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General anesthesia and cognitive impairment Butterfield, Noam Nahum Douglas 2003

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GENERAL ANESTHESIA AND COGNITIVE IMPAIRMENT by Noam Nahum Douglas Butterfield B.Sc, The University of British Columbia, 1997 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Pharmacology & Therapeutics) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA © Noam Nahum Douglas Butterfield, 2003 N.N. BUTTERFIELD ii Abstract This thesis describes clinical and laboratory studies of the relationship between general anesthesia and cognitive impairment. Clinical studies investigated whether anesthetics with faster elimination pharmacokinetics would improve recovery in patients at high-risk of developing short-term cognitive impairment. Animal experiments investigated the relationship between general anesthesia, age, and long-term cognitive impairment. Carotid endarterectomy patients are at high risk of developing postoperative cognitive impairment because of advanced age, comorbidities, and potential surgical complications. Early postoperative neurological assessment is necessary to avoid irreversible neurological complications, but may be delayed by residual anesthesia. The inhalational anesthetic desflurane is more rapidly cleared from the body than isoflurane, which may lead to earlier recovery. Patients randomly received either anesthetic. Emergence times and cognitive recovery, tested at 30 minutes (Mini-mental status exam), and at 4 and 24-hours postoperatively (comprehensive neuropsychological assessment), were not significantly different. Depressed patients who receive electroconvulsive therapy (ECT) are at high risk of developing postictal cognitive impairment because of preexisting cognitive deficits and effects of ECT. Cognitive impairment can reduce patient compliance, promote premature discontinuation of effective treatments, distress family members, and delay discharge. The parenteral anesthetic propofol is more rapidly cleared from the body than thiopental, and may reduce cognitive impairment after ECT. Patients received thiopental or propofol alternating over six consecutive ECTs. Propofol was associated N.N. BUTTERFIELD iii with less cognitive impairment (similar neuropsychological battery as in carotid study) 45 minutes after ECT. Long-term postoperative cognitive impairment in elderly patients has been attributed to general anesthesia. Clinical studies are limited in their ability to separate the effects of anesthesia from surgery. Hence, experiments were conducted in young (3-month) and aged (18- and 27-month) mice to test whether general anesthesia, administered 3 hours after training on psychomotor and spatial memory tasks, would impair cognitive performance tested approximately 24 hours later. Isoflurane or propofol anesthesia was repeated throughout training. Even with repeated administrations, general anesthesia did not cause long-term cognitive impairment in mice in any experimental condition. In summary, anesthetics with faster elimination times can improve short-term cognitive recovery in some cases (i.e. ECT patients), but in other cases (i.e. carotid endarterectomy patients), the choice of anesthetic may be less important than disease or surgical related factors. Results from the animal experiments suggest that general anesthesia does not cause long-term cognitive impairment in the elderly. N.N. BUTTERFIELD iv Table of Contents Abstract ii Table of Contents iv List of Tables viii List of Figures ix Acknowledgements x Preface - Overview of Thesis 1 Chapter 1. Literature Review 7 A. POSTOPERATIVE COGNITIVE IMPAIRMENT - DEFINITIONS AND SIGNIFICANCE 7 B. METHODS OF DETECTING POSTOPERATIVE COGNITIVE IMPAIRMENT 9 C. PATIENTS AT HIGH RISK OF DEVELOPING POSTOPERATIVE COGNITIVE IMPAIRMENT.... 11 /. ELDERLY PATIENTS 11 II. PATIENTS WITH PREEXISTING MEDICAL CONDITIONS 12 III. PATIENTS WITH PREEXISTING COGNITIVE IMPAIRMENT 13 IV. PATIENTS WITH PREEXISTING PSYCHOLOGICAL OR PSYCHIATRIC DISORDERS 13 D. SOME POSSIBLE PRECIPITATING FACTORS 13 /. EMBOLIC EVENTS DURING SURGERY 14 II. USE OF ANTICHOLINERGIC MEDICATIONS 14 III. USE OF OPIATE MEDICATIONS 15 IV. OTHER POTENTIAL PERIOPERATIVE FACTORS 16 E. WHAT IS THE RELATIONSHIP BETWEEN GENERAL ANESTHESIA AND SHORT-TERM COGNITIVE IMPAIRMENT? 18 /. DEFINITION OF GENERAL ANESTHESIA 18 II. MECHANISM OF GENERAL ANESTHESIA 18 III. PHARMACOKINETIC PROPERTIES OF COMMON GENERAL ANESTHETICS 20 IV. EFFECT OF ANESTHESIA ON COGNITIVE FUNCTION IN VOLUNTEER SUBJECTS 22 VI. EFFECT OF DIFFERENT ANESTHETIC AGENTS ON COGNITIVE RECOVERY IN HEALTHY YOUNG PATIENTS 23 VII. EFFECT OF DIFFERENT ANESTHETIC AGENTS ON COGNITIVE RECOVERY IN HEALTHY ELDERL Y PA TIENTS 24 F. DO RAPIDLY ELIMINATED GENERAL ANESTHETICS IMPROVE SHORT-TERM COGNITIVE RECOVERY IN HIGH-RISK PATIENTS? '. 24 /. CAROTID ENDARTERECTOMYPATIENTS 26 II. ELECTROCONVULSIVE THERAPY PATIENTS 27 G. WHAT IS THE RELATIONSHIP BETWEEN GENERAL ANESTHESIA AND LONG-TERM IMPAIRMENT? 28 N.N. BUTTERFIELD v /. STUDIES IN YOUNG ADULTS: VOLUNTEERS AND PATIENTS 28 II. STUDIES IN ELDERLY PATIENTS 29 III. LIMITATIONS OF CLINICAL RESEARCH 32 H. USE OF RODENTS TO STUDY THE COGNITIVE EFFECTS OF GENERAL ANESTHESIA 32 /. SHORT TERM EFFECTS OF ANESTHESIA IN YOUNG RODENTS 33 ii. LONG-TERM EFFECTS OF ANESTHESIA IN YOUNG RODENTS 34 HI. IMPLICATIONS OF PREVIOUS STUDIES 37 I. DOES GENERAL ANESTHESIA CAUSE LONG-TERM COGNITIVE IMPAIRMENT IN 'HIGH RISK' ANIMALS—AGED RODENTS? 38 1.2. Aims and Questions Addressed in this Thesis 38 CLINICAL TRIALS. RELATIONSHIP BETWEEN PHARMACOKINETIC PROPERTIES OF GENERAL ANESTHETICS AND SHORT-TERM COGNITIVE IMPAIRMENT IN HIGH RISK PATIENT POPULATIONS 42 Chapter 2. Does Desflurane Anesthesia Improve Cognitive Recovery Compared to Isoflurane in Elderly Patients Undergoing Carotid Endarterectomy? 43 2.1 Introduction 43 2.2 Methods 44 A. ETHICS 44 B. PATIENTS 44 C. STUDY DESIGN 45 D. ANESTHETIC DETAILS 47 E. SURGICAL DETAILS 47 F. COGNITIVE AND PSYCHOMOTOR ASSESSMENTS 48 G. DATA HANDLING AND STATISTICAL ANALYSIS 49 2.3 Results 50 A. DEMOGRAPHICS 50 B. SURGICAL AND ANESTHETIC DETAILS 50 C. EMERGENCE 50 D. COGNITIVE AND PSYCHOMOTOR ASSESSMENTS 53 2.4 Discussion 60 Chapter 3. Does Propofol Anesthesia Reduce Cognitive Impairment Compared to Thiopental in Depressed Patients Receiving Electroconvulsive Therapy? 65 3.1 Introduction 65 N.N. BUTTERFIELD vi 3.2 Methods 67 A. ETHICS 67 B. PATIENTS 67 C. STUDY DESIGN 67 D. ANESTHETIC DETAILS 69 E. ECT TREATMENT DETAILS 69 F. EMERGENCE 69 G. NEUROPSYCHOLOGICAL ASSESSMENTS 71 H. DATA HANDLING AND STATISTICAL ANALYSIS 71 3.3 Results 72 A. DEMOGRAPHICS 72 B. ANESTHETIC DETAILS 72 C. SEIZURE DURATION 72 D. EMERGENCE 73 E. COGNITIVE ASSESSMENTS 73 3.4 Discussion 76 LABORATORY STUDIES. RELATIONSHIP BETWEEN GENERAL ANESTHESIA, AGE, AND LONG-TERM COGNITIVE IMPAIRMENT IN MICE 81 Chapter 4: Does General Anesthesia Impair Cognitive Function in Aged Mice? .82 4.1 Introduction 82 4.2 Methods and Materials 84 A. ETHICS 84 B. ANIMALS 84 C. BARNES CIRCULAR MAZE 84 /. ASSESSMENT OF SPATIAL LEARNING AND REFERENCE MEMORY 87 D. ACCELERATING ROTAROD 87 /. ASSESSMENT OF PSYCHOMOTOR LEARNING AND MEMORY 88 E. ISOFLURANE ANESTHESIA 88 F. PROPOFOL ANESTHESIA 91 G. STUDY DESIGN 91 /. EFFECT OF ONE EPISODE OF ISOFLURANE GENERAL ANESTHESIA ON PERFORMANCE OF A PRE-LEARNED SPATIAL MEMORY TASK 91 N.N. BUTTERFIELD vii //. EFFECT OF REPEATED GENERAL ANESTHESIA ON ACQUISITION AND RETENTION OF A SPATIAL REFERENCE MEMORY TASK 92 III. EFFECT OF REPEATED ANESTHESIA ON ACQUISITION AND RETENTION OF A PSYCHOMOTOR TASK 92 I. DATA HANDLING AND STATISTICAL ANALYSES 93 4.3 Results 95 A. EFFECT OF A SINGLE EPISODE OF ISOFLURANE G E N E R A L ANESTHESIA ON RETENTION OF A P R E - L E A R N E D SPATIAL REFERENCE MEMORY TASK 95 B. EFFECT OF REPEATED ISOFLURANE GENERAL ANESTHESIA ON ACQUISITION AND RETENTION OF A SPATIAL R E F E R E N C E MEMORY T A S K 95 C. EFFECT OF REPEATED ISOFLURANE ANESTHESIA ON ACQUISITION AND RETENTION OF A PSYCHOMOTOR T A S K 96 D. EFFECT OF REPEATED PROPOFOL ANESTHESIA ON ACQUISITION AND RETENTION OF A SPATIAL R E F E R E N C E MEMORY TASK 98 E. EFFECT OF REPEATED PROPOFOL ANESTHESIA ON ACQUISITION AND RETENTION OF A PSYCHOMOTOR T A S K 98 4.4 Discussion 106 Chapter 5. General Discussion 118 A. SUMMARY OF FINDINGS AND CONTRIBUTIONS OF THE CLINICAL STUDIES 119 B. SUMMARY OF FINDINGS AND CONTRIBUTIONS OF THE ANIMAL STUDIES 122 C. A R E A S FOR FUTURE CLINICAL R E S E A R C H 124 D. A R E A S FOR FUTURE LABORATORY RESEARCH 125 Appendix I: Related research 128 The influence of choice of anesthetic on ictal EEG 128 A. INTRODUCTION 128 B. METHODS 128 C. RESULTS 129 D. DISCUSSION 129 Appendix II. Documents and Forms 130 A. ECT STUDY CONSENT FORM 130 B. CAROTID ENDARTERECTOMY STUDY CONSENT FORM 133 Bibliography 136 N.N. BUTTERFIELD viii List of Tables Table 1a. Previous studies that assessed influence of anesthetic agents on short-term cognitive recovery in rodents (excluding studies in aged rodents) 40 Table 1b.' Previous studies that assessed influence of anesthetic agents on long-term cognitive recovery in rodents (excluding studies in aged rodents) 41 Table 2. Demographics and operative data for carotid endarterectomy patients: desflurane vs. isoflurane 51 Table 3. Recovery profile after carotid endarterectomy: desflurane vs. isoflurane 52 Table 4. Previous studies that assessed influence of anesthetic agent on cognitive recovery after ECT 68 Table 5. Anesthetic details and recovery profile after ECT: propofol vs. thiopental 74 Table 6. Cognitive test performance 45 minutes after ECT: propofol vs. thiopental 75 Table 7. Calculation of required volume of isoflurane for closed chamber Anesthesia 116 N.N. BUTTERFIELD ix List of Figures Figure 1. Carotid endarterectomy study flowchart 46 Figure 2. Mini-mental status exam (MMSE) scores 15-30 minutes after carotid endarterectomy: desflurane vs. isoflurane 54 Figure 3. Finger Tapping speed at baseline and at 4 and 24 hours after carotid endarterectomy: desflurane vs. isoflurane ..55 Figure 4. Simple Reaction Time at baseline and at 4 and 24 hours after carotid endarterectomy: desflurane vs. isoflurane 56 Figure 5. Choice Reaction Time at baseline and at 4 and 24 hours after carotid endarterectomy: desflurane vs. isoflurane 57 Figure 6. Trail Making Test, parts A and B, at baseline and at 4 and 24 hours after carotid endarterectomy: desflurane vs. isoflurane 58 Figure 7 (a,b,c). Rey Auditory Verbal Learning Test (RAVLT) at baseline and at 4 and 24 hours after carotid endarterectomy: desflurane vs. isoflurane 59 Figure 8. ECT study flowchart 70 Figure 9. Diagram of Barnes maze 86 Figure 10. Diagram of anesthetic chamber 90 Figure 11. Design of repeated general anesthesia experiments 94 Figure 12 (a,b). Average time to escape the Barnes spatial maze before and after isoflurane anesthesia in 3 and 18-month old mice 99 Figure 13 (a,b). Effect of repeated isoflurane anesthesia on the time to escape the Barnes spatial maze in 3 and 18-month old mice 100 Figure 14. Effect of repeated isoflurane anesthesia on the time to escape the Barnes spatial maze in 27-month old male mice 101 Figure 15 (a,b). Effect of repeated isoflurane anesthesia on the average time (5 daily trials) to fall off an accelerating rotarod in 3 and 18-month old mice 102 Figure 16. Effect of repeated isoflurane anesthesia on the average time (5 daily trials) to fall off an accelerating rotarod in 6-month old mice 103 Figure 17. Effect of repeated propofol anesthesia on the time to escape the Barnes spatial maze in 3 and 18-month old mice 104 Figure 18 (a,b). Effect of repeated propofol anesthesia on the average time (5 daily trials) to fall off an accelerating rotarod in 3 and 18-month old mice 105 Figure 19. Anesthetic chamber for one mouse 115 N.N. BUTTERFIELD x Acknowledgements First I would like to thank my parents, David and Yaffa, and my sister, Kinneret, for their endless support, encouragement and love. I am indebted to Drs. Bernard MacLeod and Peter Graf for, most importantly, taking me under their wing and instilling me with knowledge and skills to pursue a lifetime of academia. You have made my doctoral studies both memorable and enjoyable. I am thankful to Dr. Craig Ries, whose vigilant scrutiny of my work has benefited me immensely, and Dr. Michael Walker who demonstrated to me a passion for pursuing science for the sake of science. I am also grateful for Dr. Ernie Puil's additional guidance and support. I also appreciate the unconditional support and patience of my friends. Kim Ali, Kyle Frederiksen, Jason Odegard, and Gordie Warner have stuck by me since grade school, and Chad and Sonia Townsend for their endless patience and understanding. Various individuals I met in university have also provided me with laughs, acted as sounding boards, and made my UBC experience memorable, including Ellen Wong, Kevin Peters, Claudia Jacova, Luigi Franciosi, Sonia Franciosi, Terence Gilhuly, Andrew Karwowski, Clifford Pau, Israeli Ran, and Guilda Sarraf (for influencing my decision to begin doctoral studies). I am grateful to Barb, Dave and Alan Conder who have provided a home for me throughout my studies. The mix of clinical and laboratory studies gave me the opportunity to work with clinicians, nurses, and bench scientists from a variety of disciplines. Members of the UBC Dept. of Pharmacology & Therapeutics whom I particularly like to acknowledge are Drs. Morley Sutter, for sharing his knowledge of ethics in science, Bhagavatula Sastry and David Quastel, for their unique and helpful insights into my work, Issy Laher, for graduate advice, Sultan Karim and Cathy Pang for sharing a good bottle of wine at the end of a busy week, Dr. Stephan Schwarz, for his collaboration and support, and Dr. David Godin for his friendship. From the UBC Dept. of Psychiatry, I want to first thank Dr. Athanasios Zis for his mentorship, friendship, and for providing me with many academic opportunities outside the direct scope of my thesis. Completing my psychiatric study would not have been possible without the tireless work of Jeanette Eyre, and the assistance of the other ECT nursing staff. From the Dept. of Anesthesiology, I am grateful to all the anesthesiologists that showed patience N.N. BUTTERFIELD xi and cooperation with my clinical studies and the nursing staff in the operating rooms, the postanesthetic care unit and the daycare wards at UBC Hospital for allowing me the time to conduct psychometric testing in a busy hospital setting. From the UBC Dept. of surgery, I appreciate the support of Drs. Peter Fry and Lynn Doyle in the carotid endarterectomy trial. Laboratory studies could not have been completed without the help of the undergraduate students that have helped along the way, including Jessica Leung, Kenny Woo, Sui Hong Yong, Shaneel Sharma, Karl Burkat, and the Carole Federico, who always offered to do more than I asked. A thesis cannot be easily completed without the tireless aid of the staff at the Dept. of Pharmacology & Therapeutics including, Maureen Murphy, Wynne Leung, and Janelle Stewart Bick Lu. My research could not have been completely without the help of Christian Caritey, the Departmental Shop technician, with whom I shared both happiness and frustration (when the first maze we built fell, and split). I would be paying off debt's for many years had it not been for the financial support provided by the Gertrude Langridge Graduate Scholarship in Medical Sciences, the UBC Graduate Fellowship, the Shaughnessy Hospital Volunteer Society Fellowship in Health Care, as well as a grant-in-aid provided by Astra-Zeneca Inc. for the carotid endarterectomy study. Finally, Julie Lee, there are few words I can say that express my thanks for the patience and love you provided me throughout my graduate studies. Your endless support has been invaluable. And the greatest gift I could have asked for is to have a twin brother. Yaron, thanks for being there from the very start. N.N. BUTTERFIELD 1 Preface - Overview of Thesis Cognitive impairment can occur following anesthesia and surgery. While most patients experience some degree of cognitive impairment shortly after emerging from anesthesia (Curtis and Stevens, 1991), usually the impairment is transient, uneventful, and does not represent a major clinical problem. However, certain patient populations are at risk of developing more pronounced short-term, as well as long-term cognitive postoperative impairment. Such patients include the elderly (Cryns et al., 1990; Moller et al., 1998), those with cardiovascular or cerebrovascular disease (Parikh and Chung, 1995), and those with preexisting cognitive or psychiatric disorders, particularly depression (Ritchie et al., 1997; Ancelin et al., 2001). Short-term postoperative cognitive impairment in these high-risk patients is important, particularly if the impairment impedes effective medical care. There are multiple aetiologies for short-term cognitive impairment, including exposure to general anesthesia (see reviews by Herbert, 1987; Hindmarch and Bhatti, 1987). In fact, studies in young, healthy, volunteer subjects (to whom anesthetics have been administered without any medical indications) provide strong evidence that general anesthesia alone can cause short-term cognitive impairment (Korttila et al., 1975; 1977; 1992; Eger et al., 1997). The degree and duration of cognitive impairment may be related to the pharmacokinetic properties of the anesthetics administered (Curtis et al., 1991). In other words, anesthetics that have low blood and tissue solubility (desflurane) or that are rapidly metabolised after administration is terminated (propofol), tend to lead to faster recovery (Curtis et al., 1991). Studies that have shown faster cognitive recovery following the use of rapidly eliminated anesthetics, have been mostly conducted in healthy, adult populations (Pollard et al., 2003). It is unclear whether the use of anesthetics with fast elimination N.N. BUTTERFIELD 2 pharmacokinetic properties, would benefit patients at high risk of developing postoperative cognitive impairment, in part because patients with preexisting cognitive, cardiovascular and psychiatric disease tend to be excluded from controlled intervention studies (Ritchie et al., 1997; Ancelin et al., 2001). While research is made easier by avoiding the confounding factors that high-risk patients bring to a clinical trial, excluding high-risk patients prevents exploration of the relationships between the risk factors, anesthesia, and cognitive impairment (Ancelin et al., 2001). Since it is these high-risk patients that stand to gain the most benefit from more rapid cognitive recovery, clinical trials were conducted to compare the effects of short- and long-acting anesthetics on cognitive recovery in high-risk patients, carotid endarterectomy and ECT patients. Carotid endarterectomy patients are at particularly high risk of developing postoperative cognitive impairment because of advanced age, preexisting cerebrovascular and cardiovascular disease, diabetes and hypertension, and the risk of embolic and hypoxic damage during surgery (Wilke et al., 1996; Jenkins and Wong, 1987). Prolonged confusion and delayed cognitive recovery hinders rapid neurologic assessment. Rapid assessment is necessary to enable prompt management of postoperative complications, which otherwise quickly become irreversible (Wilke et al., 1996; Garrioch and Fitch, 1993). Previous studies in the elderly have demonstrated that desflurane results in faster recovery than isoflurane, because of its low lipid and blood solubility (Bennett et al., 1992; Juvin et al., 1997). It was hypothesized that desflurane would result in more rapid cognitive recovery than an anesthetic isoflurane, in elderly patients undergoing carotid endarterectomy. Electroconvulsive therapy patients are at high-risk of post-ECT cognitive impairment because of preexisting cognitive dysfunction (resulting from their depression), treatment induced cognitive impairment, and repeated exposure to N.N. BUTTERFIELD 3 general anesthesia (American Psychiatric Association, 2001). The frequency and severity of cognitive side effects following ECT can affect patient safety, particularly in outpatients, can influence the decision to modify or discontinue beneficial treatments, and can reduce patient compliance (American Psychiatric Association, 2001). Previous studies have demonstrated that the use of propofol results in faster recovery than thiopental because of its rapid termination of action (Pollard et al., 2003). It was hypothesized that propofol would reduce the degree of cognitive impairment following ECT compared to thiopental anesthesia. In both the ECT and carotid study, a similar battery of neuropsychological tests, that included measures of attention, pyschomotor function, learning and memory, was used. Some patient populations are at high risk of developing long-term cognitive impairment, particularly elderly patients (Moller et al., 1998). The consequences of long-term cognitive impairment include reduced quality-of-life, inconvenience and stress for patients1 families, and