closed-loop controlled total intra venous anaesthesia

248 Pages·2013·9.91 MB·English

CLOSED-LOOP CONTROLLED TOTAL
INTRAV ENOUS ANAESTHESIA
by
CHAODONG
A thesis submitted to the University of Plymouth
In partial fulfilment for the degree of
DOCTOR OF PHILOSOPHY
Department of Communication and Electronic Engineering
Faculty of Technology
in collaboration with
Derriford Hospital
October 2003
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Closed-Loop Controlled Total Intravenous Anaesthesia
By
Chao Dong
Anaesthesia is important for both surgery and intensive care and intravenous anaesthetics are
widely used to provide rapid onset, stable maintenance, and rapid recovery compared with
inhaled anaesthetics. The aim of the project on which this thesis is based was to investigate a
reliable and safe methodology for delivering total intravenous anaesthesia using closed-loop
control technology and bispectral analysis of human electroencephalogram (EEG) waveform.
In comparison with Target Controlled Infusion (TCI), drug effect is measured during drug
infusion in closed loop anaesthesia (CLAN). This may provide superior safety, better patient
care, and better quality of anaesthesia whilst relieving the clinician of the need to make
recurrent and minor alterations to drug administration.
However, the development of a CLAN system has been hindered by the Jack of a 'gold
standard' for anaesthetic states and difficulties with patient variability in pharmacokinetic and
pharmacodynamic modelling, and a new and generic mathematical model of a closed-loop
anaesthesia system was developed for this investigation. By using this CLAN model,
investigations on pharmacokinetic and phannacodynamic variability existing in patients were
carried out. A new control strategy that combines a Proportional, Integral, Derivative (PID)
controller, bispectral analysis of EEG waveform and pharmacokinetic/ pharmacodynamic
models was investigated.
Based on the mathematical model, a prototype CLAN system, the first CLAN system capable
of delivering both hypnotics and analgesics simultaneously for total intravenous anaesthesia,
was developed. A Bispectral Index (BIS), derived from power spectral and bispectral analysis
on EEG waveform, is used to measure depth of anaesthesia. A supervision system with built
in digital signal processing techniques was developed to compensate the non-linear
characteristics inherent in the system while providing a comprehensive protection mechanism
for patient safety. The CLAN system was tested in 78125 virtual patients modelled using
published data. Investigations on intravenous anaesthesia induction and maintenance with the
CLAN system were carried out in various clinical settings on 21 healthy volunteers and 15
patients undergoing surgery. Anaesthesia targets were achieved quickly and well maintained
in all volunteers/patients except for 2 patients with clinically satisfactory anaesthesia quality.
Author's Declaration
At no time during the registration for the degree ofDoctor of Philosophy has the author·been
registered for any other University award.
This study was carried out in collaboration with Derriford Hospital. Relevant scientific and
engineering seminars and conferences were regularly attended at which work was always
presented; clinical experts in Plymouth were visited for consultation purposes, and four
papers were published.
Publications:
Dong C, Kehoe J, Henry J, Ifeachor EC, Reeve CD and Sneyd JR. Closed-Loop_Computer
Controlled Sedation with Propofol. British Journal of Anaesthesia, 1998, 81, 63'1p.
Dong C, Kehoe J, Henry J; Ifeachor EC, Reeve CD and Sneyd JR. Does Notrous Oxide Affect
Closed-Loop Sedation With Propofol. British Journal of Anaesthesia, 1999a, 83, 516p.
Dong C, Wrigley.S, Ifeachor EC, Reeve CD and Sneyd JR. Closed-Loop Sedation During
Knee Surgery Under Epidural Anaesthesia. British Journal of Anaesthesia, 1999b, 83, 516p-
517p.
Sneyd JR, Dong C, Reeve CD and Ifeachor EC. Using simulations in the design of an
anesthesia system. Simulation & Gamiilg,2001. 32(2):pp 205-2'14.
Conferences attended:
1998 Annual Meeting of Anaesthesia Research Society
1999 Annual Meeting of Anaesthesia Research Society
MrOhao Dong
Date 31 October 2003
Acknowledgements
Firstly I thank my supervisor team (Professor E.C. Ifeachor, Professor Robert J. Sneyd, and
Dr Kit Reeve) for the efforts they have made on this project, special thanks go to Steven L.
