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Background and Aim: The use of anesthetic infusions based on pharmacokinetic values associated with anesthetic plan and bispectral index in dogs have not been well-documented in the literature. This study aimed to evaluate the bispectral index (BIS) change based on pre-propofol and establish clinical anesthetic depth changes during propofol sequential target-controlled infusion (STCI) in dogs with a plasma target of 5 µg/mL. Materials and Methods: Twenty healthy male dogs aged 1-3 years and weighing 9.8-44 kg were recruited. These dogs were pre-medicated intramuscularly with methadone (0.2 mg/kg) and acepromazine (0.03 mg/kg). After 30 min, propofol anesthetic induction and maintenance were initiated using STCI according to dog pharmacokinetic (PK) parameters. Subsequently, the target plasma concentration of propofol was set at 5 µg/mL for both anesthetic induction and the 120 min maintenance. Then, TivaTrainer v.9.1 software was used to calculate anesthetic infusion rates in a TCI plasmatic concentration mode using the PKs model optimized by covariates for propofol TCI in dogs. The BIS value was recorded every 5 min from the beginning of induction until the end of anesthesia. Finally, analysis of variance was performed on numerical data using the Friedman test, followed by the Bonferroni adjustment (p<0.05). Results: A statistical difference was observed between the baseline BIS value (T0), with a median value of 84.5 (81-97), and BIS after every 15 min (T15) of inducing anesthesia. Surgical anesthetic depth was also reached in 18 of 20 dogs after 10 min of infusion and in all dogs after 20 min, with a median BIS value of 72 (53-89) at the time of surgical anesthesia depth. Results also showed no BIS variation (p<0.05) between anesthetic moments after anesthetic induction with a substantial amplitude of BIS in the surgical anesthetic depth. Moreover, the maximum depth of anesthesia in all dogs by clinical evaluation was reached after 20 min of anesthesia and then remained stable throughout the anesthetic period. Conclusion: This study suggested that most dogs (90%) attained a surgical depth of anesthesia within 15 min of STCI onset, with a plasma target of 5 µg/mL and no change in anesthetic depth throughout the period anesthesia lasted. Furthermore, median BIS values remained high even after dogs reached the surgical depth of anesthesia, indicating that the comparison of BIS values of dogs and humans should not be considered for classifying anesthetic and hypnotic depths in dogs.

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Introducción: La administración manual en bolo ha evolucionado desde la infusión volumétrica basada en regímenes farmacológicos estandarizados, hasta los sistemas de infusión controlada por objetivo y los más sofisticados sistemas de circuito cerrado. Objetivo: Describir los principios tecnológicos y aplicaciones clínicas extendidas de la infusión controlada por objetivo y los sistemas de circuito cerrado. Métodos: Se realizó una revisión no sistemática de la literatura, en bases de datos científicas como Cochrane Database of Systematic Reviews, Pubmed/Medline, EMBASE, Scopus, Web of Science, EBSCOhost, Science Direct, OVID y el buscador académico Google Scholar, en el mes de septiembre del año 2020. Desarrollo: La disponibilidad y portabilidad de dispositivos electrónicos con capacidad de procesamiento avanzado a precios relativamente accesibles, el perfeccionamiento del aprendizaje automático e inteligencia artificial aplicado a las decisiones médicas, y las iteraciones tecnológicas complejas incorporadas en los sistemas de circuito abierto y cerrado, desarrollados originalmente en el campo de la Anestesiología, han posibilitado su expansión a otras especialidades y entornos clínicos tan disímiles como el tratamiento de la diabetes mellitus, administración de fármacos antineoplásicos, ventilación mecánica, control de las variables hemodinámicas y la terapia antimicrobiana en pacientes críticos. Conclusiones: La infusión controlada por objetivo y los sistemas de circuito cerrado se han convertido en tecnologías maduras, seguras y viables, aplicadas clínicamente en múltiples naciones y escenarios, con un desempeño superior a los sistemas manuales tradicionales(AU)

