FACULTY OF VETERINARY MEDICINE Reduction and reversal of the undesirable effects of medetomidine with two α2-adrenoceptor antagonists, vatinoxan and atipamezole, in sedated and ketamine- anaesthetized dogs Heta Turunen Department of Equine and Small Animal Medicine University of Helsinki Finland Reduction and reversal of the undesirable effects of medetomidine with two α2-adrenoceptor antagonists, vatinoxan and atipamezole, in sedated and ketamine-anaesthetized dogs Heta Turunen DOCTORAL DISSERTATION To be presented for public examination, witH tHe permission of tHe Faculty of Veterinary Medicine, University of Helsinki in AtHena 107 Auditorium, Siltavuoren Penger 3 A, Helsinki June 1st 2020, at 14 o’clock afternoon Supervised by Professor Outi Vainio, DVM, PhD, DECVPT Docent Marja Raekallio, DVM, PhD Docent Juhana Honkavaara, DVM, PhD Faculty of Veterinary Medicine University of Helsinki Finland Reviewed by Professor Paulo Steagall, DVM, MSc, PhD, ACVAA Department of Clinical Sciences Faculty of Veterinary Medicine University of Montreal Canada Professor Eddie Clutton, BVSc, DVA, ECVAA, MRCA, FRCVS The Royal (Dick) School of Veterinary Studies and The Roslin Institute University of Edinburgh United Kingdom Opponent Professor John Verstegen, DVM, MSc, PhD, ECAR School of Veterinary Medicine and Science University of Nottingham United Kingdom ISBN 978-951-51-6147-5 (paperpack) ISBN 978-951-51-6148-2 (pdf) Layout: Stella Wnuk/Mainostella Unigrafia 2020 To my four-legged friends CONTENTS ABSTRACT ......................................................................................................................................................... 6 LIST OF PUBLICATIONS ..................................................................................................................................... 8 1 INTRODUCTION ............................................................................................................................................. 9 2 REVIEW OF THE LITERATURE ....................................................................................................................... 10 2.1 Clinical and pharmacodynamic effects of medetomidine in dogs ...................................................... 10 2.1.1 Sedation and antinociception ....................................................................................................... 10 2.1.2 Physiological changes in dogs ....................................................................................................... 11 2.1.2.1 Haemodynamics and respiration ............................................................................................... 11 2.1.2.2 Endocrine and gastrointestinal function ................................................................................... 12 2.2 Reduction of the undesirable effects of medetomidine in dogs ......................................................... 13 2.2.1 Dose adjustment ........................................................................................................................... 13 2.2.1.1 Co-administration of butorphanol with medetomidine ........................................................... 14 2.2.2 Pharmacological strategies to attenuate medetomidine-induced cardiovascular adverse effects ................................................................................................................................................................. 15 2.2.2.1 Atropine and glycopyrrolate ...................................................................................................... 15 2.2.2.2 Peripheral α₂-adrenoceptor antagonist vatinoxan .................................................................... 15 2.2.2.3 Ketamine ..................................................................................................................................... 17 2.2.2.4 Anaesthesia with isoflurane ....................................................................................................... 18 2.2.3 Prevention of prolonged sedation ................................................................................................ 19 2.3 The use of atipamezole in dogs ............................................................................................................ 20 2.3.1 Reversal of sedation ...................................................................................................................... 20 2.3.2 Reversal of cardiovascular and respiratory depression ............................................................... 20 3 AIMS OF THE STUDY .................................................................................................................................... 22 4 MATERIALS AND METHODS ........................................................................................................................ 23 4.1 Animals ................................................................................................................................................. 23 4.2 Study design .......................................................................................................................................... 24 4.3 Instrumentation, drugs and dosages ................................................................................................... 24 4.4 Measurements and assessments ......................................................................................................... 25 4.4.1 Cardiopulmonary measurements ................................................................................................. 27 4.4.2 Body temperature ......................................................................................................................... 27 4.4.3 Clinical assessment of sedation, anaesthesia induction and intubation ..................................... 27 4.4.4 Quality of recovery and owner questionnaire .............................................................................. 28 4.5 Concentrations of drugs in plasma ...................................................................................................... 29 4.6 Statistical analyses ............................................................................................................................... 30 4.6.1 Studies Ⅰ and Ⅱ ........................................................................................................................... 30 4.6.2 Study Ⅲ ......................................................................................................................................... 30 5 RESULTS ....................................................................................................................................................... 31 5.1 Cardiovascular effects .......................................................................................................................... 31 5.1.1 Systemic vascular resistance index ............................................................................................... 31 5.1.2 Mean arterial pressure .................................................................................................................. 32 5.1.3 Heart rate ....................................................................................................................................... 34 5.1.4 Cardiac index ................................................................................................................................. 35 5.1.5 Associations between cardiovascular variables and changes ...................................................... 37 5.2 Pulmonary effects ................................................................................................................................. 38 5.3 Arterial pH and lactate ......................................................................................................................... 39 5.4 Sedation, hypnosis, induction and tracheal intubation ...................................................................... 39 5.5 Recovery ............................................................................................................................................... 41 5.5.1 Recovery from anaesthesia ........................................................................................................... 41 5.5.2 Recovery from sedation and owner questionnaire study ............................................................ 41 5.6 Concentrations of drugs in plasma ...................................................................................................... 41 6 DISCUSSION ................................................................................................................................................. 44 6.1 Reduction of medetomidine’s undesirable cardiovascular effects with vatinoxan during sedation, ketamine anaesthesia and atipamezole reversal ...................................................................................... 44 6.2 Pulmonary effects of medetomidine, butorphanol and vatinoxan .................................................... 46 6.3 Influence of ketamine anaesthesia induction on medetomidine’s cardiopulmonary effects with and without vatinoxan ...................................................................................................................................... 46 6.4 Reversal of medetomidine’s undesirable cardiopulmonary effects with atipamezole and interactions of the two α₂-adrenoceptor