Shafer in the University of Stanford for his permission to use the code from the ST ANPUMP
in this project which speeded up my software development. Thanks also go to the Graseby
company for the free loan of a Graseby 3400 medical infusion pump. Many thanks to Dr Jane
Kehoe, Dr Jenney Henry, Dr Aileen Craig, and Dr Sophia Wrigley in Derriford NHS
Hospital, and all volunteers/patients in all clinical experiments.
Finally, I have to say, if there were no understanding from my wife Pinglian Jin, I could not
have done so much on this project, especially for her encouragement and support during the
writing-up when I faced huge pressure from work.
Glossary of Terms
STANPUMP -- A TCI shareware program with pump driver
SlMO -- Single-Input Multiple-Output
CLAN Closed-Loop Anaesthesia
CACI Computer Assisted Continuous Infusion
TCI Target Controlled Infusion
DOA -- Depth of Anaesthesia
PID -- Proportional, Integral, Derivative
EEG Electroencephalogram
BIS Bispectral Index
SEF Spectral Edge Frequency
MF -- Median Frequency
AEP Auditory Evoked Potential
AER Auditory Evoked Response
PK -- Pharmacokinetic
PD -- Pharmacodynamic
eT
-- Target Concentration
CpT -- Target Plasma Concentration
Cer -- Target Effect Site Concentration
CpcALC Calculated Plasma Concentration
CecALC Calculated Effect Site Concentration
Nb Early cortical latency in EEG waveform after auditory stimulation
TABLE OF CONTENTS
I. INTRODUCTION ......................................................................................................................................................... I I
1.1. BACKGROUND OF INTRAVENOUS DRUG ADMINISTRATION ................................................................................ 11
1.2. PROBLEMS IN DEPTH OF ANAESTHESIA MONITORING ........................................................................................ 14
1.3. CURRENT STATE OF THE ART ............................................................................................................................. 15
1.4. AIMS AND OBJECTIVES OF THE PROJECT ............................................................................................................ 18
1.5. OUTLINE OF THE THESIS ..................................................................................................................................... 19
2. INTRAVENOUS ANAESTHESIA .................................................................................................................................. 2 I
2.1. INTRODUCTION ................................................................................................................................................... 21
2.2. MONITORING DEPTH OF ANAESTHESIA .............................................................................................................. 22
2.2. I. Clinical Signs ................................................................................................................................................ 2 2
2.2.2. Drug Concentration ...................................................................................................................................... 22
2.2.3. Human Electroencephalogram (EEG) Signal ............................................................................................... 23
2.2.4. Aspect A-1000 EEG Monitor .................................................................................................................... ... 25
2.3. INTRAVENOUS DRUG DELIVERY ......................................................................................................................... 25
2.3.1. Pharmacokinetics .......................................................................................................................................... 2 5
2.3.2. Pharmacodynamics .................................................................................................................................. .... 29
2.3.3. Accuracy ofP harmacokinetic Model and Patient Variability ...................................................................... 30
2.3.4. Manually Controlled Drug Infusion .............................................................................................................. 32
2.3.5. Target Controlled Infusion ............................................................................................................................ 33
2.3.6. Closed-loop Controlled Drug Infusion ................................ ...................................................................... 34
2.3. 7. Graseby 3400 Anaesthesia Pump .................. ............................................................................................ 35
2.4. ANAESTHETIC DRUGS ......................................................................................................................................... 35
2.4.1. Propofo/ ........................................................................................................................................................ 3 5
2.4.2. A/fen/ani/ ....................................................................................................................................................... 3 7
2.4.3. Dmg Interaction between Propofol and Alfentani/ ....................................................................................... 38
3. CLOSED-LOOP ANAESTHESIA ...................................... ...................................................................................... 39
3.1. INTRODUCTION ................................................................................................................................................... 39
3. 1./. Open loop Control ........................................................... ............................................................................ 39
3.1.2. Closed-Loop Control .................................................................................................................................. 40
3.2. CLOSED-LOOP CONTROL SYSTEMS .................................................................................................................... 42
3.2.1. Introduction .................................................................................................................................................. 42
3.2.2. Transient and Steady State Analysis ..................................................... ...................................................... 43
3.2.3. Root Locus Analysis ..................................... ............................................................................................ 48
3.2.4. Frequency Response Analysis ...................... .................................................................................. .......... 50
3.2.5. Bilinear Transformation .............................................................................................................................. 53
3.2.6. System Compensation ............................................................................................................................. ..... 55
3.2. 7. PID Control ........................................................................................................................................... ...... 57
3.3. HIGHER ORDER SPECTRA .............................................................................................................................. 60
3. 3.1. Introduction ................................................................................................................................................. 60
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3. 3. 2. Power Spectrum ......................................................................................................................................... 60
3.3.3. Bispeclmm .................................................................................................................................................. 62
