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Point of Care Intravenous Anaesthetic Measurement in Anaesthesia and Critical Care By Point of Care Intravenous Anaesthetic Measurement in Anaesthesia and Critical Care by Dr Nicholas John Cowley A Thesis Submitted to The University of Birmingham for the Degree of DOCTOR OF MEDICINE (MD) School of Clinical and Experimental Medicine College of Medicine and Dentistry University of Birmingham Date of Submission: May 2014 i University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Contents Abstract ................................................................................................................. iii List of Chapters ...................................................................................................... v List of Figures ........................................................................................................ xii List of Tables ......................................................................................................... xvii Declaration ............................................................................................................ xx acknowledgements ................................................................................................. xxiii List of Abbreviations ............................................................................................... xxiv ii Abstract Maintenance of anaesthesia using the intravenous agent propofol has markedly increased following the development of pharmacokinetic models for drug delivery. These models estimate drug concentrations based on a small cohort of patients used to develop the model. It is proposed that an analyser capable of determining propofol concentrations at the point of care may lead to an improved accuracy of drug delivery. Validation work on an analyser with the novel capability of measuring blood propofol concentrations in near real time, developed in collaboration with our department, has been analysed. Results demonstrate a high level of precision for samples in the clinical range between 0.25 and 10µg.ml-1 (bias 0.13 µg.ml-1, precision -0.1 to 0.4 µg.ml-1). A review of the literature and supplementary experimentation were performed in order to determine whether variation in methods of blood sample preparation for analysis were significant. Wide variations in reported methods of blood preparation were found, which have implications for the validity of published data. Further work in the clinical setting was carried out using the novel propofol analyser to further research its potential use in patients with organ dysfunction, as well as to further explore propofol pharmacokinetics in a diverse patient cohort. Studies were performed in intensive care correlating blood propofol concentrations with depth of sedation, and demonstrating a correlation with level of organ failure. The Marsh model of Target Controlled Anaesthesia was poorer at predicting propofol concentration in patients with significant organ dysfunction than in those without organ failure (correlation coefficient 0.36 vs. 0.73 respectively). Studies in the operating room were performed in which measured propofol concentrations were compared with those predicted using the Marsh model. Results demonstrated significant inaccuracies of the model (bias 32%, precision - 8.7 to 72.6%). Anaesthetists relied on estimated concentrations of anaesthetic, with 46% iii making no changes to the set concentration. A method of Marsh model bias correction using a single blood propofol measurement was tested. Results demonstrated insufficient predictability to allow a single point calibration. Use of a model with better performance during early anaesthesia, or multiple sampling may yield more promising results. iv List of Chapters 1 Chapter 1 - Introduction ................................................................................... 1 1.1 General Anaesthesia ........................................................................................................ 1 1.2 Inhalational Anaesthesia .................................................................................................. 2 1.3 Determining Amount of Anaesthetic Delivered During Maintenance Anaesthesia .................. 4 1.4 Intravenous Anaesthesia .................................................................................................. 7 1.5 Propofol ........................................................................................................................ 12 1.5.1 Chemistry ...........................................................................................................................13 1.5.2 Mechanism of Action ............................................................................................................14 1.5.3 Metabolism .........................................................................................................................15 1.5.4 Pharmacokinetics .................................................................................................................16 1.5.5 Pharmacodynamics ..............................................................................................................19 1.5.5.1 Central nervous system................................................................................................................... 19 1.5.5.2 Respiratory System ......................................................................................................................... 20 1.5.5.3 Cardiovascular System .................................................................................................................... 21 1.5.6 Side Effects .........................................................................................................................21 1.5.7 Contraindications .................................................................................................................23 1.6 The Administration of Propofol Intravenous Anaesthesia .................................................. 24 1.6.1 Manually Controlled Infusion Systems ....................................................................................25 1.6.2 Target-Controlled Infusion (TCI) ...........................................................................................27 1.6.3 Differences between pharmacokinetic models for propofol .......................................................31 1.6.3.1 Propofol TCI in paediatrics .............................................................................................................. 35 1.6.3.2 Propofol TCI in the obese population ............................................................................................... 36 1.6.4 The Evaluation of Target Controlled Infusion Systems .............................................................38 1.6.5 Effect-Site Estimation ...........................................................................................................39 v 1.6.6 Advantages and Disadvantages of Target Controlled Infusion ..................................................40 1.7 Methods of Measuring Blood Propofol Currently Available ................................................. 42 1.7.1 High Performance Liquid Chromatography (HPLC) ..................................................................42 1.7.2 Gas Chromatography (GC) ....................................................................................................44 1.7.3 Mass Spectrometry ..............................................................................................................44 1.8 Surrogate Methods of Estimating Blood Propofol Concentration ........................................ 45 1.9 Methods to determine depth of anaesthesia during Total Intravenous Anaesthesia with Propofol ................................................................................................................................ 46 1.9.1 Introduction ........................................................................................................................46 1.9.2 Depth of Anaesthesia Monitors ..............................................................................................48 1.9.2.1 Bispectral Index Monitor (BIS) ......................................................................................................... 48 1.9.2.2 Entropy .......................................................................................................................................... 49 1.9.2.3 Narcotrend ..................................................................................................................................... 50 1.9.2.4 Patient State Analyser (PSI) ............................................................................................................ 50 1.9.2.5 Auditory Evoked Potential Monitor (AEP) .......................................................................................... 51 1.9.3 Weaknesses of Depth of Anaesthesia Monitoring ....................................................................51 2 Chapter 2 – Clinical validation
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