OBJETIVO: Determinar la valoración del Índice de Disfunción Orgánica Múltiple de Marshall en pacientes con sepsis en el Hospital Nacional 2 de Mayo. DISEÑO: Estudio prospectivo observacional con un diseño descriptivo longitudinal. LUGAR: Servicio de emergencia del Hospital Nacional 2 de Mayo. PACIENTES: Se evaluaron a 71 pacientes adultos con sepsis admitidos entre el 1 de julio al 31 de octubre del 2004 en el servicio de emergencia del Hospital Nacional 2 de Mayo. MEDIDAS Y RESULTADOS: Se encontró que de los 71 pacientes; 39 (54.9 %) fueron mujeres y 32 (45.1 %) fueron hombres; el foco séptico que más predominó fue el pulmonar con 42 casos que representa el 59.16 %, seguido por el foco dérmico con 11 casos. En cuanto al Índice de Disfunción Orgánica Múltiple (IDOM) se encontró que a partir del tercer día la elevación del mismo se correlacionó directamente con la mortalidad en forma altamente significativa (p<0.05), observándose un RR de 44.25, con una sensibilidad y especificidad del 90 % y 95 % respectivamente. CONCLUSIONES: Se evidenció que el poco difundido y poco aplicado Índice de Disfunción Orgánica Múltiple (IDOM) de Marshall sí tiene utilidad como instrumento de valoración, seguimiento y predicción de eventos adversos (fallecimiento) en pacientes sépticos (críticos), en relación a los demás scores (APACHE II, SOFA), por ser estos últimos de mayor complejidad en su aplicación y de necesitar mayor apoyo logístico.

No description available.

The aims of this Thesis were to investigate early markers of neonatal sepsis and patient-factors affecting the pharmacokinetics and pharmacodynamics (PKPD) of aminoglycosides in the treatment of neonatal sepsis. A prospective cohort study of neonates commenced on gentamicin for suspected sepsis was performed between 1 July 2002 and 28 February 2007. Receiver operator characteristics (ROC) plots were used to assess potential markers of sepsis against culture positive sepsis. When sepsis was first suspected, the most promising tests were interleukin (IL) IL-12(p70) with an area under the curve (95% CI) for the ROC of 0.74 (0.63-0.86), and which (with a cut-off at 75 pg/mL) had a sensitivity (95% CI) of 28% (20-36%) and a specificity of 98% (96-100%). IL-10 had a sensitivity of 17% (10-23%) and a specificity of 99% (97-100%). Retrospective studies of neonates treated with gentamicin, amikacin and netilmicin for suspected sepsis were used to identify patient characteristics that affected aminoglycoside PKPD properties. Population PK modelling used NONMEM� v.5 to determine aminoglycoside clearance (CL) and volume of distribution (V). Logistic regression was used to examine the treatment outcome measures (serum peak and trough concentrations and ototoxicity). Simulations of new dosing regimens were undertaken for netilmicin and amikacin using MATLAB� The final gentamicin PK covariate model gave CL = 0.097 x (current weight/2)[1.3] x (postnatal age/7)[0.29] and V = 1.07 x (current weight/2)[0.8]+ (confirmed sepsis) x 0.13. A 10% increase in gentamicin V in neonates with sepsis was estimated. For amikacin, 17 (35%) of 49 episodes of confirmed sepsis met the treatment failure criteria from 12 (15%) individual patients. The final amikacin PK covariate model was CL = 0.23 x (current weight/2)[0.691] x (postmenstrual age/40)[3.23] and V = 0.957 x (current weight/2)[0.89]. PD analysis determined risk factors linked to hearing impairment in neonates treated with amikacin included: co-medication with vancomycin, high C-reactive protein concentration and low gestational age. Simulation of a new amikacin dosing regimen recommended: 15 mg/kg 36 hourly, 14 mg/kg 24 hourly, and 15 mg/kg 24 hourly, for neonates [less than or equal to] 28 weeks, 29 to 36 weeks, and [greater than or equal to] 37 postmenstrual age, respectively. For netilmicin, the final PK covariate model was CL = 0.192 x (current weight/2)[1.35] x (postmenstrual age/40)[1.03], V = 1.5 x (current weight/2)[0.3]. Simulation of a new optimal dosing regimen for netilmicin was: 5 mg/kg 36 hourly, 5 mg/kg 24 hourly, 6 mg/kg 24 hourly, and 7 mg/kg 24 hourly, for neonates [less than or equal to] 27, 28 to 30, 31 to 33, and [greater than or equal to] 34 weeks postmenstrual age, respectively. IV infusions representing gentamicin administration to neonates of 2.5 kg and 0.5 kg in the NICU setting (30 minutes gentamicin infusion then a 30 minute saline flush) showed the larger neonates received 80% of the drug within 60 minutes. This increased to 90-95% by 75 minutes. However, in extremely low birth weight neonates (0.5 kg), only 60% of the intended gentamicin dose was delivered by 60 minutes (70% by 75 minutes). In conclusion: IL-12(p70) and IL-10 were identified as promising diagnostic tests to confirm sepsis in neonates. Confirmed sepsis caused a 10% increase in V of gentamicin in neonates, suggesting larger initial dosages (mg/kg) are required for effective treatment of neonates with sepsis. Aminoglycoside clearance in neonates is predominantly affected by current weight, postmenstrual age or postnatal age. Adjusting netilmicin and amikacin doses based on current weight, and dosing interval based on both postmenstrual age and current weight improves drug efficacy. Identification of co-medication with vancomycin, low gestational age, and high C-reactive protein during treatment with amikacin increases risk of hearing impairment. The delivery of gentamicin administrated by IV infusion is substantially extended in extremely low birth weight neonates.

