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Durante a cirurgia de revascularização do miocárdio com circulação extracorpórea e hipotermia (CEC-H) ocorre alteração na efetividade do propofol e na sua farmacocinética realizada a partir das concentrações plasmáticas do propofol total no decurso do tempo. A ligação do propofol à proteína plasmática parece estar alterada em consequência de diversos fatores incluindo a hemodiluição e a heparinização que ocorre no início da circulação extracorpórea, uma vez que se reportou anteriormente que a concentração plasmática do propofol livre aumentou durante a realização da circulação extracorpórea normotérmica. Por outro lado, a infusão alvo controlada é recomendada para manter a concentração plasmática do propofol equivalente ao alvo de 2 &#181g/mL durante a intervenção cirúrgica com CEC-H. Se alterações significativas na hipnose do propofol ocorrem nesses pacientes, então o efeito aumentado desse agente hipnótico poderia estar relacionado à redução na extensão da ligação do fármaco as proteínas plasmáticas; entretanto, o assunto ainda permanece em discussão e necessita de investigações adicionais. Assim, o objetivo do estudo foi investigar as concentrações plasmáticas de propofol livre em pacientes durante a revascularização do miocárdio com e sem o procedimento de CEC-H através da abordagem PK-PD. Dezenove pacientes foram alocados e estratificados para realização de cirurgia de revascularização do miocárdio com circulação extracorpórea (CEC-H, n=10) ou sem circulação extracorpórea (NCEC, n=9). Os pacientes foram anestesiados com sufentanil e propofol alvo de 2 &#181g/mL. Realizou-se coleta seriada de sangue para estudo farmacocinético e o efeito foi monitorado através do índice bispectral (BIS) para medida da profundidade da hipnose no período desde a indução da anestesia até 12 horas após o término da infusão de propofol, em intervalos de tempo pré-determinados no protocolo de estudo. As concentrações plasmáticas foram determinadas através de método bioanalítico pela técnica de cromatografia líquida de alta eficiência. A farmacocinética foi investigada a partir da aplicação do modelo aberto de dois compartimentos, PK Solutions v. 2. A análise PK-PD foi realizada no Graph Pad Prisma v.5.0 após a escolha do modelo do efeito máximo (EMAX sigmóide, slope variável). Os dados foram analisados utilizando o Prisma v. 5.0, p<0,05, significância estatística. As concentrações plasmáticas de propofol total foram comparáveis nos dois grupos (CEC-H e NCEC); entretanto o grupo CEC-H evidenciou aumento na concentração do propofol livre de 2 a 5 vezes em função da redução na ligação do fármaco às proteínas plasmáticas. A farmacocinética do propofol livre mostrou diferença significativa entre os grupos no processo de distribuição pelo prolongamento da meia vida e aumento do volume aparente, e no processo de eliminação em função do aumento na depuração plasmática e redução na meia vida biológica no grupo CEC-H. A escolha do modelo EMAX sigmóide, slope variável foi adequada uma vez que se evidenciou alta correlação entre os valores do índice bispectral e as concentrações plasmáticas do propofol livre (r2>0.90, P<0.001) para os pacientes investigados. / During coronary artery bypass grafting (CABG) surgery with cardiopulmonary bypass (CPB) profound changes occur on propofol effect and on kinetic disposition related to total drug plasma measurements in these patients. It was reported that drug plasma binding could be altered as a consequence of hemodilution and heparinization before starts CPB since free propofol plasma levels was increased by twice under normothermic procedure. In addition, the target controlled infusion (TCI) is recommended to maintain propofol plasma concentration (2 &#181g/mL) during CABG CPB-H intervention. However, whether significant changes that occur in propofol hypnosis in these patients could be related to the reduction on the extension of drug plasma binding remain unclear and under discussion until now. Then, the objective of this study was to investigate propofol free plasma levels in patients undergoing CABG with and without CPB by a pharmacokinetics-pharmacodynamics (PK-PD) approach. Nineteen patients were scheduled for on-pump coronary artery bypass grafting (CABG-CPB, n=10) or off-pump coronary artery bypass grafting (OPCABG, n=9) were anesthetized with sufentanil and propofol TCI (2 &#181g/mL). Blood samples were collected for drug plasma measurements and BIS were applied to access the depth of hypnosis from the induction of anesthesia up to 12 hours after the end of propofol infusion, at predetermined intervals. Plasma drug concentrations were measured using high-performance liquid chromatography, followed by a propofol pharmacokinetic analysis based on two compartment open model, PK Solutions v.2; PK-PD analysis was performed by applying EMAX model, sigmoid shape-variable slope and data were analyzed using Prisma v. 5.0, considering p<0.05 as significant difference between groups. The total propofol plasma concentrations were comparable in both groups during CABG; however it was shown in CPB-group significant increases in propofol free plasma concentration by twice to fivefold occur as a consequence of drug plasma protein binding reduced in these patients. Pharmacokinetics of free propofol in CPB-H group compared to OPCAB group based on two compartment open model was significantly different by the prolongation of distribution half-life, increases on plasma clearance, and biological half-life shortened. In addition, the kinetic disposition of propofol changes in a different manner considering free drug levels in the CPB-H group against OPCAB group as follows: prolongation of distribution half-life and increases on volume of distribution, remaining unchanged biological half-life in spite of plasma clearance increased. BIS values showed a strong correlation with free drug levels (r2>0.90, P<0.001) in CPB-H group and also in OPCAB group by the chosen EMAX model sigmoid shape-variable slope analyzed by GraphPad Prisma v.5.0.

