Total intravenous anaesthesia in dogs : development of a target controlled infusion (TCI) scheme for propofol

The aim of this work was to develop a propofol (PPF) based Total Intravenous Anaesthesia (TIVA) technique to be used in dogs by veterinary surgeons in practice. As PPF is a poor analgesic agent, this work also looked into the development of a co-infusion scheme for the potent alpha2-adrenoceptor agonist medetomidine (MED) and its active enantiomer dexmedetomidine (DEX). The study was divided into 4 phases. In phase one, canine PPF pharmacokinetic (PK) parameters, derived from previous studies reported in the literature, were incorporated to a Target Controlled Infusion (TCI) system. This approach, comprising computer software incorporated into a syringe driver, which will deliver PPF to a predicted blood concentration, is widely used in humans. The performance of the system was investigated in 6 greyhounds and 10 mixed-breed dogs undergoing routine dental work by comparing predicted with measured PPF concentrations in venous blood samples obtained during and following TCI PPF anaesthesia. The optimal induction target was 3 mgml-1, and an adequate depth and a satisfactory quality of anaesthesia were achieved with mean maintenance targets of between 3.4 and 4.5 mgml-1 of PPF. The performance of the TCI system was considered clinically acceptable as the Median Prediction Error (MDPE%), a measure of bias, and the Median Absolute Performance Error (MADPE%), a measure of the accuracy, were -12.47 and 28.47 respectively, in the greyhounds and 1.56 and 24.79 respectively, in the mixed-breed dogs. The system was easy to use and the quality of anaesthesia was judged to be adequate for dental work. Phase 2 illustrated the inhibitory effect of MED and DEX on PPF metabolism at the level of the cytochrome P450 in rat and canine hepatic tissue and highlighted, therefore, the possible effect on the metabolism dependant performance of the TCI system. Before designing an infusion scheme for MED and studying its possible effect on PPF PK in vivo (phase 4), the purpose of phase 3 was to characterise cardiovascular and respiratory effects of MED administered IV to dogs anaesthetised with a TCI of PPF, and to assess its suitability for use in a TIVA regime. Eighty dogs, ASA 1 or 2, aged 0.5 to 8 years, were randomly allocated into 8 groups of 10 dogs according to the dose of MED administered (Groups 1-8: 0 (saline, 0.9%, 1 ml), 0.01, 0.03, 0.1, 0.3, 1, 3, 10 mcgkg-1 MED, respectively). Following premedication, anaesthesia was induced with a PPF target blood concentration of 3 mcgml-1 and maintained with a target concentration of 3.5 mcgml-1. Cardiovascular and respiratory parameters were recorded for 15 min post induction and before saline (group 1) or MED (groups 2-8) was injected slowly over 1 min. Medetomidine induced a dose-dependent reduction in heart rate (HR) and increase in systolic arterial blood pressure (ABP). At the time of maximum observed effect (2 min post MED injection), the ED50 for ABP and HR were 2.05 and 0.187 mcgkg-1 respectively, while the ED95 (doses of MED inducing 95% of the maximum effect) values were estimated to be 18.1 mcgkg-1 and 3.1 mcgkg-1, respectively. The no effect doses for MED were 0.01 mcgkg-1 for HR, and 0.1 mcgkg-1 for ABP. Minimal respiratory effects were observed in all groups except the group receiving 10 mcgkg-1 of MED where, by the end of the recording period (20 min post MED injection), 8 of 9 spontaneously breathing dogs became apnoeic after MED administration. Phase 4 was designed to develop and assess a stepped infusion scheme for MED and DEX in the TCI PPF anesthetised dog using MED PK parameters from O. Vainio (V1 = 470 mlkg-1, K12 = 0.0954, K21 = 0.0438, K10 = 0.0489); to observe the possible PK and PD (pharmacodynamic) interactions between PPF and the 2 alpha2-adrenoceptor agonists during co-infusion; to determine the minimum blood PPF infusion target (MIT) necessary to prevent purposeful movement during supramaximal noxious stimulation (tetanic twitch for 5 sec at the level of the 4th and 5th coccygeal vertebrae) with and without a co-infusion of MED or DEX and to confirm the DEX minimum analgesic blood concentration of 0.85 ngml-1. Six female beagle dogs, 7.3 (± 2.3) years old, were anaesthetised on 4 occasions, following a randomised cross over design: PPF TCI with either co-stepped infusion of saline (PS), MED (blood target of 1.7 ngml-1, PM), low DEX (blood target of 0.85 ngml-1, PLD) or high DEX (blood target of 1.7 ngml-1, PHD). The co-infusion was started 25 min after the start of anaesthesia (instrumentation period), while the MIT determination was conducted 15 min after the last step of the co-infusion. Venous blood samples were taken at specific times for determination of the PPF, MED and DEX plasma concentrations. The performance of the TCI system for PPF in the dog was only clinically acceptable in the PS and PLD treatments with MDPE% values of 18.85 and 25.94 respectively, and MDAPE% values of 18.85 and 35.80 respectively. In this study the use of DEX 0.85 ngml-1 had a similar PPF sparing effect to the equivalent MED blood concentration of 1.7 ngml-1, but with less effects on ABP, as well as on the performance of the TCI for PPF in the dog. Therefore, it could be concluded that DEX was more advantageous than MED given by infusion in PPF anaesthetised dogs. The study also confirmed the validity of the PK of MED from the previous study. The study redefined specific PK parameters for DEX, although the MED PK parameters could also be used. The study indicated that DEX blood concentrations as low as 0.85 ngml-1 decreased the measured PPF blood concentrations necessary to maintain anaesthesia during noxious stimulation by about 38%. However, although this study supported the suitability of the co-infusion of DEX during PPF anaesthesia in the dog, and the analgesic/sedative effects of DEX were present at the lowest blood concentrations with well maintained respiratory parameters, the CV effects were marked with a decrease in HR and CO and an increase in systolic and mean ABP. Further studies are therefore necessary to establish if a lower blood concentration of DEX will provide analgesia while preserving the CV system.