Thesis (M.S.)--University of Michigan, Ann Arbor, 1975. / Typescript (photocopy). Includes bibliographical references (leaves 54-60). Also issued in print.

Thesis (M.S.)--University of Michigan, Ann Arbor, 1975. / Typescript (photocopy). eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 54-60).

Thesis (Ph.D.) - University of Queensland, 2002. / Includes bibliography.

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Dissertação de Mestrado apresentada ao Programa de Pós-Graduação em Ciências da Saúde para obtenção do título de Mestre em Ciências da Saúde. / Studies are researching immune cell death mechanisms during the course of sepsis in response to pro-inflammatory and anti-inflammatory mediators that are involved in its pathophysiology. Taurine (Tau) is an abundant amino acid in polymorponuclear leucocytes (PMN) that reacts with hypochlorous acid to form taurine chloramine (TauCl) under inflammatory conditions. In this context, we investigated potential interactions between lymphocytes and TauCl in rats submitted to cecal ligation and perforation (CLP), analyzing cell viability and cytokine secretion profile (TNF-α, IFN-γ, IL-6, IL-17A, IL-23 and IL-10). Adult male rats were divided in two groups (sham and CLP) and then were killed 24 or 120 hours after sepsis induction to isolate lymphocytes from blood and spleen. Lymphocytes (> 95,0% purity determined by differentiation with Giemsa staining) were cultured for 24 hours at a concentration of 1x106 cells/mL and activated by 2 μg/mL concanavalin A (Con-A). After 24 hours, Tau and TauCl were added at concentrations of 0.1, 0.2, 0.3, 0.4 and 0.5 (mM) for 1 hour. After this time, cells were incubated with MTT (500 μg/mL) for 3 hours to evaluate cell viability and supernatants were used to determine cytokines levels. Cells incubated with Tau exhibited better viability than those incubated with TauCl, in both time and organs. TauCl, in a time and dose-dependent ratio, decreased cytokines secretion (TNF-α, IFN-γ, IL-6, IL-17A, IL-23 and IL-10) when compared to untreated cells. These findings show a possible impairment in lymphocytes function promoted by TauCl, correlated with immunosuppression and cell death characteristic of the late stages of sepsis. / Estudos estão buscando mecanismos de morte celular durante o curso da sepse, em que respostas pró-inflamatórias e anti-inflamatórias estão envolvidas na sua complexa fisiopatologia. Taurina (Tau) é um aminoácido abundante em polimorfomucleares (PMNs) que reage com ácido hipocloroso para formar o oxidante cloramina taurina (TauCl) em condições inflamatórias. Neste contexto, foi investigado potenciais interações entre linfócitos e TauCl em ratos submetidos à ligação e perfuração cecal (CLP), por meio de análise de viabilidade celular e perfil de secreção de citocinas (TNF-α, IFN-γ, IL-6, IL-17A, IL-23 e IL-10). Ratos adultos machos foram divididos em dois grupos (sham e CLP) e subsequentemente mortos 24 ou 120 horas após a indução da sepse para isolamento de linfócitos do sangue e do baço. Linfócitos (> 95,0% de pureza determinada por diferenciação com coloração de Giemsa) foram cultivados por 24 horas a uma concentração de 1x106 células/mL e ativadas com 2 μg/mL de concanavalina A (ConA). Após 24 horas, Tau e TauCl foram adicionadas a concentrações de 0,1, 0,2, 0,3, 0,4 e 0,5 (mM) por uma hora. Após este tempo, as células foram incubadas com MTT (500 μg/mL) por 3 horas para avaliar viabilidade celular e os sobrenatantes foram usados para determinar os níveis de citocinas. Células incubadas com Tau exibiram maior viabilidade do que as células incubadas com TauCl, em ambos tempos e órgãos. TauCl, por meio de relação dose-dependente, diminuiu a secreção de citocinas (TNF-α, IFN-γ, IL-6, IL-17A, IL-23 e IL-10) quando comparadas às células não incubadas. Estes achados mostram um possível comprometimento na função de linfócitos promovido pelo efeito de TauCl, correlacionado com a imunossupressão e morte celular características dos estágios de sepse.