Introduction: Manual bolus administration has evolved from volumetric infusion based on standardized pharmacological regimens to target-controlled infusion systems and the most sophisticated closed-loop systems. Objective: To describe the technological principles and extended clinical applications of target-controlled infusion and closed-loop systems. Methods: A nonsystematic review of the literature was carried out, during September 2020, in scientific databases such as Cochrane Database of Systematic Reviews, Pubmed/Medline, EMBASE, Scopus, Web of Science, EBSCOhost, Science Direct, OVID and the academic search engine Google Scholar. Development: The availability and portability of electronic devices with advanced processing capacity at relatively affordable prices, the refinement of machine learning and artificial intelligence applied to medical decisions, as well as the complex technological iterations incorporated into open and closed-loop systems, originally developed in the field of anesthesiology, have enabled their expansion to other specialties and clinical settings so diverse as treatment of diabetes mellitus, administration of antineoplastic drugs, mechanical ventilation, control of hemodynamic variables and antimicrobial therapy in critical patients. Conclusions: Target-controlled infusion and closed-loop systems have become mature, safe and viable technologies, applied clinically in multiple nations and settings, with superior performance compared to traditional manual systems(AU)

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BACKGROUND: Propofol and remifentanil are commonly combined during total intravenous anesthesia. The impact of remifentanil in this relationship is poorly quantified in children. Derivation of an integrated pharmacokinetic and pharmacodynamic propofol model, containing remifentanil pharmacodynamic interaction information, enables propofol effect-site target-controlled infusion in children with a better prediction of its hypnotic effect when both drugs are combined. AIMS: We designed this study to derive an integrated propofol pharmacokinetic-pharmacodynamic model in children and to describe the pharmacodynamic interaction between propofol and remifentanil on the electroencephalographic bispectral index effect. METHODS: Thirty children (mean age: 5.45 years, range 1.3-11.9; mean weight: 23.5 kg, range 8.5-61) scheduled for elective surgery with general anesthesia were studied. After sevoflurane induction, maintenance of anesthesia was based on propofol and remifentanil. Blood samples to measure propofol concentration were collected during anesthesia maintenance and up to 6 hours in the postoperative period. Bispectral index data were continuously recorded throughout the study. A pharmacokinetic-pharmacodynamic model was developed using population modeling. The Greco model was used to examine the pharmacokinetic-pharmacodynamic interaction between propofol and remifentanil for BIS response RESULTS: Propofol pharmacokinetic data from a previous study in 53 children were pooled with current data and simultaneously analyzed. Propofol pharmacokinetics were adequately described by a three-compartment distribution model with first-order elimination. Theory-based allometric relationships based on TBW improved the model fit. The Greco model supported an additive interaction between propofol and remifentanil. Remifentanil showed only a minor effect in BIS response. CONCLUSION: We have developed an integrated propofol pharmacokinetic-pharmacodynamic model that can describe the pharmacodynamic interaction between propofol and remifentanil for BIS response. An additive interaction was supported by our modeling analysis.

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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 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

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BACKGROUND: The propofol pharmacokinetic model derived by Kataria et al. was recently modified to perform effect-site target-controlled infusion (TCI). Effect-site concentration (Ce) targets to induce general anesthesia with this model in children have not been described. The aim of this study was to identify propofol Ce targets associated with success rates of 50% (Ce50) and 95% (Ce95) among children 3-11 years of age. METHODS: Forty-two children were assigned to one of seven groups of six patients each according to propofol target Ce. After fentanyl administration propofol TCI was started with an assigned Ce target. A successful response was defined as loss of eyelash reflex and bispectral index < 50, 45 s after reaching the assigned Ce. Logistic regression analysis was performed to calculate propofol Ce50 and Ce95. RESULTS: Twenty-eight children had a successful response with the assigned propofol Ce. In these patients, a significant decrease in mean arterial blood pressure (79-59, P < 0.0001) and in heart rate (95-83, P < 0.0001) was observed. Propofol Ce and age showed a statistically significant effect in the logistic regression model. The overall calculated propofol Ce50 and Ce95 were 3.8 µg·ml(-1) (95% CI: 3.1-4.4 µg·ml(-1) ) and 6.1 µg·ml(-1) (95% CI: 4.6-7.6 µg·ml(-1) ), respectively. CONCLUSION: Our results identified useful propofol targets to be used with the Kataria effect-site model to induce anesthesia in children between 3 and 11 years. The recommended targets should be reduced progressively with increasing age most probably due to PK model misspecifications.