societal costs, in terms of lost productivity (Baker et al., 1978; Knill, 1990; Dijkstra et al., 1999; Johnson et al., 2002). This is a growing concern because of the growing elderly population, which in 2000, received over 40% of all surgical procedures in the United States (Rooke, 2003). Anecdotal and clinical reports frequently cite general anesthesia as a potential cause for long-term cognitive impairment in the elderly (Goldstein, 1990; Dijkstra and Jolles, 2002). In addition, one of the largest controlled studies to date found that age and duration of anesthesia were predictors of cognitive impairment one week postoperatively (Moller et al., 1998). Although long-term postoperative cognitive impairment is not the result of residual sedative effects of anesthetic drugs (based on known pharmacokinetic properties of general anesthetics), little is known about whether the drugs themselves, or the state of anesthesia, can cause long-term changes to the central nervoussystem. N.N. BUTTERFIELD 4 Clinical studies that have investigated the role of anesthesia in prolonged cognitive impairment cannot have a true control group, since it is unethical to perform surgery without anesthesia or anesthesia without surgery in high-risk patients. Furthermore, it is difficult to control for the numerous factors that might influence postoperative cognitive function independently of anesthesia, such as inadequate cognitive testing conditions, postoperative pain and fatigue (Smith et al., 1991; Duggleby and Lander, 1994; Heyer et al., 2000), and postoperative medications (Millar, 1992). In view of these limitations in clinical research, animal experiments would -be a useful alternative to explore the effects of general anesthesia on cognitive function. For the laboratory experiments in this thesis a mouse model was developed study the effects of common, clinically used general anesthetics on long-term cognitive function in aged mice. Aged mice were studied because age appears to be a significant risk factor for long-term postoperative cognitive impairment (Moller et al., 1998) . In addition, there is high degree of correspondence between age-related cognitive changes in humans and rodents (Gallagher and Rapp, 1997; Barnes, 1998; Bach et al., 1999). It is particularly useful to choose behaviours that have some analogue in humans (Barnes, 1998). Since age-related impairments in spatial learning and memory and psychomotor behaviours are found in both humans (Perlmutter et al., 1981; Uttl and Graf, 1993; Kluger et al., 1997) and rodents (Ingram, 1988; Forster et al., 1996; Gallagher et al., 1997; Barnes, 1998; Shukitt-Hale et al., 1998; Bach et al., 1999) , tasks that measure these behaviours were used in the experiments. Spatial learning and memory were assessed using the Barnes circular maze (Barnes, 1979; Fox et al., 1998) and psychomotor learning and memory were assessed using the accelerating rotarod (Jones and Roberts, 1968). C57BL/6 mice were chosen because of the well-established literature on age-related cognitive changes in this strain (Dean, N.N. BUTTERFIELD 5 III et al., 1981; Ingram and Jucker, 1999). To maximise the possibility of detecting a cognitive impairment from general anesthesia, mice were repeatedly anesthetized throughout behavioural training. The laboratory experiments were conducted to answer the following questions: 1) Does general anesthesia impair long term cognitive function? a. If general anesthesia impairs long-term cognitive function, is there an agent specific effect? b. Does the frequency of administration of anesthesia change the degree of cognitive impairment? 2) Is age a risk factor for long-term postanesthetic cognitive impairment? 3) Is there a domain (cognitive) specific impairment? 4) Does general anesthesia impair task acquisition more than performance after learning has stabilized? The following dissertation is organized into a literature review chapter, followed by three results chapters and a general discussion chapter. The review chapter contains an overview of previous studies that have investigated the relationship between anesthesia and cognitive impairment and introduces the rationale for the thesis studies. The results are presented in two sections, Clinical Trials and Laboratory Studies, that include separate chapters for each study (each chapter represents individual research manuscript(s), published or under review). For clarity, the research chapters include a more focussed introduction relevant to the study, and therefore, contain some of the literature mentioned in the literature review chapter. The general discussion contains a summary of the results and significance of this work as a whole. Related information is presented in endnotes at the end of each chapter. N.N. BUTTERPIELD CHAPTER 1 : LITERATURE REVIEW N.N. BUTTERFIELD 7 Chapter 1. Literature Review A . P O S T O P E R A T I V E C O G N I T I V E I M P A I R M E N T - D E F I N I T I O N S A N D S I G N I F I C A N C E Postoperative cognitive impairment refers to impairment of one or more cognitive functions examined after anesthesia and surgery. All patients are cognitively impaired during emergence from anesthesia because by definition, emergence is the period after anesthesia but prior to return of consciousness, of orientation, and of response to verbal command. Emergence time is generally short (usually <15 minutes) (Curtis and Stevens, 1991), because of the rapid rate of elimination of both inhalational and parenteral anesthetics (Mecca, 1999). After emergence, cognitive function is expected to return to baseline levels. However, this does not always occur. Some patients experience short-term cognitive impairment, some patients experience long-term cognitive impairment, and some patients experience delirium. In rare situations, patients have experienced permanent neurologic deficits (Benzel et al., 1990; Porter et al., 1994; Hadzic et al., 1995; Black et al., 1998). There is no universally agreed upon definition for short-term or long-term postoperative cognitive impairment and the use of these terms appears somewhat arbitrary in the literature. For instance, some investigators have referred to impairment occurring 1-3 days postoperatively as long-term impairment (Herbert, 1987; Zacny et al., 1992; Ritchie et al., 1997). In contrast, impairment occurring as long as one month after surgery has been described as short-term by other investigators (Goldstein et al., 1998). The temporal spacing between the first and last postoperative cognitive assessments appears to be the main determinant of word choice. Nevertheless, there is little argument that impairment within the first postoperative day is short-term impairment and it will be referred to as such throughout this thesis. Cognitive N.N. BUTTERFIELD 8 impairment detected past the first postoperative day will be referred to as long-term impairment in this thesis. The significance of short-term postoperative cognitive impairment depends on the patient population, the timing and the severity of the impairment. Inpatients may not be able to leave the recovery room while ambulatory outpatients may not be able to be discharged from hospital as quickly (Zacny et al., 1992). This is more of a financial concern for hospital administrators than it is a concern for health professionals (Zacny et al., 1992), although there are also important safety and legal considerations. For example, premature discharge, particularly in daycase surgery, can lead to accidents and resulting litigation (Korttila, 1986; 1995). This is more relevant to younger patients who may be less likely to wait for sufficient recovery before returning to work or other daily activities than older or retired individuals. Delayed physical and emotional recovery, particularly in the elderly (Johnson et al., 2002), can also delay discharge and increase hospital costs (Parikh et al., 1995; Franco et al., 2001). In certain patient populations, delayed recovery and short-term cognitive impairment is more than an economic problem, it is an important clinical problem. Neurosurgical patients, for example, require prompt postoperative neurologic assessment (Duffy and Matta, 2000). Delayed recovery from anesthesia increases the risk of developing serious postoperative complications (Duffy and Matta, 2000). Identification of the causes and understanding methods to reduce the short-term cognitive impairment in these and other high-risk patients is essential. The significance of long-term cognitive impairment also depends on the patient population and the severity of the impairment. Long-term cognitive impairment may lead to reduced participation in social functions and impaired ability to perform efficiently at work (Johnson et al., 2002). The elderly in particular may also suffer from N.N. BUTTERFIELD 9 loss of independence that can increase stress on friends and family (Dijkstra et al., 1999). Ultimately, there may be societal costs from reduced productivity and reduced quality-of-life, although these are difficult to measure (Baker et al., 1978; Knill, 1990; Dijkstra et al., 1999). Identification of precipitating factors and methods of reducing both short and long term cognitive impairment are necessary, for reduced hospital costs, improved patient care, and better understanding of postoperative recovery, that would allow clinicians and patients to make more informed decisions prior to surgery. Delirium can also occur postoperatively, particularly in elderly orthopaedic and cardiac surgery patients (Williams-Russo et al., 1992; O'Keeffe and Ni, 1994; Dyer et al., 1995; Parikh et al., 1995; Winawer, 2001). Delirium is characterized by acute onset of disorientation, confusion and cognitive impairment (particularly inattention and disorganized thinking) that fluctuates throughout the day, and includes sleep disturbances (Lipowski, 1987; Winawer, 2001). Although cognitive impairment is a necessary component of delirium, delirium is a distinct medical condition that requires prompt medical attention. B. METHODS OF DETECTING POSTOPERATIVE COGNITIVE IMPAIRMENT A wide variety of methods has been used to detect postoperative cognitive impairment, including interviews, questionnaires, mental status exams and neuropsychological tests (see reviews by Dodds and Allison, 1998; Dijkstra et al., 2002). Postoperative interviews and questionnaires are convenient and quick to administer but provide limited information about more complex cognitive functions. When administered orientation questionnaires, for example, most patients achieve high scores within 15-30 minutes of anesthesia. Thus, a "ceiling effect" occurs early in the recovery period, which precludes the ability to detect more subtle impairment beyond N.N. BUTTERPIELD 10 this time period. Furthermore, take-home questionnaires rely on patient self-assessment, which introduces rater bias, and do not generally correspond with "objective" tests of cognitive impairment (Jones et al., 1990; Moller et al., 1993). Tests of mental status are the most frequently used methods of assessing cognition in postoperative recovery studies (Chung et al., 1990; Prior and Chander, 1982; Mann and Bisset, 1983; Bigler et al., 1985; Berggren et al., 1987; Chung et al., 1987; Chung et al., 1989; Knill, 1990; Crul et al., 1992). The most common of these is the Mini-mental status exam (MMSE) (Folstein et al., 1975). The advantage of the MMSE and other mental status tests is their portability and ease of administration. However, the information gained from mental status tests is generally limited to gross changes in cognitive function (de Jager et al., 2002). Detection of gross cognitive changes is important when screening for delirium or dementia, for which mental status tests are more useful, but these tests are less suitable for detecting more subtle cognitive impairment that can occur after surgery and anesthesia (Burker et al., 1995; de Jager et al., 2002). Neuropsychological testing provides the most reliable and sensitive indicator of postoperative cognitive impairment (Rasmussen, 2001). Numerous tests have been used to measure postoperative cognitive impairment (see reviews by Dodds et al., 1998; Dijkstra et al., 2002). Neuropsychological tests provide information about different cognitive domains, including attention and vigilance, learning and memory, verbal and language function, psychomotor function, and executive function (Lezak, 1995; Spreen and Strauss, 1998). The cognitive tests used should be standardized (Zuurmond et al., 1989), and selected based on an understanding of the type of impairment that may be present, based on the sensitivity of the test to detect the N.N. BUTTERFIELD 11 anesthetic effects (Rasmussen, 2001), and based on a theory of cognition (Graf, 1999, personal communication). The choice of tests selected for the clinical trials in this thesis was guided by the known sensitivity to the effects of anesthetic drugs, as well as the processing speed theory of cognition. Speed of processing is a theory that postulates that many higher-level cognitive functions are ultimately affected by differences in the speed of information processing (Salthouse et al., 1996). Age-related cognitive impairment may be the result of impaired processing speed (Salthouse et al., 1996; Salthouse, 2000). Speed of processing is also known to be slowed in depressed patients (Nebes et al., 2000; Tsourtos et al., 2002), and in patients that have received general anesthesia (Scott et al., 1983; Millar, 1992; Haavisto and Kauranen, 2002). Accordingly, the neuropsychological tests used herein include tests that measure speed of processing. A detailed description of the neuropsychological tests can be found in the methods section of Chapters 2 and 3. C. PATIENTS AT HIGH RISK OF DEVELOPING POSTOPERATIVE COGNITIVE IMPAIRMENT The incidence and severity of cognitive impairment following surgery and anesthesia differ according to age, type of medical intervention, pre-morbid medical condition, pre-morbid level of cognitive function, affective state, and the period of assessment. /. ELDERLY PATIENTS Most studies suggest that elderly patients are at a higher risk than young patients of developing short-term postoperative cognitive impairment (Platzer, 1989; Ritchie et al., 1997; Dodds et al., 1998; Rasmussen et al., 1999) and delirium (O'Keeffe et al., 1994; Parikh et al., 1995; Rasmussen et al., 1999; Litaker et al., 2001). The N.N. BUTTERFIELD 12 highest incidence of postoperative cognitive impairment occurs in patients that have undergone major cardiac (50-80%) or orthopaedic (30-50%) surgery (Dyer et al., 1995). Long-term cognitive impairment is also more prevalent in the elderly. A meta-analytic review of 18 studies between 1955 and 1988 indicated that geriatric patients scored approximately one standard deviation lower on postoperative cognitive tests compared to pre-test scores (mean postoperative test period was 1.8 weeks in 16 studies and 6.2 months in 5 studies) (Cryns et al., 1990). A prospective study of elective, non-emergent, non-cardiac, non-neurological surgery under general anesthesia, also reported that age was a significant predictors for cognitive impairment 1 month after surgery (Goldstein et ai, 1998). Perhaps the most compelling evidence for long-term cognitive impairment comes from the large scale prospective study by the International Study on Postoperative Cognitive Dysfunction (ISPOCD) group (Moller et al., 1998). These investigators found that cognitive impairment, in non-cardiac major surgery patients, occurred in approximately 25% of patients one week after surgery and in 10% of patients after three months (Moller et al., 1998). Age was one of the risk factors at impairment at one week, and the only risk factor for impairment at three months (Moller et al., 1998). //. PATIENTS WITH PREEXISTING MEDICAL CONDITIONS Poor preexisting medical condition and the presence of concomitant diseases increases the risk of postoperative cognitive impairment, particularly in elderly patients (Parikh et al., 1995; Ancelin et al., 2001). Studies have shown that elderly patients with pre-existing cardiovascular or pulmonary disorders are at higher risk of developing postoperative cognitive impairment than healthy elderly patients (Crul et al., 1992). Preexisting cerebrovascular disease, particularly arthrosclerosis of the carotid arteries, N.N. BUTTERFIELD 13 may also increase risk of postoperative cognitive impairment (Russell, 2002). ///. PATIENTS WITH PREEXISTING COGNITIVE IMPAIRMENT A poor preoperative cognitive status is also associated with a higher incidence of postoperative cognitive impairment. Smith et al. (1986) found that elderly patients (approximately 50-70 years old) with low preoperative memory scores (visual object naming test) also had greater postoperative memory deficits. Chung et al. (1989) reported that low postoperative MMSE scores were highly correlated with low baseline MMSE scores. Smith et al. (1991) found that increased choice reaction time variability was predicted by poor preoperative mental status (Clifton Assessment Procedure for the Elderly) in 48 to 88 year old patients. Ancelin et al. 2001 also found that elderly patients with a recent history of cognitive impairment were at high risk of developing cognitive impairment after orthopaedic surgery. IV. PATIENTS WITH PREEXISTING PSYCHOLOGICAL OR PSYCHIATRIC DISORDERS. Preexisting psychological or psychiatric disorders, particularly depression, has also been shown to increase the risk of postoperative cognitive impairment. This is most common in elderly orthopaedic (Berggren et al., 1987; Ancelin et al., 2001; Galanakis et al., 2001) and cardiac patients (Savageau et al., 1982; Strauss et al., 1992; Millar ef al., 2001). D. SOME POSSIBLE PRECIPITATING FACTORS The factors responsible for causing postoperative cognitive impairment remain unclear. Some factors are better understood than others, for example, embolic events in cardiac and orthopaedic patients and the use of perioperative drugs such as anticholinergics and opiates (to which elderly patients are particularly sensitive). N.N. BUTTERFIELD 14 /. EMBOLIC EVENTS DURING SURGERY The high incidence of postoperative cognitive impairment in cardiac patients has been attributed to microembolic events during the use of the cardiopulmonary bypass pump (Pugsley et al., 1994). These microembolic events may cause focal cerebral infarcts leading to postoperative cognitive impairment (Croughwell et al., 1994; Mills, 1995; Murkin, 1995; Murkin et al., 1995). The similar incidence of cognitive impairment in both young and elderly cardiac patients also supports this hypothesis (Dyer et al., 1995). Hip-replacement and other elderly orthopaedic patients also demonstrate a high incidence of postoperative confusion and cognitive impairment (Rogers et al., 1989; Williams-Russo et al., 1992; Williams-Russo et al., 1995). Many of these patients are exposed to fat emboli during surgery, particularly if the surgery involves reaming of bone marrow (Jacobson et al., 1986; Edmonds et al., 2000). Fat emboli has been suggested to be an important factor resulting in postoperative cognitive impairment in these patients (Jacobson et al., 1986; Edmonds et al., 2000). Orthopaedic patients also tend to be older and often have preexisting cognitive impairment and cerebrovascular disease (Berggren et al., 1987). //. USE OF ANTICHOLINERGIC MEDICATIONS Use of anticholinergic medications (for example, atropine and scopolamine), or medications with anticholinergic properties (for example, tricyclic antidepressants and benzodiazepines), is commonly suggested to be involved in precipitating postoperative cognitive impairment (Gustafson et al., 1988; Tune et al., 1981; Smith et al., 1986; Berggren et al., 1987; Miller et al., 1988; Parikh et al., 1995). Considerable evidence for the involvement of central cholinergic pathways in memory and other cognitive N.N. BUTTERFIELD 15 functions supports this argument, as does the known functional disturbance of these pathways in the elderly (Bartus et al., 1985; Perry, 1998). Although anticholinergic medication contributes to postoperative cognitive impairment in some cases (Tune et al., 1981; Smith et al., 1986; Berggren et al., 1987; Parikh et al., 1995), it does not explain the cognitive deficits that occur in studies that do not include anticholinergic medications. Furthermore, recent investigations have indicated that benzodiazepine premedications may not be a major risk factor of postoperative cognitive impairment, even in the elderly. Fredman et al. (1999) showed that midazolam premedication, compared to saline, did not affect emergence, extubation time, or orientation time in elderly patients undergoing short urologic procedures (under propofol / desflurane anesthesia). Psychomotor recovery, as tested using the Digit Symbol Substitution Test, Mini-mental status exam, and Shape Sorter Test was similarly unaffected. A study of long-term postoperative cognitive impairment (1 week after surgery), did not find a significant association between cognitive impairment, which affected at