3.3.4. EEG Application ........................................................................................................................................... 63
4. A MATHEMATICAL MODEL OF CLOSED-LOOP CONTROLLED ANAESTHESIA ................................................ 69
4.1. INTRODUCTION ................................................................................................................................................... 69
4.1.1. Feedback Signals .......................................................................................................................................... 69
4.1.2. Control Strategy ............................................................................................................................................ 69
4.1.3. System Block Diagram .................................................................................................................................. 71
4.2. PHARMACOKINETIC MODEL ............................................................................................................................... 72
4.3. PHARMACODYNAMIC MODEL ............................................................................................................................. 77
4.4. PATIENT MODEL. ................................................................................................................................................ 80
4.5. TARGETCONTROLLER ........................................................................................................................................ 85
4.6. INFUSION RATE GENERA TOR .............................................................................................................................. 86
4.7. DISCUSSION AND CONCLUSION .......................................................................................................................... 86
5. INVESTIGATION OF CLOSED-LOOP ANAESTHESIA ............................................................................................ 88
5.1. INTRODUCTION ................................................................................................................................................... 88
5.2. TARGETING ON PLASMA OR EFFECT SITE DRUG CONCENTRATION .................................................................... 88
5.3. TARGETING ON MIXED SITES ............................................................................................................................. 90
5.4. EXPLORING PATIENT VARIABILITY .................................................................................................................... 92
5.5. INVESTIGATION OF THE CLAN SYSTEM MODEL ON PATIENT VARIABILITY ...................................................... 96
5.51. Methods ............................................................. ........................................................................................... 96
5.5.2. Investigation on Pharmacokinetic Variability .. ........................................................................................... 97
5.5.3. Investigation 011 Pharmacodynamic Variability ......................................................................................... 100
5.6. DISCUSSION AND CONCLUSION ........................................................................................................................ 102
6. DESIGN OF CLOSED-LOOP ANAESTHESIA SYSTEM ................................................................. ........................ 105
6.1. INTRODUCTION ................................................................................................................................................. I 05
6.2. SYSTEM SPECIFICATIONS .................................................................................................................................. 105
6.2.1. Hardware Components and lnte1jaces ....................................................................................................... I 05
6.2.2. Sampling Period. ......................................................................................................................................... 107
6.2.3. PID Controller ............................................................................................................................................ I 07
6.2.4. Data Acquisition ......................................................................................................................................... 108
6.2.5. Anaesthesia Pump Control. ......................................................................................................................... 108
6.2.6. Patielll Safety Control ................................................................................................................................. I 08
6.2.7. User Interface ............................................................................................................................................. 109
6.3. DATAACQUISITION .......................................................................................................................................... I09
6.3.1. Packet Format from RAW EEG Port .......................................................................................................... 110
6.3.2. Data Format from Processed EEG Port ..................................................................................................... Ill
6.3.3. Implementation of Data Acquisition ........................................................................................................... 112
6.4. TARGET CONTROLLED INFUSION ...................................................................................................................... 114
6.4.1. Implementation ofP hannacokinetic Model ................................................................................................ 115
6.4.2. Infusion Rate Algorithm ............................................................... .............................................................. 117
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6.5. PID CONTROLLER ............................................................................................................................................ 121
6.5.1. Design Method ............................................................................................................................................ 121
6.5.2. Estimation ofI nitial Gains .......................................................................................................................... 123
6.5.3. Search of Optimal Gains ............................................................................. ............................................... 124
6.5.4. Gain Evaluation .......................................................................................... ............................................... 126
6.5.5. Manual Adjustment ..................................................................................................................................... 133
6.6. SYSTEM CONTROL BY SUPERVISION ................................................................................................................. 134
6.6.1. Normal Operation ................................................................. ..................................................................... 135
6.6.2. Anaesthesia Induction ............................................................. ................................................................... 137
6.6.3. Anaesthesia Maintenance ..................................................... ..................................................................... 137
6.6.4. Response to Light Anaesthesia and Stimulation ......................................................................................... 13 7
6.6.5. Response to Overshoot and Undershoot ..................................................................................................... 138
