Total Intravenous Anaesthesia in dogs: Development of a Target Controlled Infusion (TCI) scheme for propofol A thesis presented for the degree of Doctor of Philosophy Thierry Beths Companion Animal Sciences Faculty of Veterinary Medicine University of Glasgow April 2008 © Copyright Thierry Beths, 2008 II Summary 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 alpha - 2 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 μgml-1, and an adequate depth and a satisfactory quality of anaesthesia were achieved with mean maintenance targets of between 3.4 and 4.5 μgml-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 μgkg-1 MED, respectively). Following premedication, anaesthesia was induced with a PPF target blood concentration of 3 μgml-1 and maintained with a target concentration of 3.5 μgml-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 Thierry Beths, 2008 III injection), the ED for ABP and HR were 2.05 and 0.187 μgkg-1 respectively, while the ED 50 95 (doses of MED inducing 95% of the maximum effect) values were estimated to be 18.1 μgkg-1 and 3.1 μgkg-1, respectively. The no effect doses for MED were 0.01 μgkg-1 for HR, and 0.1 μgkg-1 for ABP. Minimal respiratory effects were observed in all groups except the group receiving 10 μgkg-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 alpha -adrenoceptor agonists during co-infusion; to determine 2 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. Thierry Beths, 2008 IV TABLE OF CONTENTS Summary..........................................................................................................................................2 List of Chapters...............................................................................................................................5 List of Tables..................................................................................................................................11 List of Figures.................................................................................................................................13 Dedication.......................................................................................................................................15 Declaration......................................................................................................................................16 Acknowledgements.........................................................................................................................17 Abbreviations..................................................................................................................................18 Thierry Beths, 2008 V LIST OF CHAPTERS CHAPTER 1: GENERAL INTRODUCTION AND REVIEW OF THE LITERATURE...............................19 1.1 ANAESTHESIA...................................................................................................................20 1.2 THE HISTORY OF INTRAVENOUS ANAESTHESIA...............................................................21 1.3 TECHNIQUES USED TO ADMINISTER TIVA........................................................................23 1.3.1 Anaesthetic Infusion Systems........................................................................................23 1.3.2 The Concept of Target Controlled Infusion..................................................................24 1.3.3 Evaluation of Target Controlled Infusion Systems.......................................................24 1.3.4 Use of Target Controlled Infusions...............................................................................25 1.4 TIVA IN VETERINARY MEDICINE......................................................................................25 1.4.1 Alternatives to co-infusions of opioids with propofol...................................................26 1.5 PROPOFOL.........................................................................................................................26 1.5.1 Metabolism of propofol.................................................................................................27 1.5.2 Pharmacokinetics of propofol.......................................................................................28 1.5.3 Pharmacodynamic characteristics of propofol.............................................................29 1.6 ALPHA -ADRENOCEPTOR AGONISTS.................................................................................30 2 1.6.1 Medetomidine................................................................................................................30 1.6.1.1 Metabolism of medetomidine...............................................................................31 1.6.1.2 Pharmacokinetics of medetomidine......................................................................33 1.6.1.3 Pharmacodynamic characteristics of medetomidine.............................................33 1.6.2 Dexmedetomidine..........................................................................................................35 1.6.2.1 Pharmacokinetics of dexmedetomidine................................................................35 1.6.2.2 Pharmacodynamic characteristics of dexmedetomidine.......................................35 1.7 DRUG INTERACTIONS........................................................................................................36 1.7.1 Pharmacokinetic interaction.........................................................................................36 Thierry Beths, 2008 VI 1.7.2 Pharmacodynamic interactions....................................................................................37 1.7.2.1 Propofol-medetomidine........................................................................................37 1.7.2.2 Propofol-dexmedetomidine...................................................................................37 1.8 PURPOSE OF THIS STUDY...................................................................................................38 CHAPTER 2: DEVELOPMENT OF A TARGET CONTROLLED INFUSION SYSTEM FOR PROPOFOL IN THE DOG...........................................................................................................39 2.1 INTRODUCTION..................................................................................................................40 2.1.1 Determination of pharmacokinetic parameters............................................................40 2.1.2 Optimisation of blood propofol targets.........................................................................41 2.1.3 Evaluation of the performance of the TCI system.........................................................43 2.1.4 Goal of the study...........................................................................................................44 2.2 MATERIALS AND METHODS...............................................................................................44 2.2.1 