acid (LA) activates PI3K/Akt pathway in neuronal cells. It is possible, therefore, that treatment with LA will attenuate cardiac dysfunction during sepsis/septic shock through a PI3K/Akt-dependent mechanism. To test this possibility, we treated mice with LA prior to lipopolysaccharide (LPS) challenge. Cardiac function was analyzed by echocardiography 6 h after LPS challenge. LPS significantly suppressed cardiac function as evidenced by decreases in EF% and FS% in mice. However, LA pretreatment significantly attenuated cardiac dysfunction following LPS challenge. LA pretreatment also improved survival in LPS-challenged mice. Furthermore, LA markedly attenuated the LPS-induced inflammatory response in myocardium, as evidenced by decreases in the upregulation of VCAM-1, ICAM-1 and iNOS, as well as myocardial leucocytes infiltration. Moreover, LPS challenge significantly decreased the phosphorylation levels of Akt and Gsk-3β, which was prevented by LA pretreatment. More importantly, inhibition of PI3K/Akt signaling by Wortmannin (WM) completely abrogated the LA-induced protection in cardiac dysfunction following LPS challenge. Collectively, our results demonstrated that LA improved cardiac function during endotoxemia. The mechanism was through, at least in part, preserved activation of the PI3K/Akt signaling.

Bakgrund: Sepsis definieras som en kroppslig reaktion på infektion och klassificeras som ett livshotande medicinskt tillstånd. Post-sepsis kännetecknas av hög mortalitet och morbiditet samt svår återhämtning. Därför är det viktigt att identifiera och sammanställa de problem patienter träffar på efter sepsis vård genom att bedöma deras livskvalitet efter sepsis. Syfte: Syftet med studien var att beskriva skillnader i livskvalitet efter genomgången sepsis, vid olika tidpunkter och i jämförelse med andra grupper i befolkningen. Metod: Litteraturstudien innefattar åtta empiriska studier med kvantitativ metod och sökning gjordes i databaserna Pubmed och Cinahl. Artiklarna kvalitetsgranskades, analyserades och sammanställdes i text och tabeller. Resultat: Artiklarna använde olika mätinstrument som inkluderar Short-Form Health Survey (SF-36), EuroQol-5 Dimensions (EQ-5D) och Sickness Impact Profile (SIP).Domänerna i mätinstrumentet omgrupperades för att anpassa resultaten till varandra och SF-36 användes som grundparametrar. Deltagarna upplevde ett signifikant nedsatt fysiskt och psykisk förmåga efter genomgången sepsis. Konklusion: Sepsis är en livshotande sjukdom som visade sig ha en hög grad påverkan på patienternas fysiska och mentala livskvalitet, under en lång period och återhämtning kan vara svår. Detta innebär att sepsis överlevande behöver vård under sjukhusvistelse samt även efter utskrivning. Ökad förståelse och kunskap behövs för att främja insatser som lindrar samt förbättrar livskvalitet hos sepsis överlevande. / Background: Sepsis is defined as a disturbed bodily reaction to infection and is classified as a life-threatening medical condition. Post-sepsis is characterized by high mortality and morbidity as well as difficult recovery. Therefore, it is important to identify and compile the problems patients encounter after sepsis care by assessing patients’ quality of life after sepsis. Aim: The purpose of the study was to describe differences in quality of life after surviving sepsis, at different times and in comparison, with other population groups. Methods: The literature study contains eight empirical studies with quantitative methods found in Pubmed and Cinahl. The articles were cross-examined, analyzed, and compiled in text and tables. Results: The articles used various quality-of-life measuring instruments that include the Short-Form Health Survey (SF-36), EuroQol-5 Dimensions (EQ-5D) and the Sickness Impact Profile (SIP). The domains in the measuring instrument were regrouped, and domains from SF-36 were used as base parameters. Patients experienced impaired physical and mental ability after sepsis. Conclusion: Sepsis is a life-threatening disease that has been shown to have a high degree of impact on patients’ physical and mental quality of life over a long period of time, and recovery can be difficult. This shows that sepsis survivors need care during the hospital stay and after discharge. Increased understanding and knowledge are needed to promote efforts that alleviate and improve the quality of life of sepsis survivors.

Sepsis is a severe blood stream infection that claim the lives of almost 220,000 Americans annually. Delayed patient treatment results in multi-organ failure, morbidity, mortality, and increased hospital length of stay. Timely sepsis management enables hospitals to have decreased expenses, increased patient survival, and judicious interventions. The problem addressed in this project was the lack of sepsis- training for registered nurses (RNs) working in the emergency department (ED) of a 628-bed hospital in the southeastern United States. Under the direction of the director of the ED, 269 patient charts were reviewed during 2014 to February 2015 for data related to a sepsis diagnosis. Data showed that 19.4% (n = 103) of patients diagnosed with sepsis had the sepsis order set implemented by the ED nurse. The purpose of this project was to create an educational sepsis-training program for ED nurses. The program included a 2-hour educational module on signs and symptoms of sepsis, including guidelines from the Surviving Sepsis Campaign and the Emergency Nurses' Association. Stetler's Model of Research Utilization and Benner's Novice to Expert conceptual frameworks supported the project. The director of professional practice provided formative feedback on module content and the program evaluation tool. Director feedback indicated that content was beneficial in educating ED nurses on the signs and symptoms of early sepsis recognition. The ED director has now mandated that all ED nurses take the training module and posttest. The project has the potential to improve early sepsis recognition by ED staff and to improve patient outcomes, thus promoting positive social change for patients, families, and nurses.

Sepsis is an organ dysfunction life-threatening disease that is caused by a dysregulated body response to infection. Sepsis is difficult to detect at an early stage, and when not detected early, is difficult to treat and results in high mortality rates. Developing improved methods for identifying patients in high risk of suffering septic shock has been the focus of much research in recent years. Building on this body of literature, this dissertation develops an improved method for septic shock prediction. Using the data from the MMIC-III database, an ensemble classifier is trained to identify high-risk patients. A robust prediction model is built by obtaining a risk score from fitting the Cox Hazard model on multiple input features. The score is added to the list of features and the Random Forest ensemble classifier is trained to produce the model. The Cox Enhanced Random Forest (CERF) proposed method is evaluated by comparing its predictive accuracy to those of extant methods.

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.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25157号 / 医博第5043号 / 新制||医||1070(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 石見 拓, 教授 西浦 博, 教授 江木 盛時 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM