Studio della farmacocinetica del Propofol, progettazione e validazione di un sistema di target controlled infusion nel gatto

Total intravenous anesthesia (TIVA) is an actual topic and a still developing research area. Technological progress makes equipment for infusion increasingly sophisticated, reliable and safe. Latest infusion systems have been developed incorporating microprocessors and algorithms based on the drug’s pharmacokinetic and pharmacodynamic parameters for the population involved. The aim of this research project was to develop and validate a system for target-controlled infusion (TCI) for administering propofol to domestic cats. Knowledge on behavior of propofol, administered as a continuous infusion in cats are, at present, still few and sometimes contradictory. It is well known that cats differ substantially from other animals in the ability to form glucuronide conjugates of some xenobiotics, particularly low molecular weight phenolic derivatives. A system for propofol infusion, allowing to predict as accurately as possible, the actual behavior of the drug and the concentrations at any time-point of anesthesia, may help reducing perianesthetic risk and improve quality of anesthesia. As no publications could be found reporting three-compartment pharmacokinetics for propofol in cats, the first part of the this work was dedicated to the development of a pharmacokinetic model, on 7 cats, premedicated with medetomidine, ketamine and methadone, anesthetized with propofol and maintained with isoflurane anesthesia, during gonadectomy. A two-compartment and a three-compartment pharmacokinetic linear model were obtained, the latter being considered the most appropriate to describe plasma concentration-time profile, based on appearance of observed and predicted concentrations and determined by least square linear regression and applying Akaike's information criterion. The tri-compartmental pharmacokinetic data obtained in the first part of the project were used for implementation of a TCI system prototype (TCI-1), based on the free software, Computer Control Infusion Pump (CCIP) Ver 2.0E, available online (http: / / www.cuhk.edu.hk / med / ans / softwares.htm). We analyzed the performance of the TCI-1 system during the course of anesthesia for gonadectomy in 9 premedicated cats, and target concentrations for induction, maintenance and extubation were reported. The mean concentration, as measured by HPLC, in venous blood, two minutes after intubation was 4.92 ± 2.43 μg ml-1 and for maintenance, 4.74 ± 2.70 μg ml-1. The indices for system prediction error, MDPE%, MDAPE%, divergence (% / hour) and wobble, calculated as described by Varvel et al. (1992), reported as median [10 / 90 percentile], were 63.50 [31.24 / 151.93], 63.50 [32.28 / 151.93], -22.77 [- 331 / 26.57], 20.32 [9.8 / 43.10], respectively. Despite it has demonstrated to be manageable in its clinical use, the system has significantly underestimated the actual concentrations, as expected for a single bolus derived pharmacokinetic model. The next step was to optimize the TCI-1 system, modifying the pharmacokinetic data set through computer simulations. The new system (TCI-2.0) was assessed for predictive performance, in 6 cats, calculating MDPE%, MDAPE%, divergence (%/hours) and wobble, and it was compared to the results obtained with the TCI-1 system. Mean concentration, measured by HPLC, in venous blood of cats, two minutes after intubation was 3.23 ± 0.87 μg kg-1. Mean maintenance target concentration, calculated as the mean of targets set introduced in the system, during anesthesia, was 6.44 ± 1.27 μg ml-1, while average concentrations measured by HPLC during the same time period , was 5.56 ± 2.46 μg ml-1. Values of MDPE%, MDAPE%, divergence and wobble, reported as median [10 / 90 percentile], were -1.85 [-35.19 / 31.08], 29.67 [16.85 / 43.93], -39.08 [-50.02 / 8.23], 18.93 [10.49 / 25.01], respectively. Prediction curves, obtained by the system TCI-2.0 were similar to actually measured plasma concentrations. The resulting values for MDPE and MDAPE fall within the range described in human and veterinary literature for the validation of TCI systems in the clinical setting (MDPE <± 20% and MDAPE <30-40%). Difference in accuracy and bias observed between the two systems, TCI-1 and TCI-2.0 were statistically significant. Timing and dose of induction, maintenance, and extubation were also compared. Differences between the two systems, for doses and timing of administration and extubation, were not found to be statistically significant. Obtained results are, in the author’s opinion, of significant scientific relevance, as they provide: • A three-compartment pharmacokinetic model for propofol in cats, never described previously in the literature. • A TCI system for propofol administration in cats, validated for prediction performance and easy to use in a clinical setting. • reference values for plasma concentrations of propofol required for intubation, maintenance of anesthesia and extubation, in cats premedicated with medetomidine, ketamine and methadone, anesthetized with target infusion of propofol.