Made available in DSpace on 2016-01-26T12:51:53Z (GMT). No. of bitstreams: 1 margarethdibo_tese.pdf: 1810718 bytes, checksum: 4df01c13c55a541f2c4aff4668fbacd7 (MD5) Previous issue date: 2004-03-17 / Fundação de Amparo a Pesquisa do Estado de São Paulo / The strategy to contain the vector of Dengue fever in the state of São Paulo is centered around a reduction in breeding places and by chemical controls. To obtain better results in the reduction of the vectorial density it is important to incorporate other measures in the routine approach. Egg traps are considered to be preventative and control measures of Aedes aegypti, however, there are no studies that define the favorite egg-laying locations in residences. The utilization of an infusion of Panicum maximum in traps increases its attractiveness to vector females and increases the number of eggs collected. This study aims to contribute to techniques by using traps to evaluate the number of weeks this infusion remains attractive to females. More importantly, it aims to assess the egg-laying behavior of the Aedes aegypti and Aedes albopictus populations in Mirassol, a town situated in the region of São José do Rio Preto, Brazil. Traps with egg-collecting paddle were installed in 200 houses in 20 blocks giving a total of 10 houses to each block. Half of the blocks were chosen at random for the installation of traps baited with the infusion and in the other half, traps with ordinary water were installed. Two egg-traps were placed inside the house (bedroom and living room) and two outside (one under cover and the other in the open). Weekly visits were made from September to December 2002, to analyze all the traps, collecting the existing sticks and leaving new ones. In the laboratory the viable and nonviable eggs on the sticks were counted. Positive sticks were considered to be those on which eggs were found and these were correlated with the type of trap, infusion or water, the location of the trap within the house and the number of weeks after the start of the trial. A sample of these sticks was placed in water, to hatch the larvae with the aim of identifying the species. The mean numbers of eggs and larvae of the Aedes aegypti and Aedes albopictus were calculated and associated with the location within the house, the type of trap used, infusion or water, and the week number. Analyzing the number of positive sticks, and the mean number of eggs on the traps, it was evidenced that the traps with infusion were more attractive/stimulating for egg-laying for females of the genera Aedes than those with water in the first three weeks of exposition. The uncovered outdoor traps were the most favored location for egg-laying during the entire study period; in second place were the outdoor ones under cover. High values of the Spearman correlation coefficients and p-values less than 0.004 demonstrated a strong correlation between the positivity and the mean number of eggs, indicating that one variable predicts the other. From the analysis of the hatched larvae, Aedes aegypti were identified on 99.6% (CI 95%: 99.04 99.84) of the sticks and Aedes albopictus on 1.8% (CI 95%: 1.19 2.70) of them. In Mirassol the probability of finding eggs of Aedes aegypti on any one stick under these circumstances is greater than 99%. / A estratégia para controle do vetor do dengue no estado de São Paulo está centrada na redução de criadouros e ações de controle químico. Para a obtenção de melhores resultados na redução da densidade vetorial é importante que se incorpore outras medidas de uso rotineiro. Armadilhas de oviposição são consideradas medidas de vigilância e controle de Aedes aegypti, entretanto não existem estudos sobre locais do domicílio preferidos para oviposição. A utilização de infusão de Panicum maximum em armadilhas propicia maior atração às fêmeas do vetor e coleta de maior quantidade de ovos. Através deste estudo, procurou-se subsidiar as técnicas para o uso de armadilhas, avaliar durante quantas semanas a referida infusão manteve sua atração sobre as fêmeas e, principalmente, avaliar o comportamento de oviposição de populações de Aedes aegypti em Mírassol, cidade situada na região de São José do Rio Preto. Instalaram-se armadilhas de oviposição em 200 casas, divididas em 20 quadras, distribuindo-as em 10 casas por quadra. Foram sorteadas 50% das quadras para instalação de armadilhas iscadas com infusão, e nas demais se instalou armadilhas com água. Duas armadilhas foram colocadas no intradomicílio (quarto e sala) e duas no peridomicílio (uma sob cobertura e outra ao relento). Foram feitas visitas semanais entre setembro e dezembro de 2002, para a análise de todas as armadilhas, e substituição das palhetas. Em laboratório, contaram-se ovos viáveis e inviáveis existentes nas palhetas. A presença de ovos na palheta significou a sua positividade, a qual foi verificada quanto à presença ou não de infusão, local de instalação na casa e número de semanas. Uma amostra destas palhetas foi colocada em água, para eclosão de larvas, visando à identificação específica. Os números médios de ovos e de larvas Aedes aegypti e Aedes albopictus foram quantificados segundo o posicionamento no domicílio, presença de armadilha iscada com infusão ou água e o número de semanas. Analisando-se Nota de Resumo as positividades e os números médios de ovos das armadilhas, obteve-se que as armadilhas iscadas com infusão mostraram-se mais atraentes/estimulantes para oviposição pelas fêmeas do gênero Aedes que as com água, nas três primeiras semanas de exposição. O relento foi o local com maior preferência para oviposição durante todo o estudo; em segundo lugar encontrou-se o coberto. Elevados valores dos coeficientes de correlação de Spearman e valores de p inferiores a 0,004 mostraram forte correlação entre positividade e média de ovos, indicando que uma variável prediz a outra. A partir das análises das larvas eclodidas, identificou-se a presença de Aedes aegypti em 99,6% (IC 95%: 99,04 -99,84) das palhetas e de Aedes albopictus em 1,8% (1C95%: 1,19 - 2,70) delas. Em Mirassol, a probabilidade de se encontrar ovos de Aedes aegypti em uma palheta sob estes condições é superior a 99%.

