Abordagem PK-PD do propofol na revascularização do miocárdio para estudo da influência da circulação extracorpórea na ligação às proteínas plasmáticas e no efeito hipnótico / PK-PD Model to investigate the free propofol plasma levels versus the hypnotic drug effect in patients undergoing coronary artery bypass grafting concerning the influence of CPB-hypothermia on drug plasma binding

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 µg/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 µg/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 µg/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 µg/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

Modelagem farmacocinética-farmacodinâmica do propofol em pacientes submetidos à cirurgia cardíaca com anestesia venosa contínua alvo-controlada / Propofol pharmacokinetic-pharmacodynamic modeling in patients submitted to cardiac surgery with continuos venous target controlled anesthesia

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 (CEC). 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 cirurgica. O objetivo do presente estudo foi investigar a famacocinética 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 famacocinético de 3 compartimentos, que necessita apenas da inclusão de dados individuais do paciente, tais como peso corporal...

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 µg/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 µg/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 µg/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 µg/mL) and after surgery (TCI: 1 µg/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 µg/mL (linearity, r2 0.9977), 0.05 µg/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, ß, γ) for CPB compared to CONTROL, once plasma levels for CPB Group were lower than CONTROL in the period of study.