Sviluppo di un modello farmacocinetico per l'infusione endovenosa assistita da computer (TCI) di propofol nel cane, ottimizzato mediante lo studio di covariabili distributive Pharmacokinetic model for intravenous propofol administration assisted by computer (TCI) in dogs improved by the study of the covariate effects

If three-quarters of a century ago there were those who criticized intravenous anaesthesia describing it as "an ideal method of euthanasia" (Halford, 1943), today, the use of injectable anesthetics to induce and maintain anaesthesia has become commonly used in human medicine and is becoming increasingly widespread in the veterinary medicine. The basic purpose of intravenous anaesthesia is to achieve anesthetic blood concentrations which will result in the desired effect (Morgan, 1983). Compared to intermittent bolus administration, minimizing fluctuations in the plasma concentration of the drug, intravenous infusion reduces the risk of over and under-dosing, which are potentially responsible for side effects and therapeutic ineffectiveness, respectively. To date, computer-assisted infusion (best known under the acronym TCI) can be considered the most advanced and effective technique for intravenous administration of drugs in anaesthesia (Shafer and Egan, 2016). Among these drugs, propofol, thanks to a series of favorable characteristics including a pharmacokinetic profile suitable for infusion, is currently the injectable anaesthetic agent of first choice and the most widely-used in both human and veterinary medicine. Many factors can affect drugs distribution, their knowledge and specific understanding can be of great help to titrate their administration based on the real needs of individual patients. A unique feature of TCI systems is their potential ability to consider different distributive covariates that come into play during drugs infusion. TCI systems use pharmacokinetic models to calculate, in real time, the rate of infusion required to achieve and maintain the desired drug blood concentration (target) in the patient. Interindividual pharmacokinetic variability is an important point, especially in dogs if we consider the considerable intraspecific variability. The use of an appropriate set of pharmacokinetic parameters is of great importance, in fact, since such parameters often derive from studies carried out in small and homogeneous populations, for some patients real concentrations can significantly deviate from those predicted by the model. The study and inclusion of covariates in pharmacokinetic models, allows TCI systems to predict concentrations with a lower risk of error, allowing their safe use in a wider range of patients with different demographic and physiological characteristics or clinical status (van den Nieuwenhuyzen et al., 2000; Egan, 2003; Schnider et al., 2016). In the field of human medicine, target controlled infusion is already considered a mature and safe technology, with several existing TCI systems approved for propofol infusion as part of routine anaesthesia practice (Absalom et al., 2016; Schnider et al., 2016). In veterinary medicine, the development of this technique is only at the beginning instead. At present, only three single-variable pharmacokinetic models validated for clinical use have been described in literature, two for propofol TCI in dogs (Beths et al., 2001; Lee et al., 2012), one for TCI of propofol in cats (Cattai et al., 2016). Purposes of the research project: " To obtain a population pharmacokinetics of propofol administered by infusion in dogs, meanwhile, studying the effect of some covariates on the distribution of the drug in this species. " To elaborate a final pharmacokinetic model for the computer-assisted infusion of propofol in dogs, optimized by the inclusion of significant covariates. " To evaluate the performance of the new TCI model for its use in the context of common anesthetic practice. The present thesis consists of a first part, structured in three chapters, of general introduction and review of existing literature related to propofol, totally intravenous anaesthesia (TIVA) and target controlled infusion (TCI); and a second part related to the experimental research. The latter is divided into two chapters, one for the first phase of research dedicated to the development of the optimized pharmacokinetic model through the study of covariates, one for the second phase dedicated to the validation of the model. To date, the use of propofol to induce and maintain anaesthesia or sedation is commonly used in human medicine and is progressively spreading in veterinary medicine. From this research we have acquired new knowledge that will allow us to better understand the kinetics of propofol administered as a continuous infusion in dogs, and how this is affected by some variables. The first pharmacokinetic model for computer-assisted infusion of propofol, optimized by covariates and usable in a clinical setting over a wide range of dogs, has been developed and tested. In addition, target reference values for the induction and maintenance of anaesthesia with propofol, and for the awakening and extubation, have been identified.