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OBJECTIVE: To evaluate efficacy of Propofol at Cp 2.5 µg/ ml administered by Target Controlled Infusion (TCI) using Marsh Modified Model, in pre-medicated with midazolam/ fentanil Latin-American women (Venezuelans) during oocyte retrieval for In Vitro Fertilization. METHODS: Prospective, descriptive study included 72 women, 18-44 years old, ASA I-II, non obese, undergoing oocyte retrieval, pre-medicated with midazolam 0.04 mg/kg and fentanil 2µg/kg and received anesthesia based in Propofol at Cp 2.5µg/ml by Target Controlled Infusion using Marsh Modified Model. Demographic data, propofol doses, duration of procedure and recovery time was registered using descriptive statistic. Anesthesia efficacy was measured by Biespectral Analysis (BIS), Intra-Operative Movements Scale (0 to 5) graded, Postoperative Pain by Visual Analog Scale (VAS) and nausea/vomits incidence. ANOVA and Pearson Chi2 were used with an error of 0.05. RESULTS: Age average was 33.04±6 years old, procedure average time 18.06±8min, Propofol total doses 146.64±53 mgs, Propofol infusion doses average 155.2±3µg/Kg/min. During procedure, 70.8% of patients had no movement, 22.2% movement Grade I and 6.9% Grade II. (Grade I-II movement did not interfere with procedure continuity). 70.8% achieved BIS 40-50 and 93.1% had BIS equal o less than 60. There was a statistic significant correlation between BIS 40-50 and no movements. Recovery post-anesthesia time was 25.2±8 min. 98.6% of patients reported excellent comfort. CONCLUSION: With midazolam/fentanil pre-medication, Propofol at Cp 2.5µg/ml by TCI using Marsh Modified Model showed a 93% of effectiveness during oocyte retrieval in Latin-American women subjected to IVF, allowing an ultra- fast recovery time.

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OBJECTIVE: To evaluate the effects of three different target-controlled remifentanil infusion rates during target-controlled propofol infusion on hemodynamic parameters, pain, sedation, and recovery score during oocyte retrieval. METHODS: Sixty-nine women were scheduled for oocyte retrieval. Target-controlled propofol infusion at an effectsite concentration of 1.5 μg/mL was instituted. The patients were randomly allocated to receive remifentanil at an effect-site concentration of either 1.5 (group I, n = 23), 2 (group II, n = 23) or 2.5 ng/mL (group III, n = 23). Hemodynamic variables, sedation, pain, the Aldrete recovery score, and side effects were recorded. RESULTS: Hemodynamic variables, sedation and pain scores and the number of patients with the maximum Aldrete recovery score 10 min after the procedure were comparable among the groups. The number of patients in group III with the maximum Aldrete recovery score 5 min after the procedure was significantly lower than that in groups I and II. One patient in group II and one patient in group III suffered from nausea. CONCLUSION: Similar pain-free conscious sedation conditions without significant changes in hemodynamic parameters were provided by all three protocols. However, target controlled infusion of remifentanil at 1.5 or 2 ng/mL proved superior at providing early recovery compared to 2.5 ng/mL.