Animals.........................................................................................................................44 2.2.2 TCI Equipment..............................................................................................................44 2.2.3 Anaesthetic protocol.....................................................................................................45 2.2.4 Blood sampling.............................................................................................................46 2.2.5 Blood propofol analysis................................................................................................46 2.2.6 Data handling...............................................................................................................48 2.2.7 Statistical analysis........................................................................................................48 2.3 RESULTS............................................................................................................................48 2.3.1 Optimisation of blood propofol targets.........................................................................53 2.3.2 Evaluation of the performance of the TCI system.........................................................54 2.4 DISCUSSION.......................................................................................................................61 2.4.1 Propofol target concentrations for induction...............................................................61 2.4.2 Induction doses.............................................................................................................62 2.4.3 Propofol target concentrations for maintenance..........................................................63 2.4.4 Maintenance infusion rate............................................................................................64 Thierry Beths, 2008 VII 2.4.5 Side effects....................................................................................................................65 2.4.6 Extubation time.............................................................................................................66 2.4.7 Evaluation of the performance of the TCI system.........................................................66 2.5 CONCLUSIONS...................................................................................................................68 CHAPTER 3: PHARMACOKINETIC INTERACTION BETWEEN PROPOFOL AND THE ALPHA - 2 ADRENOCEPTOR AGONIST MEDETOMIDINE AND ITS ENANTIOMERS - IN VITRO STUDY IN RAT AND DOG TISSUES.........................................................................................69 3.1 INTRODUCTION..................................................................................................................70 3.1.1 Goal of the study...........................................................................................................71 3.2 MATERIALS AND METHODS..............................................................................................71 3.2.1 Animals.........................................................................................................................71 3.2.2 Isolation of hepatic microsomes...................................................................................71 3.2.2.1 Rats.......................................................................................................................71 3.2.2.2 Dogs......................................................................................................................72 3.2.2.3 Protein content......................................................................................................72 3.2.3 Propofol study...............................................................................................................72 3.2.3.1 Incubation mixture................................................................................................72 3.2.3.2 Time course pilot study.........................................................................................73 3.2.3.3 Study of the effect of medetomidine and its enantiomers on propofol metabolism in rat and dog microsomes....................................................................................................73 3.2.3.4 Propofol analysis...................................................................................................74 3.2.4 Medetomidine, dex- and levomedetomidine analysis....................................................74 3.2.5 Statistical analyses........................................................................................................74 3.3 RESULTS............................................................................................................................75 3.3.1 Pilot study: Effect of propofol concentration on rat and canine hepatic microsomal activity .......................................................................................................................................75 Thierry Beths, 2008 VIII 3.3.2 Effect of medetomidine, dex- and levomedetomidine on rat and canine hepatic microsomal activity...................................................................................................................75 3.4 DISCUSSION.......................................................................................................................83 CHAPTER 4: DOSE RESPONSE STUDY OF THE CARDIO-RESPIRATORY EFFECTS OF MEDETOMIDINE IN DOGS ANAESTHETISED WITH A TARGET CONTROLLED INFUSION OF PROPOFOL.........................................................................................................87 4.1 INTRODUCTION..................................................................................................................88 4.1.1 Cardiovascular effects of Medetomidine......................................................................88 4.1.1.1 Arterial Blood pressure (ABP)..............................................................................88 4.1.1.2 Heart rate...............................................................................................................89 4.1.2 Respiratory effects of medetomidine.............................................................................90 4.1.3 Perioperative use of medetomidine...............................................................................91 4.1.4 Cardiovascular effects of propofol...............................................................................92 4.1.4.1 Arterial blood pressure..........................................................................................92 4.1.4.2 Heart rate...............................................................................................................92 4.1.4.3 Respiratory effects................................................................................................93 4.1.5 Propofol and medetomidine premedication (cf section 4.1.3)......................................93 4.1.6 Goal