O propofol é um sedativo eficiente, largamente empregado em anestesia e geralmente associado a grande números de analgésicos opióides em cirurgias de grande porte, como a cirurgia cardíaca de revascularização do miocárdio (RM) com ou sem circulação extracorpórea (CEG). Devido às suas características farmacocinéticas é administrado através de infusão alvo controlada (TCI) de forma a manter os níveis plasmáticos ótimos para obtenção de sedação e profundidade de anestesia adequadas durante a intervenção cirúrgica. O objetivo do presente estudo foi investigar a farmacocinética e farmacodinâmica do propofol administrado através de TCI em pacientes submetidos a RM com e sem CEC. Na administração da medicação hipnótica, fez-se necessária a validação do Diprifusor (AstraZeneca), incluindo a bomba de infusão e o software programado com o modelo farmacocinético de 3 compartimentos, que necessita apenas da inclusão de dados individuais do paciente, tais como peso corporal. A validação desse sistema compreendeu a estimativa do erro de previsão do Diprifusor pela utilização da razão das concentrações obtida, experimentalmente medida, e a prevista pelo modelo do software da bomba de infusão. No presente estudo comparativo, selecionaram-se 20 pacientes com base nos critérios de inclusão, que foram divididos em 2 grupos, Controle e CEC. Os pacientes foram informados em detalhes sobre os dados que cercam esse protocolo de pesquisa e assinaram o termo de consentimento livre esclarecido para participação no estudo. O protocolo for submetido e aprovado pelo CEP de todas as Instituições envolvidas (FCFUSP, InCor e CAPPesq). A taxa de infusão requerida, bem como a faixa de concentração obtida para manter o alvo de 2 &#181;g/mL e o índice bispectral de 40 (BIS) durante a cirurgia cardíaca foram monitorados. Subsequentemente, ao final da cirurgia, a taxa de infusão e a faixa de concentração do propofol plasmático requeridos para atingir o alvo de 1 &#181;g/mL também foram monitorados. Neste período, a sedação e a medida da profundidade da anestesia foram monitorados através do BIS e da Escala de Ramsay. O efeito medido através do BIS durante a infusão, no intra-operatório, atingiu o valor máximo de 40 da escala nos dois grupos. Da mesma forma, ao final da cirurgia, obteve-se nível 6 de sedação na escala de Ramsay em ambos os grupos, quando o alvo foi ajustado para 1 &#181;g/mL. Adicionalmente pela interrupção da infusão, no pós-operatório imediato, BIS e Ramsay foram registrados simultaneamente até o final do período de estudo (18-20 horas) para todos os pacientes. Efetuou-se coleta de amostras sanguíneas durante as infusões alvo (2 &#181;g/mL e 1 &#181;g/mL) e após a interrupção da infusão para o estudo da farmacocinética . Requereu-se volume de sangue inferior a 90 mL para o monitoramento plasmático e a modelagem farmacocinética. Utilizou-se a cromatografia líquida de alta eficiência, com deteto r de fluorescência (CLAE-F). O método mostrou-se bastante simples, seletivo, sensível e robusto e utilizou coluna C18 e fase móvel binária em baixo fluxo. Os limites de confiança estabelecidos para o método analítico foram: 0,1-10 &#181;g/mL (linearidade, r2 0,9977), 0,05 &#181;g/mL (LD), 0,1 &#181;g/mL(LQ), 93,9% (recuperação absoluta), 8,4 e 8,8% (precisão intra e inter dias), 91,8 e 93,3% (exatidão intra e inter dias). Adicionalmente, demonstrou-se boa estabilidade para o fármaco através de estudos de curta e longa duração, tempo de bandeja (tempo e condição de análise) e ciclos de congelamento e descongelamento, além de estudo de estabilidade das soluções padrão do propofol e do timol (padrão interno). No perioperatório, as concentrações plasmáticas evidenciaram alta flutuação, principalmente durante a intervenção para o grupo CONTROLE comparado ao grupo CEC, indicando maior erro de previsão na taxa de infusão estimada pelo software da bomba para manter o alvo no Controle. A modelagem farmacocinética foi efetuada pela aplicação do modelo aberto de 3 compartimentos que mostrou significativo aumento na eliminação do fármaco (ClT, &#223;, &#947;) no grupo CEC relativamente ao CONTROLE, uma vez que as concentrações plasmáticas obtidas no grupo CEC foram inferiores àquelas obtidas no outro grupo. A profundidade de anestesia alcançada foi de 6 na escala de Ramsay e 40 (BIS) durante a TCI , efeito máximo atingido durante essa cirurgia de alto porte. A função matemática sigmoidal foi escolhida com base na alta correlação obtida (r2 >0,9) pela modelagem PK¬PO. A curva de correlação do efeito BIS versus propofol plasmático indica que os grupos CEC e CONTROLE são diferentes, uma vez que apenas os pacientes do CONTROLE retornaram ao valor basal (BIS: 100) no período entre 6 e 8 horas do início da cirurgia e instalação da TCI de propofol. Por outro lado, registrou-se prolongamento do tempo de recuperação da hipnose (tempo de despertar) nos pacientes CEC, que se estendeu até 18 horas. Adicionalmente a modelagem indicou que a concentração efetiva (EC50) é da ordem de 4 vezes menor no grupo CEC comparado ao