Tese de Doutorado apresentada ao Programa de Pós-Graduação em Ciências da Saúde da Universidade do Extremo Sul Catarinense – UNESC, para obtenção do título de Doutora em Ciências da Saúde. / Sepsis survivors have cognitive impairments associated with decreased quality of life and increased long-term morbidity. Some of these changes are similar to the pathophysiology of neurodegenerative diseases. The receptor for advanced glycation end product ( RAGE) has been associated with progression of neuronal death in many neurodegenerative diseases such as Alzheimer's, and is an important pro- inflammatory mediator. Previous studies have shown that the use of metalloproteinase inhibitor or antioxidant can assist in reducing cognitive impairment. We analyzed biochemical parameters related to neurodegeneration in animal sepsis survivors and the possible involvement of RAGE, the inhibitory avoidance test and use of Metalloproteinase Inhibitor and Antioxidant in animals surviving sepsis. The animals were subjected to sepsis by cecal ligation and puncture ( CLP ) and thirty days after induction, hippocampus and prefrontal cortex were isolated. In the first experiment the immunocontent the _ - amyloid peptide ( Aß ), _ - synuclein, synaptophysin and phosphorylated tau were analyzed by western blot. Furthermore, it was found that the RAGE immunocontent the presence of S100_. An increase of _ -synuclein, tau and phosphorylated Ab and the hippocampus, but not in the prefrontal cortex. The immunocontent RAGE was increased in the two structures and S100_ showed no differences compared to controls in both structures. In the second experiment, we determined the levels of Aß and synaptophysin ( identical to experiment 01 procedures ) and performed the inhibitory avoidance, where the data showed that the inhibitory avoidance latency was significantly reduced in sepsis group compared to sham, suggesting damage to the memory aversive. In the third experiment procedures as experiment 01 were adopted for the animals, except for a few animals that were immediately treated the induction of sepsis with ATX and MMP 2-9 and subsequently testing the inhibitory avoidance (as experiment 02 ). Despite the fact that the inhibitory avoidance task to be a dependent of the hippocampus, it was not possible to determine a decrease in the levels of synaptophysin in the hippocampus or a relationship of increased levels of Aß and RAGE in the hippocampus with test performance of inhibitory avoidance. In the prefrontal córtex synaptophysin levels drop and small increase in their levels of treatment was observed, improved deseempenho memory. The early treatment with antioxidants can decrease cognitive impairment in long-term animals. We concluded that the brains of animals surviving sepsis have several markers of neurodegeneration and performance in the inhibitory avoidance test seems to be dependent on the levels of some of these markers, suggesting a neurodegenerative phenomenon this may be an important factor in cognitive impairment associated with long term rat sepsis survivors. / Sobreviventes a sepse apresentam danos cognitivos associados com a diminuição da qualidade de vida e aumento da morbidade a longo prazo. Algumas destas alterações se assemelham aos mecanismos fisiopatológicos de doenças neurodegenerativas. O receptor para produto final de glicolização avançada (RAGE) vem sendo associado à progressão de morte neuronal em muitas doenças neurodegenerativas, como o Alzheimer, além de ser um importante mediador próinflamatório. Estudos anteriores mostraram que o uso de Inibidor de metaloproteinase de matriz (MMP) ou antioxidante (ATX) podem auxiliar na redução do dano cognitivo. Analisaram-se parâmetros bioquímicos relacionados à neurodegeneração em animais sobreviventes a sepse e o possível envolvimento do RAGE; o teste de esquiva inibitória e uso de Inibidor de MMP e ATX em animais sobreviventes a sepse. Os animais foram submetidos à sepse por ligação cecal e punção (CLP) e trinta dias após a indução, hipocampo e córtex pré-frontal foram isolados. No primeiro experimento o imunoconteúdo do peptídeo amilóide-_ (A_), _-sinucleína, sinaptofisina e tau fosforilada foram analisados por western blot. Além disso, verificou-se o imunoconteúdo de RAGE e a presença de S100_. Houve aumento de _-sinucleína, A_ e tau fosforilada no hipocampo, mas não no córtex pré-frontal. O imunoconteúdo de RAGE esteve aumentado nas duas estruturas e S100_ não apresentou diferenças quando comparadas ao controle, em ambas as estruturas. No segundo experimento, foram determinados os níveis de A_ e sinaptofisina (procedimentos idênticos ao experimento 01) e realizada a esquiva inibitória, onde os dados mostraram que a latência na esquiva inibitória foi significativamente reduzida no grupo sepse quando comparados ao sham, sugerindo dano na memória aversiva. No terceiro experimento foram adotados procedimentos conforme experimento 01 quanto aos animais, com exceção de alguns animais que foram tratados imediatamente a indução da sepse com ATX e inibidor de MMP 2-9 e posteriormente o teste da esquiva inibitória (conforme experimento 02). Apesar do fato de a esquiva inibitoria ser uma tarefa dependente do hipocampo, não foi possível determinar uma diminuição nos níveis de sinaptofisina no hipocampo ou uma relação do aumento dos níveis de A_ e RAGE no hipocampo com desempenho no teste da esquiva inibitória. No córtex pré-frontal foi observada queda dos níveis de sinaptofisina e com pequeno aumento nos seus níveis de tratamento, melhorou o desempenho da memória. O tratamento com ATX precoce pode diminuir o deficit cognitivo a longo prazo em animais. Conclui-se que o cérebro dos animais sobreviventes a sepse apresentam vários marcadores de neurodegeneração e o desempenho no teste de esquiva inibitória parece ser dependente dos níveis de alguns destes marcadores, sugerindo um fenômeno neurodegenerativo podendo este ser um fator importante na associação com dano cognitivo a longo prazo em ratos sobreviventes a sepse.