least 48.6% of the elderly patients, and blood benzodiazepine concentration (Rasmussen et al., 1999). ///. USE OF OPIATE MEDICATIONS Opiate medications (eg. morphine, codeine, meperidine) that also have anticholinergic properties can contribute to short-term postoperative impairment (Egbert et al., 1990; Marcantonio et al., 1994; Litaker et al., 2001). The effect of opiate medications on cognition is highly correlated with the pharmacokinetic properties of the drugs. Fentanyl and sufentanil have been shown to result in more rapid return of cognitive function than morphine or meperidine, as would be expected on the basis of their elimination half-lives (Ghoneim et al., 1984). N.N. BUTTERFIELD 16 IV. OTHER POTENTIAL PERIOPERATIVE FACTORS A number of other potential factors that may influence postoperative cognitive recovery have been investigated, but the evidence for most of them is weak. One of the earliest explanations for postoperative cognitive impairment was intraoperative hypotension (Bedford, 1955; Rollason et al., 1971; Thompson et al., 1978). The investigators of these studies postulated that the hypotension could cause a decrease in cerebral perfusion during surgery, hence leading to a postoperative impairment. However, studies using modern anesthetic techniques and more rigorous study protocols have found the relationship to be weak (Townes et al., 1986) or non-existent (Moller et al., 1998; Williams-Russo et al., 1999). Intraoperative and early postoperative hypoxia have been correlated with postoperative cognitive impairment in elderly patients (Hole et al., 1980; Berggren et al., 1987; Rosenberg and Kehlet, 1992). Although hypoxia is more common in the elderly, because of the greater prevalence of vascular and respiratory disease, a well designed study by the International Study of Post-operative Cognitive Dysfunction (ISPOCD) Group did not find an association of hypoxia with postoperative cognitive impairment (Moller et al., 1998). Postoperative pain has been associated with postoperative cognitive impairment (Smith et al., 1991; Duggleby et al., 1994; Heyer et al., 2000), and delirium (Schor et al., 1992; Lynch et al., 1998; Morrison et al., 2003) in the elderly. However, under-treatment of pain in elderly patients with preexisting cognitive impairment may confound the results of these studies (Bell, 1997; Feldt et al., 1998). Specifically, increased cognitive impairment may relate to preexisting impairment rather than increased pain. A change from a familiar environment can be particularly distressing for elderly N.N. BUTTERFIELD 17 patients and is known to impair performance on cognitive tests. This is a possible factor that may contribute to postoperative confusion, at least in the elderly (Nadelson, 1976; Easton and MacKenzie, 1988). Methods to reduce the impact of an unfamiliar environment, by preoperatively orienting patients to the hospital setting and providing some of the "comforts of home", have been unsuccessful so far (Stromberg et al., 1999). Sleep deprivation has also been suggested to contribute to cognitive impairment (Ellis and Dudley, 1976; Edwards et al., 1981; Kaneko etal., 1997), but the relationship is complicated. Postoperative pain, postoperative anxiety, and visits from medical staff and relatives, and a change in normal sleeping environment can all disrupt normal sleep, but as discussed above, these factors might also impair postoperative cognitive function. Therefore, it is difficult to differentiate the effect of sleep deprivation from the effects of the associated causes of sleep deprivation. A combination of factors is also possible, as one investigator has suggested that postoperative pain may contribute to cognitive impairment indirectly by disrupting the sleep-wake cycle (Lipowski, 1987). Other studies have not found any association between poor sleep and postoperative impairment (Smith et al., 1991). Some investigators have even reported that bed rest contributes to impaired psychomotor function (Edwards et al., 1981; Korttila, 1990), although this relationship also appears to be weak (Dyer et al., 1995). In summary, numerous potential causes of postoperative cognitive impairment have been suggested, but there are conflicting results for virtually all of them. The evidence for some factors, such as embolic events in cardiac and orthopaedic patients and postoperative benzodiazepine and opioid use in elderly patients, is more compelling than for other factors. However, cognitive impairment is still found in studies of non-orthopaedic and non-cardiac patients, as well as in studies with minimal N.N. BUTTERFIELD 18 or no opioid or benzodiazepine use. This suggests that other factor(s) are important. General anesthesia remains one of the most frequently cited factors associated with short and long-term cognitive impairment. The relationship between general anesthesia and postoperative cognitive impairment will be the subject of the rest of this review chapter, as well as the studies initiated for this thesis dissertation. E. WHAT IS THE RELATIONSHIP BETWEEN GENERAL ANESTHESIA AND SHORT-TERM COGNITIVE IMPAIRMENT? /. DEFINITION OF GENERAL ANESTHESIA The term anesthesia is derived from the Greek word, 'anaisthesis', meaning 'insensible', and is defined by the Oxford dictionary edition as "the absence of sensation, especially artificially induced insensitivity to pain, usually achieved by the administration of gases or the injection of drugs". Modern general anesthesia encompasses more than simply insensitivity to pain and includes maintaining homeostasis, attenuating the physiological response to surgical stimulation, producing unconsciousness, producing amnesia for operative events and providing analgesia (Evers and Crowder, 2001). The goals of anesthesia may be summed up as "to create a reversible condition of comfort, quiescence, and physiological stability in a patient before, during, and after performance of a procedure that would otherwise be painful, frightening, or hazardous" (Beattie, 2001). Advances in anesthesiology have permitted increasingly complex surgeries to be performed on older and more fragile patients, while decreasing morbidity and mortality (Beattie, 2001). //. MECHANISM OF GENERAL ANESTHESIA Does an understanding of the mechanism of anesthesia help understand the role of anesthesia in causing postanesthetic cognitive impairment? Despite remarkable N.N. BUTTERFIELD 19 advances in the field of anesthesia, the precise mechanism and location of anesthetics effect is unknown. The lipid theory of anesthesia was prominent for most of the twentieth century, and postulated that all anesthetics exert their anesthetic effect through perturbation of the physical properties of the neuronal cell membrane, namely volume expansion and membrane fluidization (Evers et al., 2001). This theory was based on observations that anesthetic potency correlated with the lipid solubility of the anesthetic gas, known as the Meyer-Overton Rule (Evers et al., 2001). In the past decade or so, the lipid theory of general anesthesia has fallen out of favour as new evidence has emerged indicating that anesthetics act by binding directly to proteins (Franks and Lieb, 1994; Eckenhoff, 1998; Yamakura et al., 2001). Specifically, anesthetics may bind with ligand-gated ion channels including the GABA A chloride ion channel (Franks et al., 1994; Yamakura et al., 2001; Jurd et al., 2003). Binding to the G A B A A receptor causes an increase in chloride conductance, which enhances inhibitory neurotransmission and results in CNS depression (Franks et al., 1994). Nearly all anesthetics can potentiate G A B A A currents. The exceptions of ketamine and nitrous oxide suggest other molecular targets are also involved, such as N-methyl-D-aspartate (NMDA) and nicotinic acetylcholine (nACh) receptors (Franks et al., 1994; Jevtovic-Todorovic et al., 1998; Yamakura and Harris, 2000). Effects on potassium channels may also play an important role in the production of the state of anesthesia (Franks and Lieb, 1999; Ries and Puil, 1999a). The functional relevance of specific anesthetic binding sites to the state of anesthesia remains undefined. Central to the understanding of general anesthesia is an understanding of consciousness, yet the neurobiological basis for consciousness, just as the mechanism of anesthesia, remains unclear (Delacour, 1997). Nevertheless, the exchange of ideas in each field has helped in the understanding of the mechanism of general anesthesia. N.N. BUTTERFIELD 20 For example, the predominant excitation of corticothalamic neurons during wakefulness appear to play an important role in consciousness (Delacour, 1997), and recent work has identified thalamocortical neurons as a potential locus for the production of unconsciousness by inhalational anesthetics (Ries and Puil, 1999a; Ries and Puil, 1999b). The hippocampus may also contribute to cortical activation (Delacour, 1995), and both intravenous and inhalational anesthetics depress hippocampal neurotransmission (Miu and Puil, 1989; Kendig et al., 1991; Matsuoka et al., 1999; Simon et al., 2001; Ma et al., 2002). In summary, the lack of a unified theory for the mechanism of general anesthesia thus far has precluded a mechanistic solution to the question of whether general anesthesia causes postoperative cognitive impairment. One thing is clear, a fundamental aspect of general anesthesia is the profound disruption of consciousness and production of amnesia. Therefore, by definition, no general anesthetic can avoid these effects. However, upon emergence from anesthesia, return of normal cognitive functioning is expected. ///. PHARMACOKINETIC PROPERTIES OF COMMON GENERAL ANESTHETICS1 The speed and degree of return of cognitive function is affected by various factors, including the speed of elimination of the anesthetic agent from the brain, and body tissues, which is determined by pharmacokinetic properties of the drugs, and the physical status of the patient. The major advantage of inhalational anesthetics is primary elimination via the lungs, which results in a rapid decrease in the concentration of anesthetic in the blood and tissues. The blood and lipid solubility of volatile anesthetics can influence the speed of elimination. Blood:gas partition coefficients (index of anesthetic solubility in blood) of the most common inhalational anesthetics is N.N. BUTTERFIELD 21 as follows: halothane (2.3), isoflurane (1.4), sevoflurane (0.60), nitrous oxide (0.47), and desflurane (0.42). Anesthetics with low blood and fat solubility generally lead to more rapid recovery than those with higher solubility. Anesthetics that are highly soluble accumulate in the body fat over time (Stoelting and Eger, 1969). The longer the duration of anesthesia, the more anesthetic that accumulates (Stoelting et al., 1969), which can result in prolonged recovery for anesthetics with high lipid solubility like halothane (Eger, II, 1981; Evers et al., 2001). Duration of anesthesia has less effect on the speed of recovery when anesthetics with low solubility (desflurane and isoflurane) are used because these anesthetics are rapidly eliminated and have low accumulation over time (Curtis et al., 1991; Evers et al., 2001). The relationship between the duration of anesthesia and recovery also depends on the age and physical status of the patient. For example, in healthy young patients there is no significant difference in emergence between isoflurane and desflurane after approximately 4 hours of anesthesia (Azad et al., 1993), but in elderly patients anesthetized for a similarly long period, desflurane resulted in faster emergence compared to isoflurane (Bennett et al., 1992; Juvin et al., 1997). The main pharmacokinetic factors affecting the clearance of intravenous general anesthetics is lipid solubility, protein binding, and the site and rate of drug metabolism. The most commonly used parenteral anesthetics are the barbiturates, methohexital and thiopental, and the non-barbiturate propofol. Thiopental and methohexital are rapidly redistributed from the brain to fatty tissues upon discontinuation of administration, though ultimately, elimination is almost completely via liver metabolism (Stoelting, 1999). Redistribution is the primary mechanism for rapid recovery following a single bolus dose of barbiturates. However, this same mechanism is responsible for slower recovery after longer durations of barbiturate anesthesia because redistribution N.N. BUTTERFIELD 22 promotes drug accumulation in the fatty tissues (Evers et al., 2001). The accumulated anesthetic is slowly released back into the bloodstream resulting in prolonged effects on the brain (Stoelting, 1999). In contrast, propofol is rapidly metabolized by the liver, resulting in rapid drug clearance (Stoelting, 1999). The rapid clearance is minimally influenced by the duration of anesthesia. Even after an 8-hour continuous propofol infusion the half-time of propofol (time at which half of the concentration is eliminated from the tissues) is less than 40 minutes (Stoelting, 1999). Because of these pharmacokinetic properties, propofol generally results in more rapid emergence and return of cognitive function than the barbiturate anesthetics. IV. EFFECT OF ANESTHESIA ON COGNITIVE FUNCTION IN VOLUNTEER SUBJECTS There is little doubt that anesthetics can impair cognitive impairment in the short term. Particualyt strong evidence for this conclusion comes from results of studies conducted in volunteer subjects (people administered anesthetics with no medical indication). The duration and severity of cognitive impairment depends on the dose of anesthetic administered, the duration of administration, and the type of agent used. Studies in which subanesthetic concentrations of general anesthetics were administered to volunteers indicate that cognitive impairment can occur (Bruce et al., 1974), but does not last longer than 30 minutes. Cheam et al. (1995) reported that recovery of psychometric tests was complete by 10-20 minutes following inhalation of concentrations of 50% N 2 0 in a small number of healthy male volunteers. Galinkin et al. (1997) showed that administration of either 30% N 2 0 or 0.6% sevoflurane for 35 minutes did not impair psychomotor function (DSST) longer than 30 minutes after discontinuing administration. Low concentrations of isoflurane (9.5% and 14.1% of the minimum alveolar concentration (MAC)) administered for 15 minutes to six young N.N. BUTTERFIELD 23 healthy volunteers impaired reaction time and critical flicker fusion test (CFFT) but for no longer than 30 minutes (Yoshizumi et al., 1993). When volunteer subjects have been anesthetized, longer durations of cognitive impairment occur than following exposure to trace concentrations. A series of studies were conducted that used simulated driving skills to assess recovery following anesthesia. Subjects were impaired for 8 hours after methohexital (Korttila et al., 1975), for 6 hours after thiopental anesthesia (Korttila et al., 1975), and for 1 hour after propofol anesthesia (Korttila et al., 1992). After brief inhalational anesthesia (3.5 minutes), driving skills were impaired for 4-5 hours (Korttila et al., 1977). After long (8 hours) duration anesthesia with 1.25 MAC desflurane or sevoflurane, psychomotor performance was slower with sevoflurane, 60 and 90 minutes after anesthesia (Eger et al., 1997). Subjects were also given a questionnaire 1 week after anesthesia to estimate time to recovery of various endpoints including mental recovery. Volunteers who received desflurane reported feeling "normal in all respects" by around 12 hours after anesthesia, whereas those that received sevoflurane did not feel normal for 72 hours (Egeref al., 1997). VI. EFFECT OF DIFFERENT ANESTHETIC AGENTS ON COGNITIVE RECOVERY IN HEALTHY YOUNG PATIENTS In young, healthy adults, most studies indicate that the type of anesthetic agent, whether intravenous or inhalational, can influence the speed of emergence and/or recovery (Pollard et al., 2003). Older barbiturate anesthetics such as methohexital and thiopental generally result in delayed emergence and delayed return of psychomotor function compared to propofol (Boysen et al., 1989; Mackenzie and Grant, 1985) although there are exceptions (Pollard et al., 2003). Differences in recovery following inhalational anesthesia is generally related to the pharmacokinetic properties of the N.N. BUTTERFIELD 24 agents (see Section E.III.). Hence, recovery after halothane is prolonged compared to isoflurane (Eger, II, 1981); recovery after isoflurane is prolonged compared to desflurane (Tsai et al., 1992; Smith et al., 1994; Fletcher et al., 1991; Smiley et al., 1991; Lee et al., 1993; Dupont et al., 1999). With sevoflurane recovery is only slightly prolonged compared to desflurane (Nathanson et al., 1995; Dupont et al., 1999). VII. EFFECT OF DIFFERENT ANESTHETIC AGENTS ON COGNITIVE RECOVERY IN HEALTHY ELDERLY PATIENTS The type of anesthetic can also affect the speed and cognitive recovery in healthy elderly patients. Some investigators have shown that in geriatric patients undergoing short ambulatory urologic procedures, desflurane was associated with 73% "fast-track" eligibility compared to 43% for isoflurane and 44% for propofol (Fredman et al., 2002). "Fast track" eligibility refers to readiness for rapid hospital discharge of outpatients. In contrast, other studies have shown that while desflurane may to lead to earlier emergence and recovery of psychomotor function compared to propofol and isoflurane there is no significant influence on time of discharge from the postanesthetic care unit (PACU) (Bennett et al., 1992; Juvin et al., 1997; Solca et al., 2000). Desflurane may result in more rapid emergence than sevoflurane, but as expected from low blood:gas solubilities of both agents, mental status (MMSE) does not differ by one hour postoperatively (Chen et al., 2001). As with the studies in the healthy young patients, the clinical significance of small differences in short-term recovery is not clear. F. DO RAPIDLY ELIMINATED GENERAL ANESTHETICS IMPROVE SHORT-TERM COGNITIVE RECOVERY IN HIGH-RISK PATIENTS? The studies reviewed in the previous sections indicate that short-term impairment can occur after general anesthesia. Furthermore, the choice of anesthetic N.N. BUTTERFIELD 25 agent can influence short-term cognitive recovery. This was true in the healthy patient populations studied, both young and old. However, the clinical significance of some of these differences in emergence and recovery in healthy adult patients has been questioned, particularly with regard to desflurane and isoflurane (Dexter and Tinker, 1995). Specifically, the theoretical advantage of rapid recovery in ambulatory procedures, resulting in a more rapid recovery, faster patient turnover, and decreased hospital costs often does not occur (Dexter et al., 1995). This is because hospital protocol and procedures often do not permit faster discharge times (Dexter et al., 1995; Juvin et al., 1997; Fletcher et al., 1991; Ghouri et al., 1991). Second, earlier recovery may increase the analgesic requirements for postoperative pain management (Curtis et al., 1991; Solca et al., 2000). Finally, for most patients there is no obvious clinical advantage to "wake up faster", and a few extra minutes recovering is unlikely to cause any suffering. While the clinical advantage of differences in short-term recovery in healthy patients is questionable, specific patient populations may benefit from these differences. For example, patients with concomitant diseases that are at high risk of developing postoperative cognitive impairment may benefit from the use of anesthetics with theoretically more rapid elimination pharmacokinetic properties. Most controlled clinical trials exclude such high-risk patients because many factors other than the anesthetic may influence cognitive recovery (Ritchie et al., 1997; Dijkstra et al., 1999; Ancelin et al., 2001). Excluding high-risk patients simplifies research by avoiding these potential confounding factors. Unfortunately, it does not permit investigation of interaction between the effects of anesthesia, age, concomitant diseases, and cognitive impairment. It is the high-risk patients that are often excluded who would actually benefit the most from improved short-term postoperative recovery. N.N. BUTTERFIELD 26 To address the question of whether high-risk patients would benefit from the use of anesthetics with favourable pharmacokinetic properties, I designed and implemented two clinical trials. Each trial included patients that are at high risk of developing short-term postoperative cognitive impairment, carotid endarterectomy and electroconvulsive therapy patients. Not only are these patients at high risk of developing postoperative cognitive impairment, the advantages of improved short-term cognitive recovery are clear (discussed in the following sections). /. CAROTID ENDARTERECTOMY PATIENTS Patients that require carotid endarterectomy, which is used in the prophylaxis of stroke (Wilke et al., 1996), are at high risk of developing postoperative cognitive impairment. The