CONTROLE. Finalmente, apesar das menores concentrações plasmáticas para o propofol no grupo CEC, consequência da elevada depuração plasmática, o efeito máximo do hipnótico durante a intervenção foi semelhante nos dois grupos, sendo que a principal diferença entre eles reside na sedação residual registrada nos pacientes CEC. Esses resultados podem ser justificados em parte pelo aumento da fração livre de propofol no plasma e provavelmente em função de alteração na interação fármaco¬receptor, decorrência da CEC na cirurgia de revascularização do miocárdio. Em conclusão, a CEC afeta a farmacocinética e a farmacodinâmica do propofol no paciente cirúrgico. Por outro lado o dispositivo (Diprofusor, AstraZeneca) para a administração alvo controlada necessita de ajustes e adaptação para a TCI de propofol neste tipo de cirurgia, incluindo-se ainda no ajuste, a diferenciação para o paciente que possui a CEC associada. / Propofol is an effective sedative, largely applied in anesthesia and in general it is associated to opioids for analgesia in major surgeries, like the cardiac surgery to coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (CPB). It is administered by a target controlled infusion system (TCI) to maintain the optimal depth of sedation and anesthesia during the intervention, due to its pharmacokinetic characteristics. The objective of this study was to investigate the influence of CPB in pharmacokinetics and in pharmacodynamics of propofol, applying PK-PD modeling. For drug administration, Diprifusor (AstraZeneca), including pump plus software must enter individual data as body weight from the patient, once pharmacokinetic parameters were included previously. To validate this system of infusion, the prediction error by target controlled infusion must be estimated by comparison between obtained and predict concentration plasma ratio. In the present protocol, 20 patients (10 CONTROL and 10 CPB) were selected based on inclusion criteria for the comparative study. Patients were informed in details about the investigation and before the protocol starts, they signed the informed written consent to participate of the study. Protocol was approved by the local ethical committees of all institutions involved. Rate of infusion and the range of obtained plasma propofol concentrations required to reach 2 &#181;g/mL and to maintain the bispectral index (BIS:40) during cardiac surgery were monitored. Subsequently, at the end of surgery, both rate of infusion and range of obtained plasma propofol concentrations required to reach 1 &#181;g/mL were monitored either. Depth of sedation was assessed with BIS during all period reaching maximum effect in 40 at level of sedation in the operative period. At the end of surgery, the Ramsay score achieved sedation level 6, when the target plasma propofol was adjusted to 1 &#181;g/mL; Additionally, at the end of infusion in the postoperative period, BIS and Ramsay were monitored simultaneously up to 18-20 hours for all patients. Blood samples were collected and propofol plasma levels were monitored during (TCI : 2 &#181;g/mL) and after surgery (TCI: 1 &#181;g/mL). Blood samples also were collected at the end of infusion for pharmacokinetics. Volumes of blood lower than 90 mL were necessary for drug monitoring and pharmacokinetic purposes. Plasma levels were determined by a quite simple, selective, sensitive and robustness analytical method HPLC, using fluorescence detector, C18 column, and binary system at low flow rate. Confidence limits were: 0.1-10 &#181;g/mL (linearity, r2 0.9977), 0.05 &#181;g/mL(LD), 0.1 flg/mL(LQ), 93.9% (absolute recovery), 8.4 and 8.8% (intra and inter day precision), 91.8 and 93.3% (accuracy intra and inter day). Additionally, good stability was shown for the drug and its internal standard (tymol). Plasma levels showed a large fluctuation for the CONTROL compared to CPB in the perioperative period, mainly during the surgical intervention, indicating a higher predicting error for CONTROL group. Pharmacokinetics applying three compartment open model showed significant increases on drug elimination (ClT, &#946;, &#947;) for CPB compared to CONTROL, once plasma levels for CPB Group were lower than CONTROL in the period of study. Depth of sedation reached level 6 Ramsay score and 40 (BIS) during TCI, the maximum effect recorded during this major surgery. A sigmoidal mathematical function was choosed (r2>O.9) after PK-PD modeling. BIS effect versus propofol plasma concentration curve indicates that CPB patients are different from CONTROL, once only CONTROL patients recovered to baseline up to 6-8 hours of the starting of surgery, while a prolongation of recovery up to 18 hours, measured by awakening time, was observed in CPB patients; additionally, the effective concentration (EC50) was 4 times lower for CPB compared to CONTROL Group. Finally, in spite of lower plasma concentration in CPB, as a consequence of higher clearance, similar maximum effect were reached in both groups during the intervention and the main difference is based on a residual sedation in CPB patients after surgery. In fact, this data can be justified probably due to changes in free drug plasma levels and in drug-receptor interaction as a result of cardiopulmonary bypass in CABG surgery. In conclusion, cardiopulmonary bypass affects the pharmacokinetics and pharmacodynamics of propofol in CABG patients and the device for TCI (Diprifusor, AstraZeneca) must be adjusted for cardiac surgery with differences in CPB included.

