Sepse bacteriana é a maior causa de morbimortalidade na faixa etária pediátrica e neonatal. A detecção precoce do quadro séptico é difícil, devido os sinais iniciais da doença serem inespecíficos. A possibilidade da existência de exame laboratorial capaz de identificar precocemente quadros sépticos melhoraria o prognóstico desses pacientes. Várias proteínas de fase aguda foram estudadas como marcadores de infecção sendo a proteína C reativa (PCR) a mais utilizada. A procalcitonina (PCT), um pró-hormônio, encontra-se elevado precocemente em quadros sépticos em crianças e adultos. Estudo prospectivo com 14 crianças submetidas à cirurgia cardíaca com circulação extra-corpórea (CEC), com dosagens seriadas de procalcitonina e proteína C reativa, serviram como modelo de resposta inflamatória sistêmica sem infecção com dosagens antes da CEC, após a CEC no primeiro, segundo e terceiro dia após cirurgia, enquanto 14 crianças com sepse/choque séptico dosagens seriadas de PCT e PCR foram obtidas sequencialmente antes do tratamento antibioticoterápico e a cada dia até o terceiro dia. Em crianças sépticas a PCT demonstrou ser superior a PCR como marcador de sepse assim como para diferenciar quadros inflamatórios sistêmicos. / Bacterial sepsis is a major cause of morbidity and mortality in neonates and children. Early detection of bacterial sepsis is difficult because the first signs of this disease may be minimal or nonspecific. The availability of a laboratory test to accurately and rapidly identify septic neonates and children would be of great value in improving the outcome of these patients. Several acute-phase proteins have been used for the diagnosis of bacterial sepsis and C reactive protein (CRP) is the usual marker. It has been reported that the concentration of procalcitonin (PCT), a pro-hormone, is markedly higher in children and adults with sepsis. In a prospective study, 14 children were enrolled after cardiac surgery with cardiopulmonary bypass (CPB), these group represent the non infected children with inflammatory response. Blood samples were obtained before CPB, after CPB, on the first, second and third day after surgery. Another group with 14 children with sepsis or septic shock were enrolled, and blood samples were obtained before antibiotic start, on the first, second and third days. In septic children PCT concentration is a better diagnostic marker of sepsis and to differentiate inflammatory response than CRP.

Le choc septique est défini par une hypotension persistante malgré un remplissage vasculaire adéquat en présence d’une réponse inflammatoire systémique suite à une infection. Il est responsable de 10% des admissions en réanimation et malgré des progrès thérapeutiques constants, la mortalité liée au sepsis varie entre 30% et 60% dans les cas de choc septique. Dans 50% des cas, le choc septique est associé à une insuffisance surrénale relative ce qui diminue la probabilité de survie des patients. Les patients sont alors traités avec de l’hydrocortisone et de la fludrocortisone, mais ce traitement est très controversé. Pour la première fois, nous avons pu mettre au point et valider une technique de quantification de la fludrocortisone plasmatique après une prise de 50 μg. Cette technique a pu ensuite être utilisée pour l’obtention de l’étude pharmacocinétique/pharmacodynamique de la fludrocortisone chez le volontaire sain et le patient septique avec insuffisance surrénale relative. Enfin, nous avons étudié la distribution et l’élimination de cette molécule chez la souris saine et deux modèles de sepsis. Les paramètres pharmacocinétiques montrent que la demi-vie de la fludrocortisone est d’environ 1 h, avec un délai d’absorption d’environ 50 minutes. Nos travaux ont permis de mettre en évidence qu’il existe deux populations de patients : les absorbants et les non-absorbants la fludrocortisone, qui représentent 30 % des patients testés, ce qui pourrait être à l’origine de la controverse sur les effets bénéfiques de cette molécule sur la survie des patients. Cependant nous n’avons pu mettre en évidence aucun effet hémodynamique de cette molécule sur les patients septiques. / The septic shock is defined by persistent hypotension despite fluid resuscitation with systemic inflammation due to infection. This is the cause of 10% of the admission in intensive care unit. Despite steady progress in therapeutics, the mortality of patients with sepsis varies between 30% to 60% for a septic shock. In 50%, the septic shock is associated to relative adrenal insufficiency which decrease survival probability of the patients. The patients receive hydrocortisone and fludrocortisone but this treatment is still controversial. For the first time, we developped and validated a quantification method of low concentration fludrocortisone in plasma. This method were used for the pharmacokinetic/pharmacodynamic study of fludrocortisone in healthy volunteers and patients with septic shock associated with relative adrenal insufficiency. Then we studied the distribution and elimination of this molecule in two mice models of sepsis. The pharmacokinetic parameters show that the half-life of fludrocortisone is about 1h and the delay of absorption is about 50min. Our study shows two groups of patients : absorbent patients and non-absorbent patients which have no detectable fludrocortisone concentrations in plasma. This population represents 30% of the population. This could be the reason of the controversial results. No hemodynamic effetc were found in patients with septic shock due to fludrocortisone after low-dosage administration.