risk of postoperative cognitive impairment in these patients stems from the natures of the disease and the risks of surgery. Carotid endarterectomy patients are elderly and usually have premorbid cardiovascular disease and cerebrovascular disease, hypertension and diabetes, and preexisting cognitive impairment, including asymptomatic patients (Wilke et al., 1996; Benke et al., 1991). During surgery, a 30-45 minute period of carotid artery clamping is often required, which disrupts cerebral blood flow resulting in transient cerebral ischemia. In addition, there may be embolic events that result from fragments of atherosclerotic plaque dislodged during surgery. Because these multiple factors create a high risk of postoperative complications, prompt neurological assessment is essential. If assessments are delayed because of residual effects of anesthesia, early detection of neurologic complications becomes difficult, and adverse events can quickly become irreversible (Wilke etal., 1996; Jenkins et al., 1987). Isoflurane is one of the most commonly used inhalational anesthetic. N.N. BUTTERFIELD 27 Suggestions that it may be neuroprotective have made it a popular anesthetic in neurosurgical cases, including carotid endarterectomy (Duffy et al., 2000). However, desflurane is rapidly becoming an inhalational agent of choice because of its potential for more rapid postanesthetic recovery than older anesthetics (Dexter et al., 1995; Juvin et al., 1997; Patel and Goa, 1995). We hypothesized desflurane would result in more rapid emergence and return of cognitive function than isoflurane in patients undergoing carotid endarterectomy. Cognitive function was tested at 15 minutes, 4 hours and 24 hours after carotid endarterectomy. A complete description of the prospective, randomized, double-blind trial can be found in Chapter 2. //. ELECTROCONVULSIVE THERAPY PATIENTS Electroconvulsive therapy (ECT) is one of the most commonly performed medical procedures requiring general anesthesia (McCall et al., 1999). It is used to treat medication resistant and cognitive therapy resistant depression, emergent suicidal cases, and other psychiatric illnesses (American Psychiatric Association, 2001). ECT patients are at high-risk of developing postanesthetic cognitive impairment because of the nature of their disease and the risks of ECT. Depression, preexisting cognitive impairment, exposure to anesthesia and seizure induced cognitive impairment all contribute to cognitive impairment shortly after ECT (American Psychiatric Association, 2001). While modifications of many ECT parameters have helped reduce the severity of postictal cognitive impairment, cognitive impairment continues to be the most important factor limiting the use of ECT (Miller et al., 1985; Sackeim et al., 1986; Weiner et al., 1986b; Sackeim et al., 1993; Lerer et al., 1995; McElhiney et al., 1995; Lisanby et al., 2000; Sackeim etal., 2000; American Psychiatric Association, 2001). Barbiturate anesthetics, such as thiopental, remain the most commonly used N.N. BUTTERFIELD 28 anesthetics for ECT (American Psychiatric Association, 2001). Although propofol has been demonstrated to result in faster recovery than thiopental in ambulatory surgeries (Pollard et al., 2003), its use in ECT remains limited (American Psychiatric Association, 2001). We hypothesized that propofol would reduce postictal cognitive impairment compared to thiopental anesthesia in patients receiving ECT for major depressive disorder. Cognitive function was tested at 45 to 60 minutes after ECT. A complete description of the prospective, randomized, crossover, double-blind trial can be found in Chapter 3. G. WHAT IS THE RELATIONSHIP BETWEEN GENERAL ANESTHESIA AND LONG-TERM IMPAIRMENT? Although most patients experience full recovery after uneventful surgery and anesthesia, some patients, particularly elderly patients, suffer from long-term postoperative cognitive impairment. Reports that general anesthesia can cause long-term cognitive impairment date back as far as 1955, when Bedford attributed the long-term postoperative cognitive impairment in elderly patients to general anesthesia in his frequently cited paper, "Adverse cerebral effects of anaesthesia in old people" (Bedford, 1955). Since Bedford's paper, various studies have investigated the relationship between anesthesia and long-term postoperative but no more so than in the past decade. This increased interest in long-term postoperative cognitive impairment has occurred because the number of surgeries performed in the elderly is rapidly increasing (Rooke, 2003). Currently however, the relationship between general anesthesia and long-term cognitive impairment is poorly understood. /. STUDIES IN YOUNG ADULTS: VOLUNTEERS AND PATIENTS Suggestions that anesthesia can have long-term effects have stemmed in part N.N. BUTTERFIELD 29 from studies conducted in healthy adult volunteers. For instance, a group of healthy male volunteers anesthetized for 4 to 8 hours with halothane or isoflurane, had behavioural changes lasting up to eight days, with greater deficits following halothane (Davison et al., 1975). In this same study however, cognitive function (assessed with a comprehensive neuropsychological battery) 30 days after anesthesia actually improved, compared to controls (Davison et al., 1975). Although much less common, a few studies have also reported long-term impairment in young adult patients (Tzabar et al., 1996; Flatt et al., 1984). Flatt et al. (1984) found greater impairment following general anesthesia versus local anesthesia four days and six weeks after plastic surgery, but a high correlation with habitual caffeine use and cognitive impairment confounded the results. Tzabar et al. (1996) found that 3 days after discharge, adults that received general anesthesia for short surgical procedures reported more impairment on a cognitive failures questionnaire (CFQ) than those who received local anesthesia. The authors concluded that the cause of the impairment was residual effects of general anesthesia that persisted beyond 24 hours (Tzabar et al., 1996). //. STUDIES IN ELDERLY PATIENTS Elderly patients undergoing cardiac (Croughwell et al., 1994; Mills, 1995; Hammon, Jr. et al., 1997) or orthopaedic surgery (Gustafson et al., 1991) are at the highest risk of developing long-term postoperative cognitive impairment. The cause of impairment is likely multifactorial but appears to be closely related to the complications and progression of these diseases. However, elderly patients who undergo non-cardiac or orthopaedic major surgery are also at increased risk of long-term cognitive impairment (Marcantonio et al., 1994; Dodds et al., 1998; Moller et al., 1998; Dijkstra et N.N. BUTTERFIELD 30 al., 1999; Grichnik et al., 1999). In these patients the causes of the long-term cognitive impairment is less clear, but has been suggested to result from, at least in part, exposure to general anesthesia. In a well designed and controlled study of non-cardiac major surgery patients, cognitive impairment was shown to persist in 25% of patients one week after surgery (Moller et al., 1998). Duration of anesthesia was one of the significant risk factors (Moller et al., 1998). Grichnik et al. (1999) reported even higher incidences in a similar patient population, with 44.8% of patients impaired 6 to 12 weeks after anesthesia, and suggested that, amongst other causes, intolerance to the effects of general anesthesia may be an important causative factor. A number of studies compared the effects of regional versus general anesthesia on postoperative cognitive impairment. Most of these studies suggest that postoperative cognitive impairment exists in the elderly, but the influence of the anesthetic type is variable and inconsistent. Generally, the non-randomized studies have indicated that general anesthesia may cause greater cognitive impairment than regional anesthesia. Ancelin et al. (2001) found a high incidence of cognitive impairment 9 days postoperatively in elderly patients that underwent orthopaedic surgery under peridural anesthesia (76%) versus general anesthesia (62%). The epidural patients were older, had lower educational levels, and higher levels of depressive symptomatology and/or preexisting cognitive impairment than the general anesthesia patients, which may account for the higher incidence of impairment. In contrast, Gustafson et al. (1988) found that patients having epidural, spinal, or neuroleptanesthesia were actually more impaired, or more likely to develop postoperative confusion, than patients that received general anesthesia, although this study used a historical general anesthesia comparison group. N.N. BUTTERFIELD 31 Randomized studies have for the most part, not found a significant difference in the incidence or severity of postoperative cognitive impairment, with the exception of at least one study. In three randomized studies, significant long-term postoperative cognitive impairment was found, irrespective of the anesthetic technique used. Berggren et al. (1987) found a high incidence of confusion in elderly patients that had surgery for femoral neck fractures under either epidural anesthesia or halothane general anesthesia. A fairly comprehensive study of cognition following joint replacement surgery in elderly patients found no difference between general and regional anesthesia (Ghoneim et al., 1988), although a shortcoming of this study was the large variability in postoperative cognitive assessment times (anytime between one and seven days after anesthesia, and approximately three months later). Williams-Russo et al. (1995) performed a very thorough and well-controlled study in which elderly patients undergoing elective total knee replacement were randomized to receive epidural or general anesthesia. A neuropsychological assessment (that included 10 tests of memory, psychomotor and language skills), was performed preoperatively, and again one week and six months postoperatively. Both groups demonstrated cognitive impairment at each time point, but there were no significant differences between them. Hole et al. (1980) presented one of the few randomized studies in which patients were more impaired following general anesthesia compared to epidural anesthesia (elderly patients underwent total hip replacement surgery). Most studies that have compared regional and general anesthesia have one or more limitations that make interpretation difficult. For instance, non-randomized are limited by potential selection bias. Patients in the regional anesthesia groups often receive heavy sedation (Chung et al., 1989). In such cases, general anesthesia is not being compared to "pure" regional anesthesia. Furthermore, while these studies N.N. BUTTERFIELD 32 provide clues about the role of anesthesia in cognitive impairment, they do not directly address the role of general anesthesia. ///. LIMITATIONS OF CLINICAL RESEARCH The clinical studies reviewed, and those conducted in this thesis, help understand the effect of different anesthetic agents on short-term postoperative cognitive impairment. However, they do not provide an understanding of the specific contribution of general anesthesia to long-term cognitive impairment. Clinical studies that have attempted to understand causes of long-term impairment are inherently limited. One reason is the inability to include a proper control group, since it is unethical to perform major surgery in the absence of anesthesia or to anesthetize high-risk patients with no medical indication (because of the risks of serious adverse events from anesthesia). Furthermore, there are numerous factors that can influence cognitive function, independent of anesthesia, such as inadequate cognitive testing conditions, poor nutrition, postoperative fatigue and postoperative medications. In view of these inherent limitations, animal experiments provide an alternative approach to explore the effects of general anesthesia on cognitive impairment. Animal studies provide greater control over test conditions and allow the study of anesthesia independent of surgery. H. USE OF RODENTS TO STUDY THE COGNITIVE EFFECTS OF GENERAL ANESTHESIA Rodents have provided valuable information about the behavioural effects of drugs, including anesthetics. Most previous studies used young or adult mice to investigate short-term (Table 1a.) or long-term effects (approximately 24 hours or more) of anesthesia (Table 1b.). Only three studies have investigated the relationship between age, anesthesia and cognitive impairment (van der Staay et al., 1988; Blokland et al., 2001; Culley et al., 2003). N.N. BUTTERFIELD 33 /. SHORT TERM EFFECTS OF ANESTHESIA IN YOUNG RODENTS Recovery after anesthesia in young or adult mice, as in humans, has been shown to be rapid in some studies, but more prolonged in others (Table 1a.). La Marca et al (1995) tested the effects of intravenous anesthetics in adult rats. They found that spatial memory performance (using the 8-arm radial maze) returned to baseline levels within 15 minutes of return of the righting reflex (RoR) after i.v. bolus doses of propofol (6.12 mg/kg), alfentanil (0.09 mg/kg), and etomidate (2.51 mg/kg). After administration of fentanyl (0.06 mg/kg), sufentanil (0.007 mg/kg), and remifentanil (0.037 mg/kg), return to baseline performance took 30 minutes. Furthermore, cognitive recovery paralleled the return of baseline electroencephalogram (EEG) waveforms (EEG readings were obtained using cerebrocortical EEG electrodes, surgically implanted 4 days earlier). In this study, the cognitive impairment appeared to be related to the different pharmacokinetic profiles of the drugs with the rapidly eliminated drugs (e.g. propofol) resulting in the quickest recovery times. Alternatively put, there was a direct correlation with the time to RoR (longer time to RoR following drugs with slower elimination half-times) and return of cognitive function. In a study by Engeland et al. (1999) rats were anesthetized for approximately 25 minutes with propofol (15 to 20 mg/kg i.v. bolus), and after recovery (5 to 7 minutes later), were trained on a swim-to-platform task. Memory retention was tested two to three hours later. Whereas anesthetized rats made significantly more errors than control animals during training, both groups performed equally well during retention testing. In fact, the anesthetized rats performed better during retention testing than the control rats during training. The authors argued that the improved performance at retention testing indicates that "normal" learning occurred during anesthetic recovery, despite initially impaired performance. Alexinsky et al. (1979) found performance on a delayed matching-to-N.N. BUTTERFIELD 34 sample (DMS) task was not impaired by anesthesia (halothane) if administered approximately 8 minutes before training. When anesthesia was administered after training, memory retention was impaired in the first 8 minutes after anesthesia, but 2 or 24 hours later. In contrast to the above studies, O'Gorman et al. (1998) found that some propofol, 75 mg/kg, induced anterograde amnesia up to 12-hours after behavioural training. In this study, the investigators administered propofol (10 and 75 mg/kg i.p.) 15 minutes before training in passive avoidance task. The 10mg/kg dose of propofol did not produce amnesia. In the same set of experiments, the investigators administered 100 and 150 mg/kg i.p. doses of propofol once per hour up to six hours after training, to test retrograde effects of anesthesia. Only the 150 mg/kg dose of propofol administered between one and three hours after training produced retrograde amnesia for up to 12 hours. The finding that there is no retrograde amnesia if subanesthetic doses of propofol are administered, or if anesthesia is induced more than three hours after training, suggests there is a time and dose dependent effect. //. LONG-TERM EFFECTS OF ANESTHESIA IN YOUNG RODENTS Studies have investigated the long-term effects of anesthesia on cognition have had mixed results. Most of the studies indicate that there is no long-term impairment following anesthesia in young adult mice (Alexinsky and Chapouthier, 1979; Rosman et al., 1992; Komatsu etal, 1993; Pang et al, 1993; Komatsu et al., 1998). For example, Alexinsky and Chapouthier (1979) did not find that halothane anesthesia impaired memory any longer than 2 hours after anesthesia. The authors of this study used a delayed matching-to-sample task to assess short and long-term memory. Halothane was administered at 3.5% atm. in a 50:50 mixture of air and oxygen producing narcosis N.N. BUTTERFIELD 35 within 15 seconds. Once the DMS task was learned, a delay was introduced between stimulus and test sessions. Halothane was administered either immediately before, or at varying times after, the stimulus sessions to examine anterograde and retrograde effects. Halothane did not cause anterograde amnesia when it was administered immediately before the stimulus session. When halothane was administered just at the end of the stimulus session, there was a significant decrement of the rat's performance. However, performance returned to control levels within 2 hours. Additional assessments 24 hours after anesthesia indicated there was no long- term effect of halothane. Unfortunately, there are very few details about the anesthesia (such as the duration rats remained anesthetized). Beatty and Shavalia (1980) also failed to find any impairment in spatial memory despite large differences in the duration of anesthesia. Rats were trained on an eight-arm maze until they met a baseline requirement (17-31 sessions). After completion of the first four maze choices, the rats received an injection of methohexital. After a 4-hour delay, which included the recovery period, the rats returned to the maze to complete testing. Doses of 10, 20, 30, 40, and 50 mg/kg i.p. were tested, with 5 drug free days in between. The 50 mg/kg dose produced anesthesia for only 10 minutes. After 10 drug-free days the same rats received an injection of chloropent2 (3 ml/kg i.p.) immediately after the first four choices, and were tested after an 8-hour delay. Anesthesia lasted for approximately 2 hours with chloropent, but again anesthesia did not result in spatial memory deficits. In all the studies that did demonstrate long-term cognitive impairment, anesthesia was administered prior to behavioural training (Hendrickx et al., 1984; Rosman et al., 1992; Pang et al., 1993). Hendrickx et al. (1984) found that during the first week of recovery from anesthesia (30 minutes with 1 or 2% halothane) and surgery N.N. BUTTERFIELD 36 (tracheotomy for intubation and femoral artery and vein cannulations), spontaneous activity was reduced for up to 48 hours, passive avoidance behaviour was impaired for 4 days, and locomotor activity was reduced for 5 days, in adult Sprague-Dawley rats. This study was limited because the inclusion of surgical procedures, which could have influenced behaviour, and because of the very small sample sizes (only 1 rat was used to investigate spontaneous locomotor behaviour, and 4 rats for the behavioural analysis). Two other related studies reported long-term anterograde effects of anesthesia (i.e. when anesthesia is administered shortly prior to the behavioural task), but not retrograde effects (i.e. when anesthesia is administered after behavioural training) (Rosman et al., 1992; Pang et al., 1993). Rosman et al. (1992) examined the effects of halothane anesthesia on memory processing using single-trial inhibitory avoidance learning to measure retention. To evaluate retrograde amnesia, mice were exposed to halothane (2%) for 15, 30 and 60 minutes immediately after the training trial. Memory retention was tested 24 hours after training. Halothane anesthetized mice showed no significant deficits compared to control animals. To evaluate anterograde amnesia, mice were exposed to thirty minutes of anesthesia prior to training, initiated after recovery, and retested 24 hours later. The anesthetised mice performed as well as the controls during training, but demonstrated poor 24-hour retention compared to controls. This suggested that the impairment was due to forgetting rather than impaired acquisition. Finally, to determine the temporal gradient of anterograde amnesia, mice were anesthetized for thirty minutes and trained at various times after recovery (15 min and 2, 4 and 24 hrs later). Retention was tested 24 hours later. Anterograde amnesia only occurred in mice trained within two hours of anesthetic recovery. It was suggested that within this time-period learned information is not accessible to normal retrieval N.N. BUTTERFIELD 37 cues during retention testing. Pang et al. (1993) found that anterograde amnesia persisted up to seven days when propofol (50 and 75 mg/kg i.p.) was injected 10 minutes before training on a single trial passive avoidance task. There was a dose dependent effect, and no significant impairment was observed with 5 and 25 mg/kg doses. None of these concentrations was sufficient to produce loss of consciousness. When propofol was injected after avoidance