O propofol é um sedativo eficiente, largamente empregado em anestesia e geralmente associado a grande números de analgésicos opióides em cirurgias de grande porte, como a cirurgia cardíaca de revascularização do miocárdio (RM) com ou sem circulação extracorpórea (CEG). Devido às suas características farmacocinéticas é administrado através de infusão alvo controlada (TCI) de forma a manter os níveis plasmáticos ótimos para obtenção de sedação e profundidade de anestesia adequadas durante a intervenção cirúrgica. O objetivo do presente estudo foi investigar a farmacocinética e farmacodinâmica do propofol administrado através de TCI em pacientes submetidos a RM com e sem CEC. Na administração da medicação hipnótica, fez-se necessária a validação do Diprifusor (AstraZeneca), incluindo a bomba de infusão e o software programado com o modelo farmacocinético de 3 compartimentos, que necessita apenas da inclusão de dados individuais do paciente, tais como peso corporal. A validação desse sistema compreendeu a estimativa do erro de previsão do Diprifusor pela utilização da razão das concentrações obtida, experimentalmente medida, e a prevista pelo modelo do software da bomba de infusão. No presente estudo comparativo, selecionaram-se 20 pacientes com base nos critérios de inclusão, que foram divididos em 2 grupos, Controle e CEC. Os pacientes foram informados em detalhes sobre os dados que cercam esse protocolo de pesquisa e assinaram o termo de consentimento livre esclarecido para participação no estudo. O protocolo for submetido e aprovado pelo CEP de todas as Instituições envolvidas (FCFUSP, InCor e CAPPesq). A taxa de infusão requerida, bem como a faixa de concentração obtida para manter o alvo de 2 &#181;g/mL e o índice bispectral de 40 (BIS) durante a cirurgia cardíaca foram monitorados. Subsequentemente, ao final da cirurgia, a taxa de infusão e a faixa de concentração do propofol plasmático requeridos para atingir o alvo de 1 &#181;g/mL também foram monitorados. Neste período, a sedação e a medida da profundidade da anestesia foram monitorados através do BIS e da Escala de Ramsay. O efeito medido através do BIS durante a infusão, no intra-operatório, atingiu o valor máximo de 40 da escala nos dois grupos. Da mesma forma, ao final da cirurgia, obteve-se nível 6 de sedação na escala de Ramsay em ambos os grupos, quando o alvo foi ajustado para 1 &#181;g/mL. Adicionalmente pela interrupção da infusão, no pós-operatório imediato, BIS e Ramsay foram registrados simultaneamente até o final do período de estudo (18-20 horas) para todos os pacientes. Efetuou-se coleta de amostras sanguíneas durante as infusões alvo (2 &#181;g/mL e 1 &#181;g/mL) e após a interrupção da infusão para o estudo da farmacocinética . Requereu-se volume de sangue inferior a 90 mL para o monitoramento plasmático e a modelagem farmacocinética. Utilizou-se a cromatografia líquida de alta eficiência, com deteto r de fluorescência (CLAE-F). O método mostrou-se bastante simples, seletivo, sensível e robusto e utilizou coluna C18 e fase móvel binária em baixo fluxo. Os limites de confiança estabelecidos para o método analítico foram: 0,1-10 &#181;g/mL (linearidade, r2 0,9977), 0,05 &#181;g/mL (LD), 0,1 &#181;g/mL(LQ), 93,9% (recuperação absoluta), 8,4 e 8,8% (precisão intra e inter dias), 91,8 e 93,3% (exatidão intra e inter dias). Adicionalmente, demonstrou-se boa estabilidade para o fármaco através de estudos de curta e longa duração, tempo de bandeja (tempo e condição de análise) e ciclos de congelamento e descongelamento, além de estudo de estabilidade das soluções padrão do propofol e do timol (padrão interno). No perioperatório, as concentrações plasmáticas evidenciaram alta flutuação, principalmente durante a intervenção para o grupo CONTROLE comparado ao grupo CEC, indicando maior erro de previsão na taxa de infusão estimada pelo software da bomba para manter o alvo no Controle. A modelagem farmacocinética foi efetuada pela aplicação do modelo aberto de 3 compartimentos que mostrou significativo aumento na eliminação do fármaco (ClT, &#223;, &#947;) no grupo CEC relativamente ao CONTROLE, uma vez que as concentrações plasmáticas obtidas no grupo CEC foram inferiores àquelas obtidas no outro grupo. A profundidade de anestesia alcançada foi de 6 na escala de Ramsay e 40 (BIS) durante a TCI , efeito máximo atingido durante essa cirurgia de alto porte. A função matemática sigmoidal foi escolhida com base na alta correlação obtida (r2 >0,9) pela modelagem PK¬PO. A curva de correlação do efeito BIS versus propofol plasmático indica