Sepse bacteriana é a maior causa de morbimortalidade na faixa etária pediátrica e neonatal. A detecção precoce do quadro séptico é difícil, devido os sinais iniciais da doença serem inespecíficos. A possibilidade da existência de exame laboratorial capaz de identificar precocemente quadros sépticos melhoraria o prognóstico desses pacientes. Várias proteínas de fase aguda foram estudadas como marcadores de infecção sendo a proteína C reativa (PCR) a mais utilizada. A procalcitonina (PCT), um pró-hormônio, encontra-se elevado precocemente em quadros sépticos em crianças e adultos. Estudo prospectivo com 14 crianças submetidas à cirurgia cardíaca com circulação extra-corpórea (CEC), com dosagens seriadas de procalcitonina e proteína C reativa, serviram como modelo de resposta inflamatória sistêmica sem infecção com dosagens antes da CEC, após a CEC no primeiro, segundo e terceiro dia após cirurgia, enquanto 14 crianças com sepse/choque séptico dosagens seriadas de PCT e PCR foram obtidas sequencialmente antes do tratamento antibioticoterápico e a cada dia até o terceiro dia. Em crianças sépticas a PCT demonstrou ser superior a PCR como marcador de sepse assim como para diferenciar quadros inflamatórios sistêmicos. / Bacterial sepsis is a major cause of morbidity and mortality in neonates and children. Early detection of bacterial sepsis is difficult because the first signs of this disease may be minimal or nonspecific. The availability of a laboratory test to accurately and rapidly identify septic neonates and children would be of great value in improving the outcome of these patients. Several acute-phase proteins have been used for the diagnosis of bacterial sepsis and C reactive protein (CRP) is the usual marker. It has been reported that the concentration of procalcitonin (PCT), a pro-hormone, is markedly higher in children and adults with sepsis. In a prospective study, 14 children were enrolled after cardiac surgery with cardiopulmonary bypass (CPB), these group represent the non infected children with inflammatory response. Blood samples were obtained before CPB, after CPB, on the first, second and third day after surgery. Another group with 14 children with sepsis or septic shock were enrolled, and blood samples were obtained before antibiotic start, on the first, second and third days. In septic children PCT concentration is a better diagnostic marker of sepsis and to differentiate inflammatory response than CRP.

Due to increasing incidence and noncompliance with sepsis at a local hospital, an educational deficit was identified on the sepsis bundle in the medical intensive care unit. The purpose of this project was to develop and validate a sepsis bundle education program for all frontline staff in the MICU at a local University Hospital. The goal was for the educational tool to be validated by a multidisciplinary team to increase awareness, education, and ultimately, compliance with the severe sepsis and septic shock guidelines. The diffusion of innovation theory was utilized to support the process of change by encouraging the use of screening tools and best practice guidelines. The research question asked whether the education program meets critical care expert panel standards to educate frontline MICU staff on the sepsis bundle. The research design included a 5-member panel of experts in critical care, utilizing the Likert scale to review the proposed educational project on the sepsis bundle. Results are averaged from each reviewer. Results from the review included a unanimous '5' rating on every issue identified, equating to strongly agree on the Likert scale. This rating supported the validity of the educational project, the use of evidence-based practice and that the educational material was clear and easy to follow. Utilizing this validated tool will guide the education of sepsis, severe sepsis, and septic shock and promote social change by increasing education, awareness, recognition and early deployment of the sepsis bundle to improve patient outcomes.

