Abnormal Recovery from Anesthesia: A Marker of Early Cognitive Dysfunction in Rodent Models of Disease Público
Sinon, Christopher (Fall 2019)
Abstract
The widespread adoption of general anesthetics in the 19th century led to rapid advancements in surgical practice. However, alongside this growth there has been concern about the appearance of cognitive disturbances in the postoperative period. Large clinical research projects have begun to elucidate some of the risk factors that can predispose patients to postoperative cognitive impairments and correlated the risk for later cognitive impairments with the appearance of earlier postoperative cognitive disturbances. Unfortunately, most published work on abnormal recoveries from anesthesia exists in the form of individual case studies or uses methods that are not currently practical for translation to everyday clinical use. Preclinical models represent a promising approach towards investigating biological underpinnings of abnormal emergence and recovery. This thesis contains our work characterizing the immediate emergence and recovery from anesthesia in preclinical models of conditions known to be risk factors for developing postoperative cognitive impairments. We characterized the behavioral phenotype and neuropathology of a transgenic rat model of Alzheimer’s Disease (AD). At 12-months of age there is neuropathology consistent with the early phase of AD, but with no observed behavioral differences between wild type and transgenic rats. We compared the latency to display emergence and recovery behaviors following isoflurane exposure in 12-month wild type and transgenic rats. Recovery from isoflurane is significantly delayed in transgenic AD rats when compared to wild type. Despite this, transgenic AD rats are not more sensitive to anesthetic drugs as measured by EEG, suggesting that delayed recovery may be due to exacerbation of AD disease pathology. Additionally, we investigated how emergence and recovery behaviors are altered in a type 2 diabetes rat model. We found that these rats do not differ from wild type rats in their emergence or recovery, but prior treadmill exercise hastened recovery from anesthesia in both groups. Overall, we demonstrate the ability to identify changes in the behavioral response to anesthetics in the recovery from general anesthesia due to disease progression and prehabilitative interventions. Our results highlight the need to treat the emergence and recovery from anesthesia as distinct clinical endpoints.
Table of Contents
List of Figures and Tables
List of Abbreviations
Chapter 1 - General Introduction. 1
1.1 History of Anesthesia. 3
1.1.1 Early Anesthetics 4
1.1.2 The Beginnings of Modern Anesthesia. 6
1.1.3 Improvements in Anesthesiology 7
1.2 Historical Problems in the Study of Consciousness 8
1.2.1 The Hard Problem of Consciousness 8
1.2.2 Easy Problems of Consciousness 9
1.2.3 Animal Consciousness 11
1.3 Changes in States of Consciousness 13
1.3.1 When has conscious experience changed?. 13
1.4 Effects of General Anesthesia 14
1.4.1 Pharmacology. 15
1.4.2 Behavior 18
1.4.3 Neurophysiology. 20
1.5 Emergence and Recovery from Anesthesia. 23
1.5.1 Anesthetic Reversal 23
1.5.2 Canonical Sequence of Emergence and Recovery Behaviors in Rats 24
1.6 Cognitive Problems Arising after Surgery 25
1.6.1 Emergence Agitation. 25
1.6.2 PACU Delirium.. 27
1.6.3 Postoperative Delirium.. 28
1.6.4 Postoperative Cognitive Dysfunction. 30
1.6.5 Anesthesia Awareness With Recall 31
1.7 General Anesthesia and Postoperative Cognitive Impairments 33
1.7.1 General Anesthetics and Neurotoxicity. 33
1.7.2 General Anesthetics and Neuroinflammation. 34
1.7.3 General Anesthetics and Neurophysiology 35
1.9 Gap in Knowledge 39
1.10 Thesis Outline 40
Chapter 2 - Angiotensin Receptor Blockers as a Mediator of AD-like Cognitive Dysfunction in the TgF344-AD Rat Model 41
2.1 Abstract 41
2.2 Introduction. 42
2.2.1 The Amyloid Cascade Hypothesis of Alzheimer’s Disease. 42