que os grupos CEC e CONTROLE são diferentes, uma vez que apenas os pacientes do CONTROLE retornaram ao valor basal (BIS: 100) no período entre 6 e 8 horas do início da cirurgia e instalação da TCI de propofol. Por outro lado, registrou-se prolongamento do tempo de recuperação da hipnose (tempo de despertar) nos pacientes CEC, que se estendeu até 18 horas. Adicionalmente a modelagem indicou que a concentração efetiva (EC50) é da ordem de 4 vezes menor no grupo CEC comparado ao CONTROLE. Finalmente, apesar das menores concentrações plasmáticas para o propofol no grupo CEC, consequência da elevada depuração plasmática, o efeito máximo do hipnótico durante a intervenção foi semelhante nos dois grupos, sendo que a principal diferença entre eles reside na sedação residual registrada nos pacientes CEC. Esses resultados podem ser justificados em parte pelo aumento da fração livre de propofol no plasma e provavelmente em função de alteração na interação fármaco¬receptor, decorrência da CEC na cirurgia de revascularização do miocárdio. Em conclusão, a CEC afeta a farmacocinética e a farmacodinâmica do propofol no paciente cirúrgico. Por outro lado o dispositivo (Diprofusor, AstraZeneca) para a administração alvo controlada necessita de ajustes e adaptação para a TCI de propofol neste tipo de cirurgia, incluindo-se ainda no ajuste, a diferenciação para o paciente que possui a CEC associada. / Propofol is an effective sedative, largely applied in anesthesia and in general it is associated to opioids for analgesia in major surgeries, like the cardiac surgery to coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (CPB). It is administered by a target controlled infusion system (TCI) to maintain the optimal depth of sedation and anesthesia during the intervention, due to its pharmacokinetic characteristics. The objective of this study was to investigate the influence of CPB in pharmacokinetics and in pharmacodynamics of propofol, applying PK-PD modeling. For drug administration, Diprifusor (AstraZeneca), including pump plus software must enter individual data as body weight from the patient, once pharmacokinetic parameters were included previously. To validate this system of infusion, the prediction error by target controlled infusion must be estimated by comparison between obtained and predict concentration plasma ratio. In the present protocol, 20 patients (10 CONTROL and 10 CPB) were selected based on inclusion criteria for the comparative study. Patients were informed in details about the investigation and before the protocol starts, they signed the informed written consent to participate of the study. Protocol was approved by the local ethical committees of all institutions involved. Rate of infusion and the range of obtained plasma propofol concentrations required to reach 2 &#181;g/mL and to maintain the bispectral index (BIS:40) during cardiac surgery were monitored. Subsequently, at the end of surgery, both rate of infusion and range of obtained plasma propofol concentrations required to reach 1 &#181;g/mL were monitored either. Depth of sedation was assessed with BIS during all period reaching maximum effect in 40 at level of sedation in the operative period. At the end of surgery, the Ramsay score achieved sedation level 6, when the target plasma propofol was adjusted to 1 &#181;g/mL; Additionally, at the end of infusion in the postoperative period, BIS and Ramsay were monitored simultaneously up to 18-20 hours for all patients. Blood samples were collected and propofol plasma levels were monitored during (TCI : 2 &#181;g/mL) and after surgery (TCI: 1 &#181;g/mL). Blood samples also were collected at the end of infusion for pharmacokinetics. Volumes of blood lower than 90 mL were necessary for drug monitoring and pharmacokinetic purposes. Plasma levels were determined by a quite simple, selective, sensitive and robustness analytical method HPLC, using fluorescence detector, C18 column, and binary system at low flow rate. Confidence limits were: 0.1-10 &#181;g/mL (linearity, r2 0.9977), 0.05 &#181;g/mL(LD), 0.1 flg/mL(LQ), 93.9% (absolute recovery), 8.4 and 8.8% (intra and inter day precision), 91.8 and 93.3% (accuracy intra and inter day). Additionally, good stability was shown for the drug and its internal standard (tymol). Plasma levels showed a large fluctuation for the CONTROL compared to CPB in the perioperative period, mainly during the surgical intervention, indicating a higher predicting error for CONTROL group. Pharmacokinetics applying three compartment open model showed significant increases on drug elimination (ClT, &#946;, &#947;) for CPB compared to CONTROL, once plasma levels for CPB Group were lower than CONTROL in the period of study. Depth of sedation reached level 6 Ramsay score and 40 (BIS) during TCI, the maximum effect recorded during this major surgery. A sigmoidal mathematical function was choosed (r2>O.9) after PK-PD modeling. BIS effect versus propofol plasma concentration curve indicates that CPB patients are different from CONTROL, once only