training, there was no evidence of retrograde amnesia. Furthermore, those animals receiving the 50 mg/kg dose showed significant impairment 1, 3 and 7 days after training, compared to controls. ///. IMPLICATIONS OF PREVIOUS STUDIES The results of studies that investigated the effects of anesthesia on cognitive functioning in young and adult rodents have had mixed results. Some investigators reported that general anesthesia did not cause cognitive impairment (Beatty and Shavalia, 1980). Some observed short-term deficits (Alexinsky ef al., 1979; Hendrickx et al., 1984). Others reported long-term deficits (only in anterograde amnesia) (Rosman et al., 1992; Pang ef al., 1993). Some have had significant variation in results (Valzelli et al., 1988). Some investigators have even reported that anesthesia may improve long-term cognitive function (Komatsu et al., 1993; Komatsu et al., 1998). Many of these studies used anesthesia as a tool for understanding learning and memory rather to understand the effects in a clinically relevant manner. Nevertheless, the results are generally consistent with clinical evidence (and volunteer studies) that suggests that anesthetics can have short-term effects on cognition. In addition, most of the animal studies indicate that anesthesia does not have long-term effects on cognitive function in young or adult mice (with the exception of some studies where anesthetics were administered immediately prior to behaviour training); again, a finding N.N. BUTTERFIELD 38 consistent with most clinical studies. However, the question remains, would aged rodents be susceptible to long-term postanesthetic cognitive impairment? I. DOES GENERAL ANESTHESIA CAUSE LONG-TERM COGNITIVE IMPAIRMENT IN 'HIGH RISK' ANIMALS—AGED RODENTS? Aged rodents exhibit many of the cognitive deficits seen in the elderly human (Barnes, 1998), including slowed speed of cognitive processing, slowed psychomotor responses, and impaired spatial memory abilities (Bernstein et al., 1985; Barnes, 1998). Since elderly patients experience a higher incidence of long-term postoperative cognitive deficits than young patients, studies with young and aged rodents may provide valuable information about the relationship between anesthesia, age and cognitive impairment. To my knowledge, only three published studies have investigated the effects of anesthesia on cognition in aged animals (van der Staay et al., 1988; Blokland et al., 2001; Culley et al., 2003). Results from these studies are contradictory and leave many questions unanswered. Therefore, in addition to the clinical trials, this thesis includes a series of laboratory experiments to investigate the effects of common volatile and parenteral general anesthetics on cognition in young and aged mice. 1.2. Aims and Questions Addressed in this Thesis The main theme of this thesis was to study the role of anesthesia in causing postoperative/postanesthetic cognitive impairment in high-risk groups. Due to the complex nature and broad scope of this topic, it was not practical to tackle in its entirety in one thesis. For this reason, the thesis work focused on two specific aspects of postoperative cognitive impairment. First, since postoperative cognitive impairment is a clinical problem, two clinical trials were conducted. The intent of the clinical trials was N.N. BUTTERFIELD 39 to help understand the short-term effect of different anesthetics on cognitive recovery in patients at high risk of developing cognitive impairment, and who would gain the greatest benefits from rapid CNS recovery. The second part of the thesis deals with the relationship between age, anesthesia and long-term postoperative cognitive impairment since elderly patients are at high risk of developing long-term cognitive impairment. Because of the inherent limitations of clinical research, a series of laboratory experiments was conducted to help understand the role general anesthesia plays in long-term cognitive impairment. The main questions addressed in this thesis were: 1. Does the type of intravenous anesthetic influence short-term cognitive and psychomotor recovery in a high-risk patient population - elderly vascular patients undergoing carotid endarterectomy? 2. Does the type of inhalational anesthetic influence short-term cognitive and psychomotor recovery in a high-risk patient population - depressed patients receiving electroconvulsive therapy? 3. 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E CO c c 'ro LO LO" c\i 0 c 0 0 ro CM ^: "ro E co o .E LO" 'CD io" CN 0 0 °£ c CD I i 0 o 0 O c CD •g 'o > ro 0 > CO CO CD D_ •o 0 > 2 a. •b".i 2 CN Q.T3 CO "<* >-CD CD Q Q CO c 'c 'ro 0 v. CD JZ CN CO >. ro Q 0 3 c O ro CO 0 enflur rainin cons CN ftei ,2 T— < LO" 0 O 0 ro E 0 x: Q. E 0 i— 0 o E c 2 E ro • oo x: co ro 3 ro „ c co o a> ro O CD > < E E CD Q. E ro CO o c J Z o 4—» ro T3 CD ro CD Q < CD N ro E i < ro T3 ro co CD O c ro -g 'o > < o < '•9 ^ i i .55 ro 5 8 co c .<= o co O N.N. BUTTERFIELD 42 CLINICAL TRIALS. RELATIONSHIP BETWEEN PHARMACOKINETIC PROPERTIES OF GENERAL ANESTHETICS AND SHORT-TERM COGNITIVE IMPAIRMENT IN HIGH RISK PATIENT POPULATIONS CHAPTER 2: CLINICAL TRIAL: COGNITIVE IMPAIRMENT IN ELDERLY PATIENTS FOLLOWING CAROTID ENDARTERECTOMY. A COMPARISON OF DESFLURANE AND ISOFLURANE ANESTHESIA N.N. BUTTERFIELD 43 Chapter 2. Does Desflurane Anesthesia Improve Cognitive Recovery Compared to Isoflurane in Elderly Patients Following Carotid Endarterectomy? 2.1 Introduction Carotid endarterectomy is a commonly performed surgery that that has proven to be effective in the prophylaxis of stroke (NASCET, 1991; Hobson et al., 1993; Tu et al., 1998). This surgery involves removal of atherosclerotic'plaque that has occluded the lumen of the carotid arteries (Wilke et al., 1996; Jenkins et al., 1987). The age of the patient, the nature of the disease, and the surgery itself all contribute to an increased risk of significant postoperative neurologic complications (Wilke et al., 1996; Jenkins et al., 1987). Carotid endarterectomy patients tend to be elderly, making them more sensitive to the effects of anesthetic and adjuvant drugs (Jones and Hunter, 1996; McLeskey, 1997), and have multiple co morbid diseases, including coronary artery disease (21-65%), hypertension (40-69%), diabetes (8-40%), and peripheral vascular disease (Jenkins et al., 1987; Eagle et al., 1996). These diseases also increase the risk of postoperative cognitive impairment. The surgery often includes the use of carotid cross-clamping that may cause transient cerebral ischemia (Wilke et al., 1996). Finally, postoperative thrombosis and embolic events can occur (Wilke et al., 1996). To avoid potentially irreversible neurologic damage, complications following carotid endarterectomy must be addressed promptly (Wilke et al., 1996; Garrioch et al., 1993). However, rapid postoperative assessment of brain function is impeded by delayed recovery from general anesthesia. To facilitate recovery from anesthesia, anesthetic agents that permit rapid recovery might be beneficial. Isoflurane is one of the most commonly used anesthetics in North America, and has been popular for N.N. BUTTERFIELD 44 carotid endarterectomy because of its potential neuroprotective effects (Wilke et al., 1996; Duffy et al., 2000) (though this remains a controversial issue (Warner, 2000)). Desflurane, because of its low blood and tissue solubility generally permits rapid emergence and cognitive recovery, at least in healthy adult (Dexter et al., 1995; Patel et al., 1995) and elderly patients (Juvin et al., 1997). These potential advantages of desflurane indicate that it may be an ideal anesthetic for carotid endarterectomy. Indeed, some studies have shown that elderly patients emerge faster with a desflurane based anesthetic compared to an isoflurane based anesthetic (Bennett et al., 1992; Juvin et al., 1997; Umbrain et al., 2000), although this has not translated into earlier cognitive recovery in all cases (Bennett et al., 1992). A study was conducted to evaluate whether emergence and cognitive recovery would be quicker following a desflurane versus an isoflurane-based anesthesia in elderly patients (greater than 65 years of age) undergoing unilateral carotid endarterectomy. The primary variables were emergence time, mental status, 15-30 minutes after anesthesia, and cognitive function, 4 hours and 24 hours postoperatively (these times were chosen since neurological complications may not manifest until later in the recovery period (Naylor, 2002)). 2.2 Methods A. ETHICS The study protocol was approved by The University of British Columbia (UBC) Clinical Research Ethics Board (certificate # C98-0045). B. PATIENTS Patients scheduled to undergo carotid endarterectomy at the UBC Site of the Vancouver Hospital & Health Sciences Centre were sent a letter of intent prior to their N.N. BUTTERFIELD 45 preadmission clinic (PAC) visit. At the end of their PAC visit, the study was re-introduced to the patient. Patients were included in the study if they were right-handed, aged between 50 to 75 years and provided written informed consent. Patients were excluded if they had an American Society of Anesthesiologists' (ASA) physical status greater than 3, serious or uncorrected visual impairment, ongoing substance abuse, known or family history of reactions to the study drugs, or inadequate proficiency with English. Patients were randomised to receive either desflurane (n=10) or isoflurane (n=10). C. STUDY DESIGN Prospective, randomised, double blind, study (Figure 1). N.N. BUTTERFIELD Surgeon's Office + Potential patients receive letter of intent and copy of consent form Pre-Admission Clinic 1. History and Physical 2. Consent obtained 3. Baseline Psychometric Testing Group I Isoflurane Day of Surgery I Patients randomly assignd to either: Group D Desflurane Carotid Endarterectomy Dressing applied at end of surgery 1. Turn off inhalational anaesthetic 2. Begin timing for immediate recovery Postoperative Assessments k Stop timing when patient demostrates ability to complete a modified Mini-Mental test Memory and attention tests administered: 4 hours post-operatively 24 hours post-operatively Figure 1. Carotid endarterectomy study flowchart. N.N. BUTTERFIELD 47 D. ANESTHETIC DETAILS At the beginning of each case the anesthesiologist administered a superficial cervical plexus block (10 ml of 0.25% bupivacaine with epinephrine 1:200 000) (Murphy, 1988). The block was used to maximise analgesia and reduce the need for intra-operative and postoperative opioids, which delay recovery. The surgeon supplemented the block by infiltrating the incision site with an additional 5-20 ml. Fentanyl (1-2 /vg/kg i.v.) and propofol (1-2 mg/kg i.v.) were used for induction. Neuromuscular blockage was produced with rocuronium (0.5-0.7 mg/kg i.v.). All patients received endotracheal intubation. Following induction, patients received either desflurane or isoflurane with 60% nitrous oxide in oxygen. To reflect "real-world" anesthetic practices, the concentration of desflurane and isoflurane was left up to the anesthesiologist. Edrophonium and glycopyrrolate was recommended for reversal of residual neuromuscular blockage. To standardize the timing for recovery measurements, anesthesiologists were requested to discontinue the nitrous oxide and the volatile agent when the first skin staple was placed. The oxygen flow was increased to 10 L/min at the discontinuation of anesthesia. At the end of surgery, 2 ml of lidocaine 2% was administered via a LITA tube to minimize reaction to the endotracheal tube. E. SURGICAL DETAILS Surgeries were performed by Drs. L. Doyle and/or P. Fry. Under general anesthesia, the neck was infiltrated with 0.25% bupivacaine. The carotid artery was exposed via an incision anterior to the sternocleidomastoid muscle. Patients received approximately 3000U of heparin i.v. to prevent clotting. Carotid cross clamps were applied and the artery was opened. After endarterectomy, the artery was closed with N.N. BUTTERFIELD 48 6-0 Prolene sutures, and the wound site was closed with 3-0 Vicryl and a skin stapler over a % inch Penrose drain. Patients were transferred to the post anesthetic recovery room (PARR) where they remained for 1-3 hours until discharge to the surgical day-care ward. Patients were discharge the following day. F. COGNITIVE AND PSYCHOMOTOR ASSESSMENTS I recorded baseline cognitive measures at the end of patients' preadmission clinic visit. A battery of neuropsychological tests was administered, followed by a baseline Mini-mental status exam (MMSE) test (Folstein et al., 1975). The neuropsychological battery consisted of the following tests: Rey Auditory Verbal Learning Test (RAVLT), Finger Tapping, Simple Reaction Time, Trail Making Test (TMT) parts A and B, Choice Reaction Time, and RAVLT delayed recall. The RAVLT was used to measure immediate memory span, learning and delayed memory (Spreen et al., 1998). The version used consisted of three presentations with recall of a 15-word list. A new list was then presented, with recall, to create interference. The patient was then asked to recall the original list presented. Delayed retention of the original list was tested approximately 20 minutes after the rest of the tests were administered, and patients were asked to, "think back to the list of words that was read and recall as many words as possible". The Finger Tapping task was used to measure motor function (Lezak, 1995). The version used was part of a computerized battery developed in the UBC Dept. of Psychology by Drs. B. Uttl and P. Graf. Patients were required to tap a computer key as quickly as possible for 10 seconds. An average of five trials was calculated. The next computer task, Simple Reaction Time, was used to test the speed of making simple reaction. Patients were required to press a key in response to an 'x' that N.N. BUTTERFIELD 49 appeared at variable intervals in the middle of the computer screen. Response times were averaged for three blocks of 25 presentations. After the first two computer tasks, the patients were given the Trail Making Test, parts A and B, task to measure visuomotor and attention shifting abilities (Lezak, 1995). In TMT part A, the patient was requested to join the numbers in order without lifting the pen off the paper. In TMT part B, the patient was requested to join the numbered circles and letters in consecutive order, switching between numbers and letters as they go. Completion time and accuracy were recorded. Patients were subsequently administered a computerized Choice Reaction Time task to measure the speed of making a simple decision. In this task, one of two letters ('C and 'Z') appeared in the middle of the computer screen at random and at variable time intervals. The patient was requested to press the key that corresponded with each letter (left arrow for 'C ; right arrow for 'Z') as quickly and as accurately as possible. Postoperatively, emergence time and orientation were assessed every 30 seconds, from the time the inhalational anesthetic was discontinued until the correct responses were provided. Short-term cognitive recovery was assessed with the MMSE in the post anesthetic care unit 1 5 - 3 0 minutes after anesthesia. The neuropsychological test battery was again administered approximately 4 hours and 24 hours postoperatively, after the patient had returned to the ward. G. DATA HANDLING AND STATISTICAL ANALYSIS Repeated measures analysis of variance was used to test for differences between isoflurane and desflurane treatments. The Wilcoxon rank sum test was used to compare changes from baseline scores on the MMSE. To minimise the influence of outliers in the reaction time tasks, median reaction times from each patient were used N.N. BUTTERFIELD 50 to compute group means. P < 0.05 was considered statistically significant. All statistics were performed using Number Cruncher Statistical Systems (NCSS) (Hintze, 2001). 2.3 Results A. DEMOGRAPHICS Both groups were similar with respect to age, weight, and years of education (Table 2). There was a similar incidence of previous transient ischaemic attacks and diabetes mellitus, but significantly more hypertensive patients in the isoflurane group (Table 2). Amongst the twenty patients enrolled in the study, three patients were not willing to complete the last assessment period. This was unrelated to surgical or anesthetic factors. B. SURGICAL AND ANESTHETIC DETAILS The duration of surgery, anesthesia, and carotid cross clamp were not significantly different between each group (Table2.). The intra-operative doses of fentanyl and propofol were also similar between each anesthetic, as was the incidence of adverse events (Table 2). Two patients in the desflurane group and one patient in the isoflurane group received neostigmine with atropine for neuromuscular block reversal; the rest of the patients received edrophonium and glycopyrrolate. C. EMERGENCE There were no significant differences between desflurane and isoflurane in time of response to the command "squeeze my hand", time to eye opening, time to state first and last name or time to state the correct date and place (UBC hospital) (Table 3). N.N. BUTTERFIELD 51 Desflurane Isoflurane n 10 10 Age (yr) 74 ± 5.3 70 ± 3.4 Gender (M/F) 6/4 4/6 Weight (kg) 78 ± 12 74 ± 10 Years of education 14 ± 4 12 ± 4 Hypertension (# patients) 4 8 Diabetes mellitus f# patients) 0 1 Previous transient ischemic attack 1 2 Intra-operative Duration of surgery (min) 54 ± 11 55 ± 13 Duration of anesthesia (min) 72 ± 12 70 ± 13 Carotid cross-clamp time (min) 38 ± 17 33 ± 13 Fentanyl (pg/kg) 1.4 ± 0.5 1.9 ± 1.1 Propofol (mg/kg) 2.8 ± 1.0 2.3 ± 0.7 Postoperative Adverse Events Left sided weakness (both resolved) Hypertension Hypotension Tachycardia Bradycardia Nausea Table 2. Demographics and operative data for carotid endarterectomy patients: desflurane vs. isoflurane. Two patients in the isoflurane group received alfentanil (8.0 and 32 pg/kg, respectively). Results presented as mean ± SD were appropriate. 2/10 0/10 0/10 1/10 0/10 1/10 1/10 2/10 1/10 1/10 2/10 0/10 N.N. BUTTERFIELD Desflurane minutes Isoflurane minutes Open Eyes 8.0 ±5.0 7.5 ±4.5 Hand squeeze 8.5 ±6.0 7.0 ±2.5 Extubation time 8.0 ±5.5 5.5 ±2.5 State your first and last name? 10.5 ±6.0 9.0 ±4.5 Can you tell me where you are? 11.0 ± 6.5 9.5 ±4.5 Can you tell me what date it is? 11.5 ±5.5 10.0 ±4.5 Table 3. Recovery profile after carotid endarterectomy: desflurane vs. isoflurane. Results are presented as mean ± SD. N.N. BUTTERFIELD 53 D. COGNITIVE AND PSYCHOMOTOR ASSESSMENTS There was no significant difference in cognitive recovery (MMSE) scores at 15-30 minutes after anesthesia (Figure 2). Four hours after anesthesia, patients from both groups were impaired when tested on the Simple and Choice Reaction Time tasks (Figures 4 and 5), and on the delayed recall trial of the RAVLT (Fig 7c), but not on the Finger Tapping (Figure 3) or Trail Making tasks (Figure 6). Twenty-four hours following anesthesia, performance on the neuropsychological tasks returned to baseline in both groups, with two exceptions. Scores on the delayed recall trial of the RAVLT remained significantly below baseline in the isoflurane group (Figure 7c), and scores on the Choice Reaction task remained significantly above baseline (i.e. impaired) in the desflurane group (Figure 5). N.N. BUTTERFIELD 54 O c "3 2 E o o o c MMSE 15-30 min after anesthesia 1-1 0--1--2--3--4--5--6--7--8--9-•10-ooo ooo o o Desflurane Isoflurane Figure 2. Mini-mental status exam (MMSE) scores at 15-30 minutes after carotid endarterectomy: desflurane vs. isoflurane. There were no significant differences between the two groups. Two patients in the desflurane group and 3 patients in the isoflurane group showed significant impairment, with MMSE scores that dropped by 5 or more points. The bar in each scatter column represents group mean. N.N. BUTTERFIELD 55 E S .+i O E 25(H 225H «! 200H 175H 150-*-F i n g e r T a p p i n g Isoflurane Desflurane Baseline 4-hrs post 24-hrs post Figure 3. Finger Tapping speed at baseline and at 4 and 24 hours after carotid endarterectomy: desflurane vs. isoflurane. There were no significant differences between the two groups at any time point, nor were patients significantly impaired postoperatively, compared to baseline. N.N. BUTTERFIELD 56 S i m p l e R e a c t i o n T i m e 500-j 450-1 ^ 400H Si 350-] 1> c 300H 8 . 1 </) E 250H 200-10 j - 1 1 1 Baseline 4-hrs post 24-hrs post Isoflurane - • - Desflurane — Age-matched norm Figure 4. Simple Reaction Time at baseline and at 4 and 24 hours after carotid endarterectomy: desflurane vs. isoflurane. There were no significant differences between the two groups at any time point. Both groups were significantly impaired 4 hours after anesthesia, compared to baseline, §P < 0.05. Normative data for age-matched (70-79 year old) healthy adults (310 ± 35 ms) extrapolated from Uttl et al. (2000). N.N. BUTTERFIELD 57 Choice Reaction Time 700-j 650-1 S% 550-j "D -H 0) c 500H CD re o cu U)E 450-1 400^-c l 1 I I Baseline 4-hrs post 24-hrs post - o - Isoflurane - • - Desflurane •— Age-matched norm Figure 5. Choice Reaction Time at baseline and at 4 and 24 hours after carotid endarterectomy: desflurane vs. isoflurane. Both groups were significantly impaired 4 hours after anesthesia, compared to baseline, §P < 0.05. 