Made available in DSpace on 2016-08-12T18:48:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-12-03. Added 1 bitstream(s) on 2016-08-12T18:51:10Z : No. of bitstreams: 1 000864610.pdf: 3089089 bytes, checksum: e31156d3741c67e09c6b97faabdaf165 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Photobacterium damselae subsp. piscicida (Phdp) é importante agente causal de septicemia e pseudotuberculose, respectivamente nas fases aguda e crônica em peixes marinhos. O método de imunização e tratamento das infecções bacterianas em peixes é limitado à imunização ativa, com demanda bioenergética celular para gerar a resposta imune humoral. O uso de antibióticos na água, como forma terapêutica, resulta em resíduos na carne do peixe e no consumidor final humano, favorecendo o desenvolvimento da resistência microbiana. Este estudo teve como objetivos a produção e purificação de anticorpos IgY policlonais, extraídos da gema do ovo de galinha e específicos para as proteínas citoplasmáticas e de membrana bacteriana de Phdp e seus efeitos no controle da sepse aguda em Rachycentron canadum infectados experimentalmente. Os resultados demonstram redução do acúmulo de células na inflamação aguda induzida, pela inoculação da bactéria homóloga na cavidade celomática e na atividade respiratória de leucócitos sanguíneos nos grupos que receberam anticorpos IgY 48 horas e 15 dias antes do desafio. Verificou-se ainda redução da disseminação bacteriana em fígado, rim, baço e coração que foi correlacionada com a diminuição das lesões renais e hepáticas e demonstrada no perfil bioquímico e histopatológico. Os resultados são promissores no que tange ao uso da imunoglobulina Y como método profilático e na imunoterapia de infecções bacterianas em organismos aquáticos / The Photobacterium damselae ssp. piscicida is an important causative agent of septicemia and pseudotuberculosis in the acute and chronic phases in marine fish, respectively. The method for immunization and treatment of bacterial infections in fish is limited to the active immunization, which demands cellular bioenergy to generate humoral immune response. The use of antibiotics in the water as a form of therapy results in residues in the meat that will be consumed by humans, favoring the development of microbial resistance. Thus, the aim of the study was to produce and purify polyclonal IgY, specific for membrane proteins of P. damselae ssp. piscicida (PMBphdp), extracted from the yolk of laying hens, and to observe its effects on the control of acute sepsis in experimentally infected Rachycentron canadus. The results showed reduction of cell accumulation in acute inflammation induced by inoculation of the homologous bacteria in the coelomic cavity and decrease in the respiratory activity of blood leukocytes in groups receiving IgY antibodies at 48 hours and 15 days before the challenge. It was also observed the reduction of bacterial dissemination to the liver, kidney and heart which was correlated with the decrease in liver and kidney damage, which was demonstrated by the biochemical and histopathological profile. The results are promising regarding the use of immunoglobulin Y as prophylactic method and for immunotherapy of microbial infections in aquatic organisms