CONTROL patients recovered to baseline up to 6-8 hours of the starting of surgery, while a prolongation of recovery up to 18 hours, measured by awakening time, was observed in CPB patients; additionally, the effective concentration (EC50) was 4 times lower for CPB compared to CONTROL Group. Finally, in spite of lower plasma concentration in CPB, as a consequence of higher clearance, similar maximum effect were reached in both groups during the intervention and the main difference is based on a residual sedation in CPB patients after surgery. In fact, this data can be justified probably due to changes in free drug plasma levels and in drug-receptor interaction as a result of cardiopulmonary bypass in CABG surgery. In conclusion, cardiopulmonary bypass affects the pharmacokinetics and pharmacodynamics of propofol in CABG patients and the device for TCI (Diprifusor, AstraZeneca) must be adjusted for cardiac surgery with differences in CPB included.

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is still a syndrome generating more questions than answers. Today, research focuses mainly on two areas: understanding the pathophysiology – especially how the malfunctioning CSF system affects the brain parenchyma – and finding better methods to select patients benefiting from a shunt operation. This thesis targets the aspect of finding better selection methods by investigating the measurability of intracranial pressure via lumbar space, and determining if intraparenchymal measurement of long-term ICP-oscillations (B-waves) could be replaced by short-term measurements of CSF pulse pressure waves via lumbar space. Furthermore, I look into the interaction between the CSF system and the parenchyma itself by investigating how the cortical activity of the brain changes after long-term CSF drainage, and if there is any regress in the suggested ischemia after this intervention. Finally, I examine if the neuronal integrity in the INPH brain is impaired, and if this feature is relevant for the likeliness of improvement after CSF diversion. METHODS: The comparison of intracranial and lumbar pressure was made over a vast pressure interval using our unique CSF infusion technique, and it included ten INPH patients. Pressure was measured via lumbar space and in brain tissue, and the pressures were compared using a general linear model. Short-term lumbar pressure waves were quantified by determining the slope between CSF pulse pressure and mean pressure, defined as the relative pulse pressure coefficient (RPPC). The correlation between RPPC, B-waves and CSF outflow resistance was investigated. In a prospective study, functional MRI was used to assess brain activity before and after long-term CSF drainage of 400 ml of CSF in eleven INPH patients. The functionalities tested included finger movement, memory, and attention. The results were benchmarked against the activity in ten healthy controls to identify the brain areas improving after drainage. The ischemia (Lactate) and neuronal integrity (NAA and Choline) were measured in a similar manner in 16 patients using proton MR spectroscopy, and the improvement of the patients after CSF drainage was based on assessment of their gait. RESULTS: There was excellent agreement between ICP measured in brain tissue and via lumbar space (regression coefficient = 0.98, absolute difference < 1 mm Hg). Adjusting for the separation distance between the measuring devices slightly worsened the agreement, indicating other factors influencing the measured difference as well. RPPC measured via lumbar space significantly correlated to the presence of B-waves, but not to outflow resistance. In the prospective study, controls outperformed patients on clinical tests as well as tasks related to the experiments. Improved behaviour after CSF drainage was found for motor function only, and it was accompanied by increased activation in the supplementary motor area (SMA). No lactate was detected, either before or after CSF drainage. NAA was decreased in INPH patients compared to controls, and the NAA levels were higher in the patients improving after drainage. CONCLUSIONS: ICP can be accurately measured via lumbar space in patients with communicating CSF systems. The close relation between RPPC and B-waves indicates that B-waves are primarily related to intracranial compliance, and that measurement of RPPC via lumbar space could possibly substitute B-wave assessment as selection method for finding suitable patients for shunt surgery. Improvement in motor function after CSF drainage was associated to enhanced activity in SMA, supporting the involvement of the cortico-basal ganglia-thalamo-cortical loop in the pathophysiology of INPH. There was no evidence indicating a widespread low-graded ischemia in INPH; however, there was a neuronal dysfunction in frontal white matter as indicated by the reduced levels of NAA. In addition, the level of neuronal dysfunction was related to the likeliness of improvement after CSF removal, normal levels of NAA predisposing for recovery.