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A anestesia venosa possui muitas vantagens, pois não polui o ar ambiente sendo de fácil manuseio em lugares remotos, oferecendo estabilidade cardiovascular e boa qualidade de recuperação. O propofol, por suas características farmacológicas, é um dos fármacos mais usados em infusões contínuas. Recentes avanços em pesquisas têm confirmado o emprego cada vez maior da anestesia venosa total com a utilização de infusões alvo-controladas, baseadas em simulações farmacodinâmicas e farmacocinéticas dos fármacos com tempo real, inclusive na Medicina Veterinária. Em função disto, pretende-se revisar a anestesia alvo-controlada, proporcionando a atualização sobre o assunto, oferecendo mais uma alternativa para o profissional médico veterinário que atua nessa área

Total venous anesthesia has many advantages as it does not pollute environmental air, can be easily used in remote sites, provides cardiovascular stability and good recovery quality. Due to its pharmacology, propofol is one of the most frequently used drugs in continuous infusions. Recently, advances have also been observed in total venous anesthesia with the use of target-controlled infusions based on real-time pharmacodynamic and pharmacokinetic drug simulations in Veterinary Medicine. As a result, it was intended to revise the controlled infusion anesthesia, providing to the uptade on the subject, offering an alternative for the medical professional veterinarian who acts in this area

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A anestesia venosa possui muitas vantagens, pois não polui o ar ambiente sendo de fácil manuseio em lugares remotos, oferecendo estabilidade cardiovascular e boa qualidade de recuperação. O propofol, por suas características farmacológicas, é um dos fármacos mais usados em infusões contínuas. Recentes avanços em pesquisas têm confirmado o emprego cada vez maior da anestesia venosa total com a utilização de infusões alvo-controladas, baseadas em simulações farmacodinâmicas e farmacocinéticas dos fármacos com tempo real, inclusive na Medicina Veterinária. Em função disto, pretende-se revisar a anestesia alvo-controlada, proporcionando a atualização sobre o assunto, oferecendo mais uma alternativa para o profissional médico veterinário que atua nessa área(AU)

Total venous anesthesia has many advantages as it does not pollute environmental air, can be easily used in remote sites, provides cardiovascular stability and good recovery quality. Due to its pharmacology, propofol is one of the most frequently used drugs in continuous infusions. Recently, advances have also been observed in total venous anesthesia with the use of target-controlled infusions based on real-time pharmacodynamic and pharmacokinetic drug simulations in Veterinary Medicine. As a result, it was intended to revise the controlled infusion anesthesia, providing to the uptade on the subject, offering an alternative for the medical professional veterinarian who acts in this area(AU)

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PURPOSE: Cardiopulmonary bypass is known to alter propofol pharmacokinetics in patients undergoing cardiac surgery. However, few studies have evaluated the impact of these alterations on postoperative pharmacodynamics. This study was designed to test the hypothesis that changes in propofol pharmacokinetics increase hypnotic effects after cardiopulmonary bypass. METHODS: Twenty patients scheduled for on-pump coronary artery bypass graft (group, n=10) or off-pump coronary artery bypass graft (group, n=10) coronary artery bypass grafts were anesthetized with sufentanil and a propofol target controlled infusion (2.0 µg/mL). Depth of hypnosis was monitored using the bispectral index. Blood samples were collected from the induction of anesthesia up to 12 hours after the end of propofol infusion, at predetermined intervals. Plasma propofol concentrations were measured using high-performance liquid chromatography, followed by a non-compartmental propofol pharmacokinetic analysis. Data were analyzed using ANOVA, considering p<0.05 as significant. RESULTS: After cardiopulmonary bypass, despite similar plasma propofol concentrations in both groups, bispectral index values were lower in the on-pump coronary artery bypass graft group. Time to extubation after the end of propofol infusion was greater in the on-pump coronary artery bypass graft group (334 ± 117 vs. 216 ± 85 min, p = 0.04). Patients undergoing cardiopulmonary bypass had shorter biological (1.82 ± 0.5 vs. 3.67 ± 1.15h, p < 0.01) and terminal elimination (6.27 ± 1.29 vs. 10.5h ± 2.18, p < 0.01) half-life values, as well as higher total plasma clearance (28.36 ± 11.40 vs.18.29 ± 7.67 mL/kg/min, p = 0.03), compared to patients in the off-pump coronary artery bypass graft group. CONCLUSION: Aside from the increased sensitivity of the brain to anesthetics after cardiopulmonary bypass, changes in propofol pharmacokinetics may contribute to its central nervous system effects.

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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.

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