2.2.2 The Vascular Hypothesis of Alzheimer’s Disease. 43
2.2.3 The Renin Angiotensin System as a Therapeutic Target in Early Alzheimer’s Disease. 44
2.2.4 Candesartan, An Angiotensin Receptor Blocker (ARB) 45
2.2.5 The TgF344-AD Rat Model 46
2.2.6 Summary 46
2.3 Experimental Design and Hypotheses 46
2.4 Methods 48
2.4.1 Animals 48
2.4.2 Continuous Spontaneous Alternation Behavior Test 48
2.4.3 Novel Object Recognition Test 49
2.4.4 ARB Treatment 50
2.4.5 Water Radial Arm Maze. 50
2.4.6 Blood Pressure Readings 51
2.4.7 Tissue Collection. 51
2.4.8 Tissue Sectioning and Immunohistochemistry. 52
2.4.9 Quantification of Immunohistochemistry. 52
2.4.10 Statistical Analysis 52
2.5 Results 53
2.5.1 Amyloid-b and GFAP are increased in the hippocampus of 12-month old TgF344-AD rats 53
2.5.2 No differences in Continuous Spontaneous Alternation Test performance or Novel Object Recognition at 12-months in TgF344-AD or WT rats 55
2.5.3 Candesartan decreases mean arterial pressure for both WT and TgF344-AD rats 57
2.5.4 Amyloid-b and GFAP are increased in the hippocampus of 18-month old TgF344-AD rats 58
2.5.5 Candesartan preserves task learning on the WRAM for TgF344-AD rats 62
2.5.6 Working and Reference memory impairment in 18-month old TgF344-AD rats is partially rescued by treatment with candesartan 65
2.6 Discussion. 66
Chapter 3 - Delayed Anesthetic Recovery in 12-Month TgF344-AD Rats. 69
3.1 Abstract 69
3.2 Introduction. 70
3.2.1 Alzheimer’s Disease and Anesthesia. 71
3.2.2 Alzheimer’s Disease and anesthetic sensitivity 72
3.3 Experimental Design and Hypotheses 72
3.4 Methods 74
3.4.1 Animals 74
3.4.2 Continuous Spontaneous Alternation Behavior Test 74
3.4.3 Novel Object Recognition Test 75
3.4.4 Isoflurane Anesthesia. 76
3.4.5 Anesthetic Emergence & Recovery. 76
3.4.6 Activity Monitoring. 77
3.4.7 Wireless EEG Transmitter Implantation. 77
3.4.8 EEG Recording. 79
3.4.9 Tissue Collection. 79
3.4.10 Tissue Sectioning and Immunohistochemistry. 80
3.4.11 Quantification of Immunohistochemistry. 80
3.4.12 Statistical Analysis 80
3.5 Results 81
3.5.1 Cognitive Testing. 81
3.5.2 Emergence and Recovery from Isoflurane. 84
3.5.3 Burst Suppression. 86
3.5.4 Increased amyloid-b and GFAP in TgF344-AD rats after burst suppression. 89
3.6 Discussion. 90
Chapter 4 - Prehabilitative Exercise Hastens Anesthetic Recovery in Diabetic and non-Diabetic Rats. 94
4.1 Abstract 94
4.2 Introduction. 96
4.2.1 Diabetes and Surgery 96
4.2.2 General Anesthesia and Cognitive Dysfunction. 96
4.2.3 The Effects of Exercise on Cognitive Reserve. 97
4.3 Experimental Design and Hypotheses 98
4.4 Methods 99
4.4.1 Animals 99
4.4.2 Glucose Tolerance Test (GTT) 99
4.4.3 Treadmill Exercise. 99
4.4.4 Continuous Spontaneous Alternation Behavior Test 100
4.4.5 Isoflurane Anesthesia. 101
4.4.6 Anesthetic Emergence & Recovery. 101
4.4.7 Western Blot 102
4.4.8 Statistical Analysis 103
4.5 Results 103
4.5.1 Glucose Tolerance Test 103
4.5.2 Y-maze Continuous Spontaneous Alternation Behavior Test Performance. 104
4.5.3 Anesthetic Emergence and Recovery 105
4.5.4 PSD-95 Levels in Hippocampus 106
4.6 Discussion. 108
Chapter 5 - General Discussion. 111
5.1 Introduction. 112
5.2 Sticky Dot Test 114
5.3 Emergence from Anesthesia with AD. 116
5.4 Recovery from Anesthesia with AD. 118
5.5 Emergence and Recovery from Anesthesia with T2DM.. 120
5.6 Recovery from Anesthesia after Exercise Training. 121
5.7 Relationship between T2DM and AD. 123
5.8 Summary 124
5.9 Persistent Perioperative Neurocognitive Disorders 129
5.10 Future Directions 130
Chapter 6 - Appendix. 133
Appendix 1 – Immunohistochemistry Image Analysis 133
A1.1 Hue, Saturation and Value 133
A1.2 Positive Pixel Count Analysis 135
Appendix 2 – Extended Burst Suppression Analysis Methods 140
A2.1 – EEG Acquisition. 141
A2.2 – BSR Analysis 141
Appendix 3 – Extended EEG Recording Denoising Methods 145
A3.1 – MWT Selection Methods 146
Chapter 7 - References 151
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