24 hours postoperatively, only the desflurane patients remained significantly impaired compared to baseline performance, *P < 0.05. Normative data for age-matched (70-79 year old) healthy adults (530 ± 60 ms) extrapolated from Uttl et al. (2000). N.N. BUTTERFIELD 58 Trail Making Test A 60 50 ^ E 40' W aj ' in ® H 30 C c | 20 104 -o— Isoflurane - • - Desflurane — Age-matched norm — i 1 1 Baseline 4-hrs post 24-hrs post 175 150H ^ E 3, "J125H -H E c , i= S100H E 75-1-I Trail Making Test B Baseline 4-hrs post 24-hrs post Isoflurane Desflurane Age-matched norm Figure 6. Trail Making Test, parts A and B, at baseline and at 4 and 24 hours after carotid endarterectomy: desflurane vs. isoflurane. There was no significant impairment at any time point in either anesthetic group. Normative data for age-matched (70-79 year old) healthy adults (111.4 ± 72 s) from Spreen and Strauss (1998). ON in N.N. BUTTERFIELD 60 2.4 Discussion This study found that but there was no significant difference in emergence or early cognitive recovery between isoflurane and desflurane anesthesia for carotid endarterectomy. Although MMSE scores at 15-30 minutes were better with desflurane the result was not statistically significant. Cognitive performance four hours and 24 hours postoperatively was not different between anesthetic agents. At 24 hours, patients' cognitive function returned to baseline for most cognitive tests, though patients remained impaired on the RAVLT delayed recall and choice reaction time tasks. Two studies have been published recently that also compared anesthetic protocols during carotid endarterectomy. Umbrain et al. (2000) investigated hemodynamic and recovery characteristics of carotid endarterectomy performed under isoflurane, desflurane or sevoflurane anesthesia. The desflurane group in their study, in which alfentanil was used rather than fentanyl, had similar emergence times to that found in this study. In contrast, the times to extubation (13 ± 4 min), movement (21 ± 4 min) and verbal response (27 ± 8 min) following isoflurane anesthesia took up to three times longer than the isoflurane group in my study (5.5 ± 2.5, 7.0 ± 2.5, 9.0 ± 4.5 min, respectively). In the second study, the investigators assessed whether a remifentanil-desflurane anesthetic protocol would result in faster emergence and cognitive recovery than a fentanyl-desflurane protocol (Wilhelm et al., 2001). The fentanyl-desflurane group in the Wilhelm et al. (2001) study had virtually the same emergence times as in my study; namely, time eye opening (8.0 ± 5.3 vs. 8.0 + 5 min, respectively), time to extubation (8.2 ± 4.9 vs. 8.0 ± 5.5 min), and time to state name (13.8 ± 9.0 vs 10 ± 6.0 N.N. BUTTERFIELD 61 min). The remifentanil-desflurane protocol resulted in significantly faster emergence times than the fentanyl-desflurane protocol in all parameters studied (Wilhelm et al., 2001). Cognitive recovery (Digit Symbol Substitution Test and the Trieger Dot Test) 30 minutes and 60 minutes postoperatively was also faster with the remifentanil-desflurane group compared to the fentanyl-desflurane group. Performance had returned to within 75-90 % of baseline by 90 minutes postoperatively in both groups. The discrepancy amongst the previous studies and this one may arise in part by the differences in duration of anesthesia. The duration of anesthesia in this study, approximately 70 minutes, was about half of that reported by Umbrain et al. (2000) and Wilhelm et al. (2001), approximately 135-150 minutes. With longer durations of anesthesia, there may be a greater benefit with the use of desflurane over isoflurane (Juvin et al., 1997), but this has not been consistently found (Bennett et al., 1992). Interestingly, the emergence times between the fentanyl-desflurane protocols in my study and that by Wilhelm et al. (2001) were approximately the same recovery times as the alfentanil-desflurane protocol in the Umbrain et al. (2000) study, in spite of the considerable shorter half-life of alfentanil (Hughes et al., 1992). Presumably, if the choice of opioid is of significance, as Wilhelm et al. found, then one might expect an alfentanil-desflurane protocol to result in faster recovery than fentanyl-desflurane. The question of whether to choose desflurane'over isoflurane does not appear to be easily answered based on a comparison of the recovery profiles alone. Another consideration of which agent to choose is based on the idea of neuroprotection. As mentioned, isoflurane's potential neuroprotective properties (Warner, 2000; Duffy et al., 2000; Bickler et al., 2003) make it an attractive choice for carotid endarterectomy. However, some have suggested that the low blood solubility properties of desflurane, or even sevoflurane, may allow the protective effect of inhalational agents to be N.N. BUTTERFIELD 62 achieved even more rapidly than with isoflurane (Umbrain et al., 2000). Still other factors that may be considered when deciding on the inhalational agent to use include the pharmacoeconomic impact selected agent. Based on drug costs alone, desflurane has been shown to be more expensive than isoflurane (Boldt et al., 1998; Beaussier et al., 2002; Butterfield et al., 2002), and price reductions of isoflurane at our institution is likely to exaggerate previously established differences (manuscript in preparation). However, the cost differences are likely to be too small to outweigh the potential benefit of desflurane over isoflurane. A strength of my study was the comprehensive neuropsychological battery used to assess cognitive function. Screening tests such as the DSST used by Wilhelm et al. (2001) is not sensitive enough to detect anesthetic effects past the first 90-120 minutes since performance typically returns to baseline within this time frame (Fredman et al., 1999). The ability to detect cognitive impairment not only within the first 90 minutes but later in recovery is important since complications of carotid endarterectomy may not manifest for up to 4 hours after surgery (Naylor, 2002). Although there was no significant difference between the isoflurane and desflurane anesthetic groups 4 hours postoperatively, both groups of patients were impaired on the Simple Reaction Time Choice Reaction Time and the RAVLT delayed recall task. Had the neuropsychological tests been administered within 90 minutes after anesthesia, it is possible that a difference between the anesthetic agents would have been found. A potential limitation of my study include was the small sample sizes. However, inspite of the group sizes, the neuropsychological tests were sensitive enough to detect cognitive impairment 4 hours after surgery. The fact that there were no differences between the anesthetic groups at 4 hours suggest that the choice of anesthetic is likely less important than other factors in determining the degree of cognitive impairment at N.N. BUTTERFIELD 63 this time. This study may have benefited by the inclusion of an age-matched non-patient control group particularly since practice effects (improved performance with repeated testing) may mask the severity of cognitive impairment. However, the primary aim of this study was to investigate whether there were any differences between anesthetic protocols. The inclusion of a control group would not add to this question. Furthermore, patient recruitment was very slow. The inclusion of a control subject such as a patient's spouse, would have been impractical since many of the patients were tested after their pre-admission clinic visit, and requesting patients to remain any longer than necessary would have reduced patient recruitment even more. In summary, cognitive impairment was present after carotid endarterectomy, but there was no significant difference in the degree of impairment between the fentanyl-desflurane and the fentanyl-isoflurane anesthetic groups. Whereas the pharmacological properties of isoflurane and desflurane produce differences in cognitive recovery in healthy patients, this is not evident in carotid endarterectomy patients. Factors such as cerebrovascular disease and age differences in drug elimination appear to determine the rate of cognitive recovery, rather other than the specific anesthetic. Other studies indicate that desflurane may result in more rapid recovery than isoflurane after longer carotid endarterectomy surgeries (more than two hours) (Umbrain et al., 2000), or that the use of more rapidly metabolized opioids such as remifentanil may facilitate recovery even more (Wilhelm et al., 2001). N.N. BUTTERFIELD 64 CHAPTER 3: CLINICAL TRIAL: COGNITIVE IMPAIRMENT IN DEPRESSED PATIENTS FOLLOWING ELECTROCONVULSIVE THERAPY. A COMPARISON OF PROPOFOL AND THIOPENTAL ANESTHESIA Contents of the following chapter appear in the following publication: Butterfield NN, Graf P, Macleod BA, Ries CR, Zis AP. Propofol Reduces Cognitive Impairment After Electroconvulsive Therapy. J ECT (in press) N.N. BUTTERFIELD 65 Chapter 3. Does Propofol Anesthesia Reduce Cognitive Impairment Compared to Thiopental in Depressed Patients Receiving Electroconvulsive Therapy? 3.1 Introduction Electroconvulsive therapy (ECT) is an commonly used and effective treatment for major depression (American Psychiatric Association, 2001). Unfortunately, cognitive impairment continues to be the main complication of ECT, and the most significant factor limiting its use (Miller et al., 1985; Sackeim et* al., 1986; Weiner et al., 1986b; Sackeim et al., 1993; Lerer et al., 1995; McElhiney et al., 1995; Lisanby et al., 2000; Sackeim et al., 2000; American Psychiatric Association, 2001). Memory and non-memory cognitive deficits (attention, perception, etc.), tend to be most severe during the early post-ictal period (Squire et al., 1985; Rouse, 1988; American Psychiatric Association, 2001). Increased deficits in the acute post-ictal period may lead to increased severity of long-term side effects (Sobin et al., 1995). Prolonged confusion increases the need for close observation and delays discharge from the recovery room, slowing patient "turnover" and increasing hospital costs. Outpatients in particular benefit from a reduction of early cognitive impairment since they are often discharged shortly after ECT into the care of a responsible adult. Furthermore, acute cognitive impairment may reduce patient compliance, or may lead to unnecessary modification or discontinuation of the ECT treatments. Extensive research has shown that the severity of ECT induced cognitive impairment can be reduced through modification of treatment parameters such as stimulus waveform (Weiner et al., 1986b), stimulus intensity (Sackeim et al., 1986; Sackeim ef al., 1993; McElhiney ef al., 1995; Lisanby ef al., 2000), electrode placement (McElhiney et al., 1995; Lisanby et al., 2000), and temporal spacing of the treatments N.N. BUTTERFIELD 66 (Lerer et al., 1995). General anesthesia is another component of ECT which may influence cognitive recovery. Anesthesia is necessary to produce a brief period of unconsciousness during which muscle relaxation is induced and the electrical stimulus applied. Anesthesia for ECT is commonly induced with intravenous barbiturate agents, such as methohexital or thiopental. Although the use of the non-barbiturate propofol has increased in recent years, its acceptance as an anesthetic for ECT has been slow (American Psychiatric Association, 2001). This is due in part to the propensity of propofol to decrease seizure duration often below 25s (Bone et al., 1988; Dwyer et al., 1988; Rouse, 1988; Simpson et al., 1988; Rampton et al., 1989). Historically, a minimum seizure duration of 25 s was the hallmark of an adequate seizure (Fink, 1991). Numerous studies have since shown that although propofol reduces seizure duration, it does not reduce treatment efficacy (Mitchell et al., 1991; Fear et al., 1994; Malsch et al., 1994; Martensson etal., 1994). Propofol is a drug of choice in short ambulatory procedures (Pollard et al., 2003) because of its propensity for more rapid recovery compared with methohexital (Mackenzie era/., 1985), or thiopental (Henriksson etal., 1987; Mackenzie etal., 1985; Weightman and Zacharias, 1987). Thus, it may reduce the severity of cognitive deficits after ECT. Few studies have investigated this possibility (Table 4), and none have used a comprehensive neuropsychological battery in the early recovery period (within the first hour after ECT). This prospective, crossover study was designed to determine whether there is a difference between propofol and thiopental anesthesia on early cognitive recovery after right unilateral ECT. Patients received propofol or thiopental on alternating treatments. Cognitive function was assessed 45-minutes after ECT with neuropsychological tests that measured motor speed, reaction and decision speed, visuospatial and executive function, and immediate and delayed verbal memory. N.N. BUTTERFIELD 67 3.2 Methods A. ETHICS This study was approved by the UBC Clinical Research Ethics Board (certificate # C98-0214). B. PATIENTS Patients were included if they met the following inclusion criteria: scheduled to receive right unilateral ECT as the clinically indicated treatment for depression, with an American Society of Anesthesiologists' physical status of 1 or 2, aged between 18 to 75 years, right-handed, and able to provide written informed consent. Exclusion criteria were: serious or uncorrected visual impairment, ongoing substance abuse, known or family history of reactions to the study drugs, or inadequate proficiency with English. C. STUDY DESIGN In a prospective crossover design trial, patients received thiopental or propofol on an alternating basis throughout a course of ECT. The order of administration was randomised such that half of the patients received propofol first and the other half received thiopental first. Patients were followed for a maximum of six treatments, and a minimum of four consecutive treatments. Cognitive assessment was not performed for the first ECT as seizure threshold is determined at this time. A crossover design was chosen because of the high degree of variability between patients in type of and response to medications and response to ECT between patients in this population. 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CL-gj CN CO LO 3 ^1-o d t - +i O CM CL CO O • \ T— 0 C o CO CO c • f ^ 3 CT X CN 0 o 3 q 0 T-ro CT CT CO ro o co o E CD 2-" r o 0 -I—* ro . = CD 00 25 x ro = 1 c ro CD a3 - i ^ Q ^CO . +1 -*—< x: c co ro 0 E CO ro or LU CO _ E ro x 0 CO 3 2 CO o 0 -f—' CO CO CD iS ro 0 O E co • 0 'E w ~ o 2 Q N.N. BUTTERFIELD 69 D. ANESTHETIC DETAILS An anesthesiologist administered thiopental or propofol intravenously as needed, followed by succinylcholine (0.5-1.0 mg/kg i.v.) for muscle relaxation. Anesthesiologists were advised, before each treatment, to administer approximately equipotent doses of thiopental and propofol. At subsequent treatments, doses were adjusted based upon the response at the previous session. Timing was started at the end of the injection of the general anesthetic. The right arm was isolated from the effects of the succinylcholine by a tourniquet inflated after induction of anesthesia permitting evaluation of the unmodified seizure. Blood pressure, ECG, EEG, and pulse oximetry were monitored throughout the procedure. E. ECT TREATMENT DETAILS Right unilateral ECT at three times the seizure threshold was produced using a Thymatron ECT apparatus with flexidial controller (Somatics Inc., Lake Bluff, IL, U.S.A.) to deliver the electrical stimulus at a frequency of 70 Hz, a pulse width of 0.5 ms, and a current of 0.9 A. The duration of the stimulus was manipulated to determine the seizure threshold and to deliver the treatment. The other stimulus parameters were set by the manufacturer and remained constant throughout all treatments. Patients were moved to the recovery room after ECT. F. EMERGENCE Immediate recovery was defined as the time when the patient was able to respond to the command, "squeeze my hand". This was checked every minute until the patient complied. The researcher making the assessment was blinded to the anesthetic received. N.N. BUTTERFIELD 70 Psychiatric Ward ± Potential patients receive letter of intent and copy of consent form Consent obtained Day of ECT I Patients randomly assigned to either: Propofol (P) for first ECT then T, P, T, P, T for subsequent ECTs Thiopentone (T) for first ECT then: P, T, P, T, P for subsequent ECTs 1 • ECT + 1 I Begin timing for immediate recovery following administration of anaesthetic Postoperative Assessments Stop timing when patient demostrates ability to obey "squeeze my hand" (asked every minute until patient responds) Memory and attention tests administered: 45 min post-operatively Figure 8. ECT study flowchart N.N. BUTTERFIELD 71 G. NEUROPSYCHOLOGICAL ASSESSMENTS Short-term cognitive recovery was assessed 45 minutes after injection of the anesthetic in the patient's room, away from distractions. Details of the neuropsychological test battery are the same as previously described in the carotid endarterectomy study, with the following exceptions. The Rey Auditory Verbal Learning Test (RAVLT) did not include an interference list after the first three list presentations. Card Sorting was also included in the test battery. This task was adapted from Rabbitt (1965) and was used to test patients' ability to search and make decisions. A box that contained the target stimuli, either 'A' or 'B', was displayed on the screen. Each box also contained 0, 4, or 8 other distracter letters. There were three trials with 54 presentations each. All conditions were balanced between A and B. Patients were asked to press the left arrow key if there was an 'A' on the card and press the right arrow key if there was a 'B' on the card. The test battery required approximately 30 minutes to complete. H. DATA HANDLING AND STATISTICAL ANALYSIS Repeated measures analysis of variance was used to test for differences between propofol and thiopental treatments. To minimize the influence of outliers on the computer tasks, median performance scores for individual patients were used to calculate the group means. To determine the influence of seizure duration on cognitive performance, an analysis of covariance with seizure duration as a covariate was performed for each neuropsychological test. P-values less than 0.05 were considered statistically significant. All values are presented as mean ± SD where appropriate. Statistical calculations were performed using Number Cruncher Statistical Systems (NCSS) (Hintze, 2001). N.N. BUTTERFIELD 72 3.3 Results A. DEMOGRAPHICS Nineteen subjects were initially recruited into the study. Of these patients, two were excluded as a result of early discontinuation of their ECT treatment course, unrelated to the study. Two other patients who completed the study were excluded from data analysis. One was given lidocaine (a potent anticonvulsant) with the propofol treatments, causing significantly shortened seizure durations. The other patient experienced emergence delirium in two of four treatments (one with each anesthetic) was unable to perform the neuropsychological tests. The fifteen patients who completed the study and included in data analysis included eleven females and four males, aged 43 ±11 (SD) years, and weighing 75.5 ± 14.4 kg. Eleven patients completed all 6 study treatments, 2 patients completed 5 study treatments, and 3 patients completed 4 study treatments. B. ANESTHETIC DETAILS Both anesthetic agents were titrated to the anesthetic effect, with a mean dose of 1.9 ± 0.4 mg/kg propofol and 3.0 + 0.6 mg/kg thiopental. The ratio of mean doses (thiopental/propofol) was 1.6, which was the same as the published equipotency ratio of 1.6 (Grounds et al., 1986). The mean dose of succinylcholine was 0.6 ± 0.1 mg/kg for both propofol and thiopental treatments. One patient with a history of nausea and vomiting received dolasetron for every treatment (thus any potential influence on recovery was equivalent for each anesthetic). C. SEIZURE DURATION EEG seizure duration was shorter following propofol (32.8 ±15.1 s) compared to N.N. BUTTERFIELD 73 thiopental (47.2 ± 18.7 s) anesthesia, F(1,14) = 22.49, p < 0.001 (Table 5). An analysis of covariance revealed that cognitive function did not vary significantly with seizure duration on the neuropsychological tests (P > 0.05). Additional correlation analyses revealed that seizure duration accounted for less than 10% of the variance in performance on each of the neuropsychological tests. D. EMERGENCE Time to respond to the command "squeeze my hand" was significantly shorter following propofol (9.9 ± 2.8 min.) versus thiopental (12.1 ± 4.2 min.) anesthesia, F(1,14)= 11.06, P < 0.05 (Table 5). E. COGNITIVE ASSESSMENTS Significant improvement was observed on all neuropsychological tests (Finger Tapping, Simple Reaction Time, Choice Reaction Time, Card Sorting, Trail Making Test A and B, and RAVLT), except TMT B, after