of the study...........................................................................................................95 4.2 MATERIALS AND METHODS...............................................................................................96 4.2.1 Data Analysis................................................................................................................97 4.3 RESULTS............................................................................................................................98 4.4 DISCUSSION.....................................................................................................................107 4.5 CONCLUSIONS.............................................................................................................................114 Thierry Beths, 2008 IX CHAPTER 5: PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES OF MEDETOMIDINE AND DEXMEDETOMIDINE INFUSIONS IN DOGS ANAESTHETISED WITH PROPOFOL ADMINISTERED BY TCI...................................115 5.1 INTRODUCTION................................................................................................................116 5.1.1 Propofol and medetomidine/dexmedetomidine...........................................................116 5.1.1.1 Pharmacokinetic studies......................................................................................117 5.1.1.2 Pharmacodynamics.............................................................................................118 5.1.1.3 Analgesia.............................................................................................................119 5.1.1.3.1 Minimum medetomidine analgesic plasma concentration..............................119 5.1.1.3.2 Determination of Minimum Infusion Target (MIT) for propofol...................119 5.1.2 Goals of the study........................................................................................................120 5.2 MATERIALS AND METHODS............................................................................................120 5.2.1 Animals.......................................................................................................................120 5.2.2 Development of a medetomidine/dexmedetomidine infusion schemes........................121 5.2.3 Experimental design....................................................................................................121 5.2.4 Anaesthetic protocol...................................................................................................122 5.2.5 Determination of Minimum Infusion Target (MIT) for propofol................................124 5.2.6 Blood sampling...........................................................................................................124 5.2.7 Analyses......................................................................................................................125 5.2.7.1 Propofol...............................................................................................................125 5.2.7.2 Medetomidine and Dexmedetomidine................................................................125 5.2.8 Data Handling............................................................................................................125 5.2.9 Determination of the PK parameters for dexmedetomidine.......................................126 5.2.10 Statistical analysis..................................................................................................126 5.3 RESULTS..........................................................................................................................127 5.3.1 Development of medetomidine and dexmedetomidine infusion schemes for co-infusion in dogs anaesthetised with propofol TCI................................................................................127 Thierry Beths, 2008 X 5.3.2 Anaesthesia.................................................................................................................129 5.3.3 Pharmacodynamic study.............................................................................................132 5.3.3.1 Heart Rate...........................................................................................................132 5.3.3.2 Arterial Blood Pressure.......................................................................................132 5.3.3.3 Cardiac output.....................................................................................................132 5.3.3.4 Respiratory variables...........................................................................................137 5.3.4 Pharmacokinetic results.............................................................................................137 5.3.4.1 Propofol...............................................................................................................137 5.3.4.1.1 Assessment of the performance of the propofol TCI system..........................142 5.3.4.1.2 Determination of the MIT for propofol...........................................................142 5.3.4.2 Medetomidine-Dexmedetomidine.......................................................................148 5.3.4.2.1 Dexmedetomidine (PHD group) – Predicted vs. measured blood levels........148 5.3.4.2.2 Determination of the PK parameters for dexmedetomidine (PHD group)......148 5.4 DISCUSSION.....................................................................................................................157 5.4.1 Development of a medetomidine/dexmedetomidine infusion scheme.........................157 5.4.2 Anaesthesia.................................................................................................................158 5.4.3 Pharmacodynamics.....................................................................................................160 5.4.4 Pharmacokinetics........................................................................................................163 5.4.4.1 Propofol...............................................................................................................163 5.4.4.1.1 Assessment of the performance of the propofol TCI system..........................163 5.4.4.1.2 Determination of the MIT for propofol...........................................................164 5.4.4.2 Medetomidine/Dexmedetomidine.......................................................................166 5.5 CONCLUSION..............................................................................................................................167 CHAPTER 6: GENERAL DISCUSSION AND CONCLUSIONS...................................................................168 REFERENCES..............................................................................................................................175 APPENDICES................................................................................................................................214