From the Department of Physiology and Pharmacology Section for Anesthesiology and Intensive Care Medicine Karolinska Institutet, Stockholm, Sweden GENETIC AND COGNITIVE ASPECTS ON RECOVERY AFTER PROPOFOL ANAESTHESIA Marja Lindqvist Stockholm 2015 All previously published papers were reproduced with permission from the publisher. Cover picture: The propofol molecule by Olivia Lindqvist Published by Karolinska Institutet. Printed by Åtta.45 Tryckeri AB © Marja Lindqvist, 2015 ISBN 978-91-7549-663-4 Till mina små galningar Olivia, Klara och Simon “Om snöret inte håller, utan går av, är det bara att försöka med ett annat snöre.” Nalle Puh (A.A Milne) ABSTRACT Propofol is one of the most used intravenous anaesthetics in the western world. It is often used for ambulatory surgery due to favourable pharmacokinetic properties allowing quick onset and short emergence time. However, there is considerable interindividual variation in pharmacokinetics and dynamics as well as gender differences. Differences in metabolism due to polymorphic enzymes may be a contributing factor to this variation. To enable early and smooth discharge from hospital after ambulatory surgery, a quick postoperative cognitive recovery is essential. It is not known whether the great variation in propofol pharmacokinetics and pharmacodynamics affect the cognitive recovery of the ambulatory patient receiving propofol. By studying correlation between genotype and propofol metabolite production both in liver microsomes and in humans after propofol anaesthesia, we aimed to further describe the variations in propofol pharmacokinetics. Postoperative cognitive recovery in women undergoing ambulatory breast cancer surgery with propofol or desflurane anaesthesia was studied, using the PQRS and CFQ as assessment tools. Further the cognitive performance according to PQRS in a test re-test situation in pre-surgery cancer patients compared to controls was evaluated. Our results demonstrate a great variation in production of propofol metabolites in vitro and in vivo, but no correlation between metabolite level and genotype. Females showed a higher propofol metabolite level compared to men after both bolus dose and infusion of propofol. Cognitive recovery was similar after propofol and desflurane anaesthesia, and subjectively not complete one week after surgery. We found that pre-surgery cancer patients expressed a higher level of anxiety and had lower cognitive baseline test performance compared to controls, resulting in a high exclusion rate in the patient group. The groups had a similar re- test performance in the PQRS cognitive domain. In conclusion, we found a considerable variability in production of propofol metabolites but no correlation to genotype. There was an increased production of propofol metabolites in women compared to men. The protracted postoperative cognitive recovery assessed by PQRS and CFQ after ambulatory surgery was similar after propofol and desflurane anaesthesia, suggesting that possible remains of propofol or its metabolites do not affect cognitive performance more than residual effects of desflurane. When assessing postoperative cognitive recovery it should be acknowledged that the anxiety and stress caused by a severe disease and wait for surgery may have an impact on cognitive PQRS test performance. The use of the revised PQRS cognitive scoring system may lead to the exclusion of a considerable part of the patients due to too low baseline performance. Key words; propofol, CYP2B6, UGT1A9, propofol metabolites, gender difference, postoperative cognitive recovery, desflurane, Postoperative Quality of Recovery Scale, Cognitive Failure Questionnaire LIST OF PUBLICATIONS This thesis has been based on the following papers, which will be referred to in the text by their roman numerals. I. Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia Loryan I*, Lindqvist M*, Johansson I, Hiratsuka M, van der Heiden I, van Schaik RH, Jakobsson J, Ingelman-Sundberg M Eur J Clin Pharmacol (2012) 68:397–406 II. Sex difference in formation of propofol metabolites: a replication study Choong E, Loryan I, Lindqvist M, Nordling A, El Bouazzaoui S, van Schaik RH, Johansson I, Jakobsson J, Ingelman-Sundberg M Basic & Clinical Pharmacology & Toxicology, 2013, 113, 126–131 III. Cognitive recovery after ambulatory anaesthesia based on desflurane or propofol: a prospective randomised study Lindqvist M, Schening A*, Granstrom A*, Bjorne H, Jakobsson JG Acta Anaesthesiol Scand 2014 Oct; (9): 1111-20 IV. Cognitive baseline test and re-test performance according to the revised Postoperative Quality of Recovery Scale in pre-surgery cancer patients -a controlled study Lindqvist M, Granstrom A*, Schening A*, Bjorne H, Jakobsson JG Submitted to Acta Anaesthesiol Scand AAS-14-0556 * These authors contributed equally to the paper TABLE OF CONTENTS Introduction ................................................................................................................................ 1 Propofol ................................................................................................................................................ 4 In general .......................................................................................................................................... 4 Pharmacokinetics and pharmacodynamics ...................................................................................... 4 Genetics ............................................................................................................................................ 7 Desflurane ............................................................................................................................................ 7 Anaesthestics and gender ................................................................................................................... 7 Propofol and gender ......................................................................................................................... 8 Postoperative recovery ....................................................................................................................... 8 Neurocognitive side effects .............................................................................................................. 8 Postoperative recovery and anaesthesia ........................................................................................... 9 Postoperative cognitive recovery and regional vs. general anaesthesia ........................................ 10 Postoperative cognitive recovery and choise of general anaesthetic ............................................ 10 Assessment of Postoperative Recovery ......................................................................................... 11 Objective assessment of postoperative cognitive recovery ........................................................... 11 Aims ........................................................................................................................................... 13 Materials and Methods ........................................................................................................... 14 Ethical considerations ...................................................................................................................... 14 Paper I-II ........................................................................................................................................... 14 Livers .............................................................................................................................................. 14 Patients ............................................................................................................................................ 14 In vitro study ................................................................................................................................... 14 Anaesthesia ..................................................................................................................................... 14 Blood samples ................................................................................................................................ 15 HPLC analysis ................................................................................................................................ 15 Statistics .......................................................................................................................................... 16 Paper III-IV ....................................................................................................................................... 16 Patients and controls ....................................................................................................................... 16 Anaesthesia (paper III) ................................................................................................................... 16 Assessment of postoperative recovery (paper III, IV) ................................................................... 17 Statistics .......................................................................................................................................... 18 Summary of results .................................................................................................................. 19 Paper I ...............................................................................................................................................