propofol, compared with thiopental anesthesia (Table 6). Memory performance on the RAVLT was significantly better on all 3 immediate recall trials and on the delayed recall trial following propofol anesthesia, but there was no difference in the number of errors or intrusions. Furthermore, patients showed evidence of learning (improved performance on successive word list trials), regardless of anesthetic type. N.N. BUTTERFIELD 74 Table 5. Anesthetic details and recovery profile after ECT: propofol vs. thiopental. Propofol Mean + SD Thiopental Mean ± SD Repeated Measures ANOVA F df P Anesthetic doses (mg/kg) 1.9 ±0.4 3.0 ±0.6 — — — Succinylcholine doses (mg/kg) 0.6 ±0.1 0.6 ±0.1 — — -Seizure Duration (s) 33 ± 15 49 ± 19 21.88 14 <0.01 Time of Emergence (min) 9.9 ±2.8 12.1 ±4.2 26.03 14 <0.01 N.N. BUTTERFIELD 75 Table 6. Cognitive test performance 45 minutes after ECT: propofol vs. thiopental. Task Propofol Thiopental Repeated Measures AN OVA mean + SD mean ±SD F df P Finger Tapping (ms) 203 ± 22 214 ±28 6.52 14 <0.05* Simple Reaction Time (ms)i 338 ± 48 389 ± 84 21.78 •14 <0.01* Choice Reaction Time (ms)i 569 ± 90 616 ±129 7.01 14 <0.05* Card Sorting (ms)* 836±173 875±192 5.91 14 <0.05* Trail Making Test A (s) 38 ± 17 46 ±26 7.74 14 <0.05* Trail Making Test B (s) 93 ±49 109 ±70 1.64 14 >0.05 RAVLT Trial 1 (# of words) 4.9 ± 1.7 4.1 ±1.7 6.43 14 <0.05* RA VLT Trial 2 (# of words) 7.0 ±2.1 5.7 ±2.1 10.42 14 <0.01* RA VLT Trial 3 (# of words) 8.0 ±2.6 6.7 ±2.4 7.74 14 <0.05* RAVLT20-minute Delayed Recall (# of words) 3.5 ±2.6 2.0 ±2.1 10.93 14 <0.01* ^Group means of individual patients' median performance scores. Normative data for age-matched (40-49 years) healthy adults: Simple Reaction Time (275 ± 25 ms), Choice Reaction Time (470 ± 40 ms), and Card Sorting (760 ± 50 ms) extrapolated from Uttl ef al. (2000); Trail Making Test A (30 ± 8 s) and B (64 ± 18 s), RAVLT Trial 1 (6.4 ± 1.6), Trial 2 (9.0 ± 2.0), Trial 3 (10.5 ± 2.1) and 20-minute Delayed Recall (10.0 ± 2.9) extrapolated from Spreen and Strauss (1998). As expected, these patients are impaired compared to healthy, age-matched controls. N.N. BUTTERFIELD 76 3.4 Discussion this crossover study found that the type of anesthetic agent influenced cognitive recovery in the acute post-ictal period after ECT. Both memory and non-memory cognitive deficits, assessed using a comprehensive neuropsychological battery, were reduced following ECT with propofol compared to thiopental. Propofol also resulted in more rapid emergence and shorter seizure durations. To our knowledge, this is the first study that has investigated the effects of different anesthetics on acute cognitive recovery, using a neuropsychological battery and a crossover design (Table 4). Our findings contrast with those from previous studies that investigated the effects of anesthetic type on cognitive recovery. Three of these studies however, used only brief and simple cognitive screening instruments. Avramov et al. (1995) showed that the rate of recovery of orientation was similar for etomidate, propofol and methohexital, using a 13-item orientation questionnaire at awakening and at 5 minute intervals until discharge. Patients' scores returned to baseline within 30 minutes, regardless of anesthetic drug, or dose. Using the same orientation questionnaire, Fredman et al. (1994) showed that return of orientation was quicker with propofol than methohexital but the difference was no longer apparent 10 minutes after awakening. Although orientation questionnaires are relatively quick to administer and score, they are intended for use as screening instruments for gross cognitive impairment. As such, they lack the sensitivity to detect more subtle cognitive deficits that may occur after general anesthesia. The information provided by these questionnaires is also quite limited after 30 minutes, when the majority of patients become oriented (Curtis ef al., 1991). In the third study, cognitive function was assessed with the Mini-mental status exam (Sakamoto et al., 1999). Performance was N.N. BUTTERFIELD 77 impaired, compared to baseline, following the lowest dose of propofol, 1 mg/kg, but not after higher doses of propofol, 1.5 or 2mg/kg, or with thiamylal, 4 mg/kg. The generalizability of this study is limited however, because sine wave stimulation was used to produce the seizure. Sine wave is known to result in greater cognitive side effects than brief pulse wave (Weiner et al., 1986a; Weiner ef al., 1986b) and continued use of this technique is considered unjustified (American Psychiatric Association, 2001). Furthermore, while the MMSE is useful for detecting gross cognitive impairment, it does not provide information about more subtle cognitive functions. A slightly more detailed assessment of cognitive function after ECT was conducted by Matters ef al. (1995). Propofol was compared to methohexital every 15-minutes (for 90 minutes) after induction using the Finger Tapping test and the Digit Symbol Substitution Test. The authors failed to find a significant effect of anesthetic type and suggested that the tests may not have been sensitive enough, although finger tapping was sensitive in this study. More importantly, their study was a between subjects design, and because of the large interpatient variability in the magnitude of cognitive side effects following ECT (American Psychiatric Association, 2001), the small number of comparisons may have obscured differences due to treatment type. The only other study that used a thorough neuropsychological battery to investigate the role of anesthetics on cognitive recovery, did not detect a significant difference between propofol and methohexital (Martensson ef al., 1994). This was also not a crossover study; and, as the authors report, a difference may not be expected with such long delays between treatment and testing (five to six hours after the fifth ECT and three days after the last ECT). Their study does however, suggest that differences due to anesthesia may only be significant in the early recovery period. N.N. BUTTERFIELD 78 This study benefits from the detailed nature of the neuropsychological assessment, and the use of a multiple crossover design. In addition to measuring immediate memory span, learning and delayed memory with the RAVLT, the neuropsychological battery included tests of motor function, simple reaction speed, simple decision speed, visuomotor and attention shifting abilities, and decision speed in the presence of distractors. These tasks have significant attention and concentration components that are essential to many aspects of cognition and are known to be impaired after ECT. The use of a multiple crossover design enabled up to three comparisons per drug per patient, greatly increasing the power of the study. Interestingly, despite other limitations, the only previous studies to pick up differences in cognitive recovery as a function of anesthetic type were in fact those that utilised a crossover design (Fredman et al., 1994; Sakamoto et al., 1999). While few studies have focussed on different anesthetics effects on cognitive recovery, many have focussed on emergence characteristics. Three have specifically compared propofol and thiopental in ECT. Villalonga et al. (1993) did not find differences in time to eye opening or return of basic orientation. Zaidi and Khan (2000) reported that the ability to obey verbal commands and to sit up unaided returned earlier in the propofol treated group. Boey and Lai (1990) reported improved ability to walk 10 metres, 20 minutes after anesthesia with propofol, but no difference in time to eye opening or time to sit up unaided. In our study, emergence (time to respond to the command "squeeze my hand") was significantly faster after propofol than after thiopental anesthesia. The variability in emergence times across different studies likely reflects differences in study design and methodology, such as the start of timing (i.e. from start of induction or end of seizure, etc.), different doses of anesthetics, and frequency of assessment (every minute versus every 30 seconds). This likely accounts N.N. BUTTERFIELD 79 for the mixed results seen in studies comparing the differences between propofol and methohexital on emergence after ECT as well (Bone ef al., 1988; Rouse, 1988; Rampton ef al., 1989). This study also found that seizure duration was shorter with propofol than with thiopental, consistent with results of previous studies (Mitchell ef al., 1991; Villalonga ef al., 1993). This raises the possibility that seizure duration may account for differences in cognitive recovery. An analysis of covariance revealed that this was not the case. In fact, seizure duration accounted for less than 10% of the variance in cognitive performance suggesting that the anesthetic agents are primarily responsible for the difference in the recovery of early cognitive function in our study. A lack of correlation between seizure duration and neuropsychological testing has been reported previously as well (Martensson etal., 1994; Sakamoto etal., 1999). This study had some limitations. First, the effect of anesthetic type on psychiatric outcome could not be measured because of the crossover design used. However, there is no evidence from previous research that propofol decreases the efficacy of ECT (Mulsant ef al., 1991; Mitchell ef al., 1992; Fear et al., 1994; Malsch ef al., 1994; Martensson et al., 1994; Kirkby ef al., 1995). Another limitation was the exclusion of patients receiving bilateral ECT, which may limit the generalizability of the results to patients receiving right unilateral ECT. The study by Fredman ef al. (1994) did however, show a faster return to orientation as a function of anesthetic type following bilateral ECT. The duration of the effects of anesthesia seen in our study is also unknown. It is possible that differences in cognitive impairment resulting from anesthetic type would no longer be evident after the first few hours of recovery, as Martensson et al. (1994) reported, though a similar study using a crossover design may best answer this question. N.N. BUTTERFIELD 80 The results of this study indicate that cognitive impairment in the early recovery period following ECT is reduced with propofol compared to thiopental anesthesia. In addition to modification of ECT parameters, propofol anesthesia should be considered to reduce cognitive impairment after ECT. Decreased impairment in the early recovery period is an advantage to both inpatients, enabling them to participate in ward activities or visit with family members shortly after treatment, and outpatients who may be safely discharged from the hospital earlier. Propofol may also beneficial to patients with preexisting neurological disease such as Alzheimer's or Parkinson's disease, who are at increased risk of developing post-ictal cognitive deficits (Figiel et al., 1991; Mulsant etal., 1991). N.N. BUTTERFIELD 81 LABORATORY STUDIES. RELATIONSHIP BETWEEN GENERAL ANESTHESIA, AGE, AND LONG-TERM COGNITIVE IMPAIRMENT IN MICE CHAPTER 4: ANIMAL STUDIES: YOUNG AND AGED MICE Contents of the following chapter appear in the following publications: Butterfield NN, Graf P, Ries CR, Macleod BA. Effect of repeated isoflurane anesthesia on spatial and psychomotor performance in young and aged mice. Anesth Analg (in press). Butterfield NN, Graf, P, Ries, CR, Federico, CA, MacLeod, BA. Effect of repeated propofol anesthesia on psychomotor learning in aged mice. Soc Neurosci Abs. 2003 Butterfield NN, Graf P, Ries CR, Federico CA, Burkat KJ, MacLeod BA. Does repeated general anesthesia impair spatial learning in old mice? Soc Neurosci Abs. 2002. Butterfield NN, Ries CR, Macleod BA. An inexpensive and accurate anesthesia system for administration of anesthetics in mice. Proc West Pharmacol Soc 44:7-8; 2001. N.N. BUTTERFIELD 82 Chapter 4: Does General Anesthesia Impair Cognitive Function in Aged Mice? 4.1 Introduction Elderly patients are at a higher risk than young patients of developing prolonged postoperative cognitive impairment (Parikh et al., 1995; Dodds et al., 1998; Moller ef al., 1998). Some studies have found as many as 25% of patients impaired one week after surgery (Dodds ef al., 1998; Moller ef al., 1998). Though various causes have been proposed for these deficits (Ritchie ef al., 1997), exposure to general anesthesia is frequently cited as a potential risk factor (Smith ef al., 1986; Parikh ef al., 1995; Jones ef al., 1996; Ancelin ef al., 2001). General anesthesia may be involved in cognitive impairment in the immediate recovery period (see chapter 2 and 3), but its contribution to prolonged impairment is unclear. Clinical studies have provided clues about the role of anesthesia. However, they are inherently limited in their ability to discriminate between the effect of anesthesia and the physiological and psychological effects of surgery, postoperative pain, fatigue, and drugs on cognition. Alternatively, animal experiments may provide a better understanding of the role anesthesia plays in POCD by allowing anesthesia to be studied independently of surgery and by permitting greater experimental control. Currently, the few studies that have explored the relationship between age, anesthesia and cognitive function in animals, have produced inconsistent results. Van der Staay ef al. (1988) showed that 2 episodes of general anesthesia with halothane and thiopental, administered on separate days, did not impair spatial working or reference memory in young (6-month) or aged rats (30-month). In contrast, Culley et al. (2003) suggested that aged rats (18-month) may experience sustained spatial learning deficits after a single episode of general anesthesia with isoflurane and nitrous oxide, and that young rats' performance might actually improve. The mixed results N.N. BUTTERFIELD 83 from these studies may stem from slight differences in the sensitivity of the behavioural task used (holeboard and 12-arm radial maze, respectively). Alternatively, it is possible that the effects of a single episode of anesthesia are too subtle to cause a substantial or consistent impairment, particularly on a well-learned task, as general anesthesia was administered after learning had stabilized in both studies. Thus, the question of whether general anesthesia itself leads to prolonged cognitive impairment in aged rodents remains unanswered. The overall aim of the following investigations was to determine whether general anesthesia alone leads to prolonged cognitive impairment in mice, and whether age is a risk factor. A spatial memory and a psychomotor task were included to determine whether the effects of general anesthesia are consistent across different cognitive domains. First, the effect of a single episode of general anesthesia, administered once during the asymptotic learning period (after learning had stabilized), on spatial memory was tested. Subsequent experiments were designed to address the possibility that deficits produced by a single anesthetic episode might be too subtle to detect. Mice were repeatedly anesthetized, 2-3 hours after every training session, with the assumption that repeated anesthesia would augment the potentially subtle effects of a single administration. It was hypothesized that repeated general anesthesia with isoflurane would impair spatial and psychomotor learning and memory, compared to controls, and that aged mice would be more susceptible to anesthetic-induced cognitive impairment than young mice. The design of the repeated anesthesia experiments also permitted exploration of whether anesthesia impairs task acquisition more than performance on a pre-learned task (asymptotic performance). N.N. BUTTERFIELD 84 4.2 METHODS AND MATERIALS A. ETHICS The following series of experiments was conducted following the approval of the University of British Columbia Animal Care Committee (Certificate #: A99-0157). B. ANIMALS Young (3-4 months) and aged (18-19 months) C57BL/6 mice were obtained from the National Institute of Aging and housed at the UBC Dept. of Pharmacology & Therapeutics Animal Care Facility. Groups of ten mice were housed in large clear plastic cages with solid floors and wood chip bedding with 12-hour dark-light cycle (lights on from 6 am to 6 pm). The mice had access to food and water ad libitum. To avoid time-consuming and unreliable methods of identifying mice (eg. ink markings on the tail or ear punching), a 12 mm transponder (AVID Identification Systems Inc.) was injected subcutaneously into each mouse, dorsolateral^ between the fore and hindlimb. Each transponder emits a unique signal containing a 9-digit code that could be read by a hand held receiver ensuring that there was no misidentification of mice throughout the experiments. The injection was performed using a 12-guage needle, 3-4 days prior to experimentation. Aseptic techniques were followed. Anesthetic is not required for injection. C. BARNES CIRCULAR MAZE The spatial learning and memory experiments were conducted using the Barnes circular maze (Barnes, 1979), adapted for mice (Fox et al., 1998) (Figure 9). The maze was constructed out of a white acrylic disc, 122 cm in diameter and 1 cm thick. The maze was elevated 54 cm off the floor on a circular pedestal. Forty holes 5 cm in diameter were cut equidistant from each other and 5 cm from the edge of the disc. For N.N. BUTTERFIELD 85 each mouse, one of these holes provided an escape route to a dark home. The home consisted of a black tray that included a white area directly under the maze hole.1 Three 500 Watt lights, arranged in a triangular formation over the maze, provided a bright light to create a low-level aversive stimulus. Spatial cues on the walls surrounding the maze included a bench with two cabinets on top, Venetian blinds covering a window, a white wall with tiles, and a divider. These cues remained constant throughout the experiments. The maze was hidden from the investigator by the divider. A video camera mounted on the ceiling directly overhead the maze recorded each session. N.N. BUTTERFIELD 86 500 W lights Experimenter behind screen Figure 9. Diagram of Barnes maze. Mice were placed in the maze one at a time. Each mouse had a designated escape hole that remained constant throughout the experiment. After placing the mouse in the centre of the maze, the experimenter stood behind a screen and watched on video as the mouse searched for the escape hole. Once the mouse entered the hole, the lights were turned off and the mouse was returned to its home cage. A maximum of 300 seconds was allowed. Mice that did not enter after this time were placed in the dark tray for 30 seconds. The background (not shown) consisted of 4 distinct walls that provided spatial cues for the mice. N.N. BUTTERFIELD 87 /. ASSESSMENT OF SPATIAL LEARNING AND REFERENCE MEMORY The Barnes maze was used as a test of spatial learning and reference memory because of its sensitivity to impaired higher level cognitive functioning, its well defined learning curve, and its reliance on a relatively low level aversive stimuli - bright light (compared to forced swimming in the water maze task or food deprivation in radial arm tasks) (Barnes, 1979; Barnes et al., 1980). Reference memory is defined as memory for information that is useful across all task sessions, in contrast to working memory where mice use learnt information later in the same session. Mice received one training session each day over 1 2 - 1 5 days. The mice were randomly assigned to different escape holes around the maze, and that assignment remained constant throughout the experiment. For each session, the mouse was placed in the centre of the maze inside a cylindrical tube. The investigator stepped outside of the testing area and lifted the cylinder with a rod, allowing the mouse to explore the arena. Once the mouse entered the escape tunnel, the lights were turned off, and the time recorded. If a mouse did not escape after 5 minutes, it was placed in the escape chamber by the investigator for 30 seconds and given a score of 300 seconds. This was done for all mice in the first session to condition them to the escape chamber. The maze was wiped with distilled water before and after each mouse. All testing was performed between 8 am and 11 am. D. ACCELERATING ROTAROD The psychomotor experiments were conducted using an accelerating rotarod (Jones et al., 1968). The rod was 3.2 cm in diameter, 60 cm long and covered with duct tape to create a non-slippery surface. It was elevated 30 cm above a plastic chamber covered with wood chip bedding. The entire apparatus was divided into five N.N. BUTTERFIELD 88 equal sections to allow 5 mice to be tested simultaneously. The rod was attached to a DC motor and accelerated from 0-40 rpm over 90 seconds by ramping the input voltage. This speed was determined from pilot studies. For example, to increase the efficiency of experiments, an initial acceleration rate of 0-40 rpm over 30s was tested, but at this speed, there was a limited learning curve, and little difference between young and aged mice. When trained.at 0-40 rpm over 90 seconds, a significant learning curve was evident and