6.6.6. Emergency Handling .................................................................................................................................. /38
6.7. INTERACTIVE USER INTERFACE ........................................................................................................................ 139
6.8. TEST OF CLOSED-LOOP ANAESTHESIA SYSTEM ................................................................................................ 139
6.8.1. Test ofS ystem on Patient Safety. ................................................................................................................. 139
6.8.2. Test of System on Virtual Patients .............................................................................................................. 140
6.9. DISCUSSION AND CONCLUSION ........................................................................................................................ 145
7. EVALUATION OF THE CLOSED-LOOP ANAESTHESIA (CLAN) SYSTEM ........................................................... 146
7.1. INTRODUCTION ................................................................................................................................................. I46
7.2. SAFETY TEST OF CLAN SYSTEM ..................................................................................................................... 146
7.3. GENERALMETHODS ......................................................................................................................................... I47
7.4. PROPOFOL SEDATION ON VOLUNTEERS ............................................................................................................ 148
7. 4./. Objective ..................................................................................................................................................... 148
7.4.2. Methods .............................................................. ........................................................................................ 148
7.4.3. Results .............................................................. .......................................................................................... 149
7.4.4. Discussion .......................................................... ........................................................................................ I 57
7.5. PROPOFOLlNITROUS OXIDE SEDATION ON VOLUNTEERS ................................................................................. 166
7.5.1. Objective ..................................................................................................................................................... 166
7.5.2. Metlwds ....................................................................................................................................................... 166
7.5.3. Results ......................................................................................................................................................... 167
7.5.4. Discussion ................................................................................................................................................... 171
7.6. PROPOFOL SEDATION IN PATIENTS UNDERGOING KNEE SURGERY ................................................................... 175
7.6.1. Objective ..................................................................................................................................................... I 75
7.6.2. Methods ....................................................................................................................................................... 17 5
7.6.3. Results ......................................................................................................................................................... 176
7.6.4. Discussion ................................................................................................................................................... 178
7.7. TOTAL INTRAVENOUS ANAESTHESIA ON PATIENTS UNDERGOING BACK SURGERY ......................................... 180
7.7.1. Objective ..................................................................................................................................................... 180
7.7.2. Methods ...................................................................................................................................................... 181
7.7. 3. Results .......................................................................................................................... .............................. 182
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7. 7.4. Discussion ................................................................................................................................................... 184
8. DISCUSSIONS, FUTURE WORK AND CONCLUS/ON. ........................................................................................... /88
8.1. DISCUSSIONS .................................................................................................................................................... 188
8.2. LIMITATIONS AND FUTURE WORK .................................................................................................................... 190
8.3. CONCLUSION .................................................................................................................................................... 193
APPENDIX A DATA FORMAT TRANSMITTED BY A-1000 EEG MONITOR ........................................................... 194
A.1 PROCESSED EEG DATA PACKET AND VARIABLES ........................................................................................... 194
A.2 RAw EEG DATAPACKET ................................................................................................................................. 200
APPENDIX B CLINICAL DATA ARCHIVING ............................................................................................................. 201
8.1 FILESTRUCTURE .............................................................................................................................................. 201
8.2 FILE LoCATIONS ............................................................................................................................................... 202
APPENDIX C RUN-TIME COMMAND FILE ............................................................................................................... 204
APPENDIX D CLAN SYSTEM HARDWARE SETTINGS .............................................................................................. 206
APPENDIX E USER INTERFACE ............................................................................................................................... 208
E.1 SCREEN MESSAGES ............................................................................................................................................... 208
E.2 COMMAND MENU .................................................................................................................................................. 209
APPENDIX F LIST OF PROGRAMS DEVELOPED ... ............................................................................................. 211
F.1 CPROGRAMS ........................................................................................................................................................ 211
F.2 MATLAB PROGRAMS .......................................................................................................................................... 212
REFERENCES .................................................................................................................................................................... /88
PUBLICATIONS ................................................................................................................................................................. 220
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