Sepsis is life-threatening organ dysfunction caused by a response to infection that causes multiorgan failure. This condition causes high mortality and morbidity rates and leaves permanent disabilities. The purpose of this project was to create a sepsis protocol and an education training program for clinical staff in a hospital setting where no sepsis protocol was in place. The practice-focused question examined whether an educational program would improve clinical staff perception of their knowledge of the early recognition and management of sepsis. A literature review was conducted to identify an evidence-based practice protocol; the results were used to develop the education program for the clinical staff at the site. Malcolm Knowles'€™s theory of adult learning framed the project that included a team of 9 content experts consisting of physicians, physician assistants, and an educator who reviewed and approved the protocol and education program prior to implementation. The education program was then presented to 45 staff members including physicians, licensed vocational nurses, registered nurses, physician assistants, and nurse practitioners. Results of a 14-item knowledge test before and after the education program were examined for percent correct; results were compared using a paired-samples t test. Participant knowledge increased significantly (p <.05) from 20% correctly answering 10 of the 14 questions on the pretest to 87% answering all of the posttest questions correctly. The results of this project may promote positive social change by supporting clinical staff in early recognition and treatment of sepsis thereby reducing the morbidity and mortality that accompanies sepsis.

Bibliography: p. 137-154. / 154 p. : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis details a series of studies in patients, in human volunteers and in large animals. Haemodynamics and left ventricular systolic and diastolic mechanics are reported during lactic acidosis, during therapies for lactic acidosis, and during hyperdynamic and hypovolemic shock. The study has the unifying hypothesis that cardiac dysfunction is important in hyperdynamic and hypovolemic shock and is not caused by lactic acidosis. / Thesis (M.D.)--University of Adelaide, Dept. of Anaesthesia and Intensive Care, 1997?

Lipopolysaccharide (LPS), one of the main components of Gram-negative bacterial cell walls, is a potent endotoxin. Structures of the unique protective monoclonal antibody (mAb) WN1 222-5 in complex with Escherichia coli R2 and R4 LPS core regions show that recognition occurs in a manner similar to the innate immune receptor Toll-like receptor 4 (TLR4). Inner core LPS is shown to exist in a conserved epitope with multiple intramolecular interactions that allows the conserved epitope to bind strongly to mAb WN1 222-5. The structure of mAb FDP4, directed against truncated E. coli J-5 LPS, shows a deep pocket combining site specific for a terminal epitope that does not allow room for wild type (wt) LPS. Research into these anti-LPS binding mAbs opens up new avenues for potential septic shock therapy. The explosion of new techniques and bright x-ray sources in the 80’s and 90’s led to rapid advancement of protein x-ray crystallography; however, structure determination on some of the most important problems is now stalled due to the general inability to grow crystals of sufficient size. Recent advances in electron microscopy (EM) technology has led to improved beam characteristics, which has allowed the initiation of research to develop EM as a viable alternative to x-ray crystallography. In this research, method development using standard equipment to explore potential avenues for analysing three-dimensional protein crystals via EM has been explored. / Graduate / 0982 / 0487 / 0537 / kgomery@uvic.ca

Thesis (M. Phil.)--University of Hong Kong, 2008. / Also available in print.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Also available online.