The overall aim of this thesis was to develop, deploy and evaluate new IT-based methods for supporting treatment and assessment of treatment of advanced Parkinson’s disease. In this condition a number of different motor and non-motor symptoms occur in episodes of varying frequency, duration and severity. In order to determine outcome of treatment changes, repeated assessments are necessary. Hospitalization for observation is expensive and may not be representative for the situation at home. Paper home diaries have questionable reliability and storage and retrieval of results are problematic. Approaches for monitoring using wearable sensors are unable to address important non-motor symptoms. A test battery system consisting of both self-assessments of symptoms and motor function tests was constructed for a touch screen mobile phone. Tests are performed on several occasions per day during test periods of one week. Data is transmitted over the mobile net to a central server where summaries in different symptom dimensions and an overall test score per patient and test period are calculated. There is a web application that graphically presents the results to treating clinical staff. As part of this work, a novel method for assessment of spiral drawing impairment useful during event-driven sampling was developed. To date, the system has been used by over 100 patients in 10 clinics in Sweden and Italy. Evidence is growing that the test battery is useful, reliable and valid for assessment of symptoms during advanced Parkinson’s disease. Infusion of a levodopa/carbidopa gel into the small intestine has been shown to reduce variation in plasma drug levels and improve clinical response in this patient category. A pharmacokinetic-pharmacodynamic model of this intestinal gel infusion was constructed. Possibly this model can assist the process of individualization of dosage for this treatment through in numero simulations. Results from an exploratory data analysis indicate that severity measures during oral levodopa treatment may be factors to consider when deciding candidates for infusion treatment.

Hansen and Hansen (1988) found that angry targets in happy crowds were found more quickly and accurately than happy targets in angry crowds. This finding, they dubbed the Face-in-the-Crowd effect. Gilboa-Schechtman and colleagues (1999) found that high anxious participants show a greater enhancement of detecting angry versus happy targets. The purpose of the current studies was to replicate these findings, and to determine whether Rational and Experiential decision-making styles play a role in target detection (Study One) and crowd searching (Study Two), and if these decision-making styles interact with affective predisposition for both reaction time and galvanic skin response in the face-in-the-crowd task. In Study One, I replicated the anger superiority effect and the Anxiety x Target interaction. I also found that the Rational Group tended to be faster than the Experiential Group overall. I found that the High Trait Anxious group had higher GSR than the Low Trait Anxious group averaged over both target conditions. The Rational group had higher GSR when presented with happy targets than when presented with angry targets whereas the Experiential group did not show this difference. In Study Two, I failed to replicate the anger inferiority effect of crowd searching, but I did find that the Rational group tended to be faster than the Experiential group, especially for angry crowd searching. I also found that the Low-State-Anxious-Rational group had lower galvanic skin responses than all other groups across all analyses. The most exciting finding of these two studies was that he Rational Group demonstrated a facility for the face-in-the-crowd task, validating decision-making style as an important dimension to be considered in future face-in-the-crowd research. The research also provided support for network theories and it is hoped that future studies might endeavor to explore facial processing with this theoretical framework in mind.

Virtual tools are commonly used nowadays to optimize product design and manufacturing process of fibre reinforced composite materials. The present work focuses on two areas of interest to forecast the part performance and the production process particularities. The first part proposes a multi-physical optimization tool to support the concept stage of a composite part. The strategy is based on the strategic handling of information and, through a single control parameter, is able to evaluate the effects of design variations throughout all these steps in parallel. The second part targets the resin infusion process and the impact of thermal effects. The numerical and experimental approach allowed the identificationof improvement opportunities regarding the implementation of algorithms in commercially available simulation software. / Les eines de disseny virtual son usades de forma habitual per optimitzar el disseny i el procés productiu de peces de material compòsit reforçades amb fibra. Aquest treball es centra en dos àrees d’interès per la predicció de les prestacions de la peça i les particularitats del seu procés productiu. La primera part proposa una eina d’optimització multi-física per recolzar l’etapa de desenvolupament d’una nova peça. La estratègia es basa en la gestió intel•ligent de la informació a través d’un paràmetre de control comú, permeten l’avaluació dels canvis en totes les etapes en paral•lel. La segona part es centra en la infusió de resina, i particularment en l’impacte dels efectes tèrmics. Aquesta investigació numèrica i experimental ha permès la identificació de possibilitats de millora en la implementació d’algoritmes usats actualment en codis comercials de simulació.