Submitted by ISADORA PIMENTEL DE SOUZA (euisaps@yahoo.com.br) on 2018-08-10T17:48:48Z No. of bitstreams: 1 DISSERTACAO 10.08.pdf: 1322071 bytes, checksum: bb198d40ebd35093636b6713a6bab637 (MD5) / Approved for entry into archive by Sulamita Selma C Colnago null (sulamita@btu.unesp.br) on 2018-08-13T18:02:13Z (GMT) No. of bitstreams: 1 souza_ip_me_bot.pdf: 1322071 bytes, checksum: bb198d40ebd35093636b6713a6bab637 (MD5) / Made available in DSpace on 2018-08-13T18:02:13Z (GMT). No. of bitstreams: 1 souza_ip_me_bot.pdf: 1322071 bytes, checksum: bb198d40ebd35093636b6713a6bab637 (MD5) Previous issue date: 2018-07-23 / Introdução: O choque séptico é uma importante causa de morbimortalidade em recém-nascidos prematuros. O lactato vem sendo estudado como marcador diagnóstico e prognóstico do choque, mas os estudos no período neonatal são escassos. Objetivo: Investigar se os níveis séricos de lactato podem predizer o risco de morte em prematuros com choque séptico. Métodos: Estudo retrospectivo, longitudinal, realizado na UTI Neonatal do Hospital das Clinicas da Faculdade de Medicina de Botucatu no período de janeiro de 2014 a dezembro de 2016, após aprovação do CEP. Foram incluídos todos os prematuros menores que 37 semanas, internados na UTI, com mais de 72 horas de vida, que apresentaram diagnóstico de choque séptico e dosagem do lactato sérico nas primeiras 48 horas do choque. Foram excluídos aqueles com malformações múltiplas, infecções congênitas e erros inatos do metabolismo. Variáveis estudadas: maternas, gestacionais, neonatais, agente etiológico e dosagem do lactato. Os prematuros foram comparados em dois grupos: sobrevida e óbito. Desfecho: óbito. Análise estatística: testes paramétricos e não paramétricos com significância estatística se p<0.05. Acurácia do lactato: sensibilidade, especificidade, valor preditivo positivo e negativo. Resultados: Dentre os 456 prematuros sobreviventes por mais de 72 horas, 130 apresentaram sepse tardia (28,5%) e destes, 36 choque séptico (28%). A mortalidade no choque foi de 42%. A positividade em hemocultura foi de 36% com predomínio de Gram-positivos no grupo sobrevida e de Gram-negativos no grupo óbito. A comparação entre os grupos sobrevida e óbito, respectivamente mostrou: idade gestacional 29,5sem vs 27,5sem (p=0.05); peso de nascimento 950g vs 900g (p=0.386), idade no diagnóstico do choque 11 dias vs 7 dias (p=0.071), uso de drogas vasoativas 52% vs 93% (p=0.011). Os níveis de lactato foram maiores no grupo óbito (1,2mmol/L vs 1,7 mmol/L; p=0.043). O lactato  4mmol/L apresentou boa acurácia na predição de morte diretamente relacionada ao choque (89%) com baixa sensibilidade, 33%, mas com especificidade e valor preditivo positivo de 100% e valor preditivo negativo de 88%. Conclusão: A incidência e mortalidade do choque séptico em prematuros foram altas, sendo os muito prematuros e os de extremo baixo peso os mais acometidos. Valores de lactato  4 mmol/L apresentaram boa acurácia na predição de morte, alta especificidade e alto valor preditivo positivo. / Introduction: Septic shock is an important cause of morbidity and mortality in premature infants. Lactate has been studied as a diagnostic and prognostic marker of shock, but studies in the neonatal period are scarce. Objective: To investigate if serum lactate levels can predict the risk of death in preterm infants with septic shock. Methods: Retrospective, longitudinal study performed at the Neonatal Intensive Care Unit (NICU) of the Clinics Hospital – Botucatu School of Medicine, from January 2014 to December 2016, after approval of the Ethics Committee. All preterm infants less than 37 weeks gestational age, with more than 72 hours of life, admitted at the NICU with diagnosis of septic shock and serum lactate dosage in the first 48 hours of shock were included. Those with multiple malformations, congenital infections and inborn errors of metabolism were excluded. Variables studied: maternal, gestational, neonatal, etiologic agent and lactate dosage. The preterm infants were compared in two groups: survival and death. Outcome: death. Statistical analysis: parametric and non-parametric tests with statistical significance if p<0.05. Lactate accuracy: sensitivity, specificity, positive and negative predictive value. Results: Among the 456 preterm infants who survived for more than 72 hours, 130 had late onset sepsis (28.5%) and of these 36 septic shock (28%). The shock mortality was 42%. The positivity in blood cultures was 36%, with a predominance of Gram-positive in the survival group and Gram-negative in the death group. The comparison between survival and death groups, respectively, showed: gestational age 29.5weeks vs 27.5 weeks (p=0.05); birth weight 950g vs 900g (p=0.386), age at shock diagnosis 11 days vs 7 days (p=0.071), vasoactive drugs 52% vs 93% (p=0.011). Lactate levels were higher in the death group (1.2mmol/L vs 1.7 mmol/L, p=0.043). Lactate ≥4 mmol/L showed good accuracy in predicting death directly related to shock (89%) with low sensitivity 33%, but with specificity and a positive predictive value of 100% and a negative predictive value of 88%. Conclusion: The incidence and mortality of septic shock in premature infants were high, and very premature and extremely low birth weight were the most affected. Values of lactate  4 9 mmol/L showed good accuracy in predicting death, high specificity and high positive predictive value.