age-related performance differences became detectable. Motor control and data collection was done using MacLab 2.0. /. ASSESSMENT OF PSYCHOMOTOR LEARNING AND MEMORY The accelerating rotarod was chosen to test psychomotor learning because of its well defined learning curve and sensitivity to age and sedative-hypnotics (Forster and Lai, 1999; Smith and Stoops, 2001). On consecutive daily sessions, mice were placed on a stationary rod and acceleration was initiated. For each session, the time to fall off the rod was averaged over 5 trials, with a one minute rest break between each trial. All testing was performed between 8 am and 10 am. E. ISOFLURANE ANESTHESIA A closed system anesthetic chamber was constructed (with the help of the Departmental technician) to enable up to 10 mice to be anesthetized simultaneously (Figure 10). It was an expansion of a simpler chamber built for preliminary mouse studies (Butterfield et al., 2001 ).2 The larger chamber included a circulating fan to ensure adequate circulation of the volatile agent and exhaled gases. A cylindrical chamber was constructed of 7 mm thick clear plexiglass, and was 54 cm in length and 10 cm in internal diameter. A mesh grill elevated from the floor of the chamber allowed adequate distribution of anesthetic vapour and prevented blockage of the mouse's N.N. BUTTERFIELD 89 airway. An internal fan was used to circulate the gases, and a chamber of soda lime was used to scavenge exhaled CO2. General anesthetic procedures Anesthesia was induced and maintained within the chamber. Five to 10 mice were placed in a chamber at one time, and the chamber was flushed with 100% 0 2 until the concentration reached 95%. The 0 2 was then turned off to create a closed anesthetic system and a constant anesthetic concentration. Liquid volatile anesthetic was then injected according to a calculated volume to produce an atmospheric concentration of 1.4% (Butterfield et al., 2001). This concentration was determined in pilot trials and maintained anesthesia for all mice; as expected from previously conducted studies of anesthetic potency that indicate MAC for C57BL/6 mice to be approximately 1.3% atm. (Sonner et al., 1999). To ensure the mice were anesthetized the righting reflex was assessed every five minutes by rotating the chamber. After 30 minutes, the mice were taken out of the chamber and placed in a well-ventilated housing chamber. A warming blanket was placed underneath the chamber, and a heat lamp placed overhead provided warmth during recovery. Periodic temperature readings with an anal probe thermometer indicated that body temperature remained between 36 and 38 °C during recovery. The righting reflex, pinch reflex, and pedal reflex were used to determine recovery. N.N. BUTTERFIELD 90 Figure 10. Diagram of anesthetic chamber. Mice were placed in the chamber and 0 2 was administered at a rate of 8ml/min for 10 minutes to achieve 95% 0 2 in the chamber. The 0 2 was then turned off and isoflurane was injected. A fan was used to circulate the gases through the soda-lime (to extract CO2) and back through the chamber. The chamber was rotated every 5 minutes to assess the righting reflex. In all experiments, mice were anesthetized for 30 minutes. The concentrations of CO2, O2, and isoflurane were monitored with a Daytex-Ohmeda gas analyzer at the start and the end of anesthesia. N.N. BUTTERFIELD 91 F. PROPOFOL ANESTHESIA Each day, 2-3 hours after training on an accelerating rotarod, mice were anesthetized for approximately 30 minutes with bolus intraperitoneal injections of propofol. The initial dose required to produce a loss of righting reflex was between 300-325 mg/kg i.p.. The righting reflex was assessed every 5 minutes, and additional doses of 25 mg/kg were administered if the righting reflex returned. The control mice received a comparable volume of i.p. saline. Mice were anesthetized under a heat lamp, which resulted in mean body temperatures between 36 and 38 °C. The righting reflex, pinch reflex, and pedal reflex were used to determine recovery. G. STUDY DESIGN All experiments were conducted in a prospective, blind, randomized fashion. Experimenters responsible for either maze or rotarod testing were blinded to the treatment assignment: control or anesthesia. /. EFFECT OF ONE EPISODE OF ISOFLURANE GENERAL ANESTHESIA ON PERFORMANCE OF A PRE-LEARNED SPATIAL MEMORY TASK The first experiment was designed to investigate whether performance on a learned spatial memory task would be impaired following a single episode of anesthesia, and whether the impairment would be greater in old versus young mice. Training on the Barnes maze was conducted over 15 consecutive days, the approximate time required for performance to plateau. Two to 3 hours after the last session, half of the young mice {n = 5) and half of the old mice (n = 5) were randomly chosen to be anesthetized for 30 minutes with isoflurane. Young (n = 5) and old (n = 5) control mice received oxygen for 30 minutes. The following day, maze performance was tested as before. N.N. BUTTERFIELD 92 //. EFFECT OF REPEA TED GENERAL ANESTHESIA ON ACQUISITION AND RETENTION OF A SPATIAL REFERENCE MEMORY TASK The first experiment tested whether the ability to learn a spatial memory task was impaired by repeated isoflurane general anesthesia. A naive batch of 3-month (n = 20) and 18-month (n = 20) old female mice were each randomized to anesthesia and control groups. Mice were trained on the Barnes maze for 12 consecutive days. Three hours after each training session, mice in the anesthesia groups were anesthetized for 30 minutes with isoflurane (Figure 9). Control mice were placed in the same chamber with and administered oxygen alone, in the same manner as mice that were anesthetized. The second experiment tested the effect of repeated propofol anesthesia on maze performance. A naive batch of 3-4 month old {n = 20) and 18-month old (n = 20) female mice was used. All other aspects of the protocol remained the same. A third experiment was carried out in a group of 27-month old male mice using the isoflurane protocol. Initially, 20 mice were housed from the age of 18 months, but only 13 remained by the time they reached 27 months of age. Two mice with severe dermatitis (one with glaucoma), were killed prior to experimentation. The remaining mice were randomized to anesthesia (n = 6) and control (n = 5) groups. ///. EFFECT OF REPEATED ANESTHESIA ON ACQUISITION AND RETENTION OF A PSYCHOMOTOR TASK To further understand the effects of repeated anesthesia, and to verify if the effect were consistent across different cognitive domains, the effect of repeated general anesthesia on the ability to learn a psychomotor task was tested. Again, a naive batch of young (n = 20) and old (n = 20) female mice were randomly assigned to anesthesia and control groups. For each daily session, the time to fall off the accelerating rotarod N.N. BUTTERFIELD 93 (to a maximum of 90 seconds) was recorded and averaged over 5 trials. Mice from the anesthesia group were anesthetized for 30 minutes with isoflurane, three hours after the rotarod task (Figure 9). Control mice were placed in the same chamber with 95% oxygen. To test the effects of repeated propofol general anesthesia on rotarod performance, a naive batch of 3-4 month old (n = 20) and 18-month old {n = 20) male mice were used. Only males were available at the time of study. All other aspects of the protocol remained the same. I. DATA HANDLING AND STATISTICAL ANALYSES For experiments 1 and 2, the dependent variable was the latency to enter the escape hole. For experiment 3, the dependent variable was the latency to fall off the rotarod. Repeated measures analysis of variance (ANOVA) was used to assess the effects of sessions, treatment, and age. Wilcoxon rank sum test was used to assess the effect of anesthesia on retention in the first experiment. All differences were considered significant at P < 0.05. Statistics were performed with Number Cruncher Statistical Systems (NCSS) (Hintze, 2001). N.N. BUTTERFIELD 94 I Maze or RR 3 hrs Anes. 21 hrs Maze 3 hrs Anes. or Anterograde RR Maze or RR Day 1 Retrograde effects Day 2 Learning and Memory (Acquisition) Day 12 Stabilization (asymptote) Figure 11. Design of repeated general anesthesia experiments. Three hours after training on the Barnes maze or the accelerating rotarod (RR), mice were anesthetized. Exposure to anesthesia was initiated on the first behavioural training day and was repeated for all subsequent training sessions until asymptotic performance had been reached (in most cases 12 days or less). Anesthesia was maintained for 30 minutes with isoflurane (1.3-1.4% atm.) or propofol (300 mg/kg i.p. + 25mg/kg i.p. supplements) depending on the experiment, while controls received air or saline, respectively. i N.N. BUTTERFIELD 95 4.3 Results A. EFFECT OF A SINGLE EPISODE OF ISOFLURANE GENERAL ANESTHESIA ON RETENTION OF A PRE-LEARNED SPATIAL REFERENCE MEMORY TASK An overall analysis of sessions showed main effects for age F(1,18) = 8.61, P < 0.01 and session F(14,252) = 18.22, P < 0.001. There were no significant interactions. Following asymptotic performance, latency to find the escape hole was not significantly affected by anesthesia either in the young mice or in the old mice compared to age-matched controls (Figure 12). In fact, 4 of 5 old mice performed better after anesthesia compared to age-matched controls, although this difference was not statistically significant (Figure 12b). B. EFFECT OF REPEATED ISOFLURANE GENERAL ANESTHESIA ON ACQUISITION AND RETENTION OF A SPATIAL REFERENCE MEMORY TASK 3-month and 18-month old female mice In the experiment that compared 3-month and 18-month old mice, an overall analysis with age as a factor showed no main effect or interaction effects due to age, thus the data from the young and old mice were pooled for all subsequent analyses. Spatial memory improved over the course of the training sessions in all mice, F(10,340) = 15.79, P < 0.001 (Figure 13). There were was no main effect for treatment and no interaction effects. A regression analysis confirmed that the last 4 sessions were asymptotic, thus a separate analysis was performed on the acquisition period, sessions 2-8. During the acquisition period, there was a significant main effect for treatment F(1,204) = 7.97, P < 0.01 and session F(6,204) = 16.64, P < 0.001 and no interactions. Mice that received anesthesia found the escape hole faster than the control mice. Four aged mice were killed prior to experimentation due to severe dermatitis and N.N. BUTTERFIELD 96 scratching, known to be particularly severe in the C57BL/6 strain (Csiza and McMartin, 1976), and were not included in the analysis. 27-month old male mice In 27-month old male mice, spatial memory improved over the course of training, F(10,80) = 9.54, P < 0.001 (Figure 14). There was no main effect of treatment, F(1,8) = 0.00, P > 0.5, and no treatment x session interaction, F(10,80) = 0.47, P < 0.001, indicating that repeated general anesthesia with isoflurane did not impair spatial learning and memory compared to controls. There were significant age effects when compared to 3-month old mice, F(1,26) = 19.19, P < 0.001 and 18-month old mice, F(1,22) = 29.40, P < 0.001 (Figure14). Thus, in spite of the substantial age-related cognitive impairment in the 27-month old mice, anesthesia did not impair spatial memory performance compared to controls. One of the six mice from the anesthesia group was killed after the fourth day of training. The mouse exhibited shallow, laboured breathing near the end of anesthesia on the third training day. Although the mouse survived, normal respiratory function did not return by the following day, and exploratory activity appeared on observation to be greatly reduced. The data from the first 3 training days was excluded from analysis. C. EFFECT OF REPEATED ISOFLURANE ANESTHESIA ON ACQUISITION AND RETENTION OF A PSYCHOMOTOR TASK 3-month and 18-month old female mice Psychomotor learning improved over the course of training in all mice, F(8,272) = 13.05, P < 0.001 (Figure 15). An analysis over all sessions revealed a significant main effect for age, F(1,34) = 10.13, P < 0.01, but no significant treatment effect, age x treatment interaction, or treatment x session interaction. Analysis of the acquisition N.N. BUTTERFIELD 97 period (sessions 2-6) indicated that the rate of psychomotor learning may have been impaired by anesthesia in the old mice, F(1,64) = 8.63, P < 0.01, although maximum performance did not differ (Figure 15b). To explore the influence of the aberrantly high performance on session 3, this value was substituted with an average value of the points on either side (session 2 and session 4) before performing the repeated measures ANOVA. The result was the same (i.e. the mice in the anesthesia group still had a significantly lower score over sessions 2-6), suggesting that there may be an actual effect during the acquisition period. This effect was not observed in the young mice (Figure 15a). Two old mice from the anesthesia group were sacrificed after the first 5 days of experimentation, because of severe dermatitis and scratching, and thus were not included in the analysis. The young and old mice weighed 24.1 ± 2.0 g and 27.6 ± 1.8 g, respectively. 6-month old female mice Serendipitous results were also obtained from a group of 20 mice originally obtained for the young vs. aged psychomotor learning experiment. At the time of experimentation, it was thought that the mice were 21 months old. Upon completion of two thirds of the rotarod training sessions, it was discovered that the "aged" mice were in fact 6-months old (3-months old at the time of shipping). The National Institute on Aging Colonies had tattooed an incorrect birth date on the tails of the mice. A sample mouse that was sent to The National Institute of Aging at the end of the experiment confirmed the error. Thus, the resulting experiment was in fact a comparison of repeated anesthesia (n=10) compared to controls (n=10) in adult, 6-month old, female C57BL/6 mice (Figure 16). N.N. BUTTERFIELD 98 In these mice, psychomotor learning over the course of training was evident, but not statistically significant in either the control or the anesthetized mice. In addition, repeated general anesthesia did not impair rotarod performance, compared to controls F(1,18) = 0.02, P > 0.5. D. EFFECT OF REPEATED PROPOFOL ANESTHESIA ON ACQUISITION AND RETENTION OF A SPATIAL REFERENCE MEMORY TASK General anesthesia with propofol, repeated daily 2-3 hours after each training session, did not impair spatial learning and memory in young or old mice compared to the age matched controls (Figure 17). Spatial memory improved over the course of the training sessions in all mice (session, F(12,436)= 36.87, P < 0.001). There was a significant age effect (F(1,15)= 7.27, P < 0.05), but the treatment and age x treatment interaction effects were not significant, suggesting that repeated propofol anesthesia does not impair overall spatial memory performance. E. EFFECT OF REPEATED PROPOFOL ANESTHESIA ON ACQUISITION AND RETENTION OF A PSYCHOMOTOR TASK Propofol general anesthesia was repeated daily 2-3 hours after each training session. Despite significant age effects, performance was unimpaired following repeated propofol anesthesia in both young (treatment, F(1,18) =1.28, P=0.27) and old mice (treatment, F(1,17)= 0.09, P = 0.77), compared to controls (Figure 18). Average anesthesia time was 36.1 (SD = 8.3) min. N.N. BUTTERFIELD 99 200-2 175-o a E 1 5 ° " 8 Si 125-O +' 100-fr* 75-c = «> 50-- 1 25-a. YOUNG MICE control (n = 5) anesthesia (n = 5) r-200 -175 -150 -125 -100 -75 -50 -25 b. OLD MICE • control (n = 5) - anesthesia (n = 5) pre-treatment post-treatment pre-treatment post-treatment Figure 12 (a,b). Average time to escape the Barnes spatial maze before and after isoflurane anesthesia in 3 and 18-month old mice. Mice were anesthetized 2-3 hours after session 15 (pre-treatment) and tested 22 hours later. There was no significant difference between pre and post treatment in either young or old mice, although a trend was observed where memory in the aged anesthetized mice improved. N.N. BUTTERFIELD 100 a. YOUNG MICE b. OLD MICE 0-1 1 1 1 1 1 1 1 1 1 1 1 1—I 1 1 1 1 1 1 1 1 1 1 1 r-0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 Training Day Training Day Figure 13 (a,b). Effect of repeated isoflurane anesthesia on the time to escape the Barnes spatial maze in 3 and 18-month old mice. Day 1 represents baseline performance. Isoflurane general anesthesia, repeated daily 2-3 hours after each training session, did not impair spatial learning and memory in young or old mice compared to the age matched controls. Spatial memory improved over the course of the training sessions in all mice. As there were no significant age effects, age x treatment, or treatment x session interactions, the age groups were pooled, and the resulting analysis of the acquisition period (sessions 2-8) revealed improved performance in the anesthesia group. N.N. BUTTERFIELD 101 Training Day Figure 14. Effect of repeated isoflurane anesthesia on the time to escape the Barnes spatial maze in 27-month old male mice. Performance of the 18-month old mice depicted in figure 13b is superimposed. Day 1 represents baseline performance. Isoflurane general anesthesia, repeated daily 3 hours after each training session, did not impair spatial learning and memory in 27-month old mice compared to controls. Spatial memory improved over the course of the training sessions in all mice. There was a significant age effect when compared to 18-month (as well as 3-4 month old) mice, as well as significant session effects, indicating that despite the advanced age, the mice were still able to learn the task. There were no main treatment effects, or age x treatment, or treatment x session interactions. N.N. BUTTERFIELD 102 a. YOUNG MICE 6CH JS> 50H o E40H > «! u m § +1 30H ~' s A <4> c 20H O) c I co > 10H < b. OLD MICE -••control (n = 10) -• - anesthesia (n = 10) -O-control (n = 10) -•-anesthesia (n = 8) 3 4 5 6 7 Training Day 10 o 3 4 5 6 7 Training Day 10 Figure 15 (a,b). Effect of repeated isoflurane anesthesia on the average time (5 daily trials) to fall off an accelerating rotarod in 3 and 18-month old mice. Day 1 represents baseline performance. Isoflurane general anesthesia was repeated daily 2-3 hours after each training session. Psychomotor learning improved over the course of the training sessions in all mice. There was a significant age effect. No significant age x treatment or treatment x session interactions were detected. Repeated isoflurane anesthesia throughout the course of training did not impair psychomotor learning in young or old mice compared to the age matched controls. During the acquisition period (sessions 2-6) the rate of psychomotor learning appeared to be impaired by anesthesia, though maximum performance did not differ (Figure 15b). N.N. BUTTERFIELD 103 6-MTH ADULT MICE 6<H _ 50-(0 40 42 . o E >. ® 0 to S +1 30' 1 i E 20 1-ion anesthesia (n=10) •V-control (n=10) — i i 1 1 1 1 i i i i 0 1 2 3 4 5 6 7 8 9 10 Training Day Figure 16. Effect of repeated isoflurane anesthesia on the average time (5 daily trials) to fall off an accelerating rotarod in 6-month old mice. Day 1 represents baseline performance. Isoflurane general anesthesia was repeated daily 2-3 hours after each training session. Repeated isoflurane anesthesia did not impair psychomotor performance either during the acquisition period, or over all sessions. Anesthesia appeared to improve the rate of psychomotor learning during the acquisition period (sessions 2-6), but this was not statistically significant. N.N. BUTTERFIELD 104 a. YOUNG MICE b - 0 L D M I C E 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Training Day Training Day Figure 17. Effect of repeated propofol anesthesia on the time to escape the Barnes spatial maze in 3 and 18-month old mice. Day 1 represents baseline performance. General anesthesia, repeated daily 2-3 hours after each training session, did not impair spatial learning and memory in young or old mice compared to the age matched controls. Spatial memory improved over the course of the training sessions in all mice. As there were no significant age effects, age x treatment, or treatment x session interactions, the age groups were pooled, and the resulting analysis of the acquisition period (sessions 2-8) revealed improved performance in the anesthesia group. N.N. BUTTERFIELD 105 a. YOUNG MICE b. OLD MICE -Q-control -•-anesthesia •D-control -•-anesthesia 5CH u in g -H 30] 0' 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Figure 18 (a,b). Effect of repeated propofol anesthesia on the average time (5 daily trials) to fall off an accelerating rotarod in 3 and 18-month old mice. Day 1 represents baseline performance. Propofol general anesthesia was repeated daily 2-3 hours after each training session. Despite significant age effects, performance was unimpaired following repeated propofol anesthesia in both young and old mice, compared to controls. Training Day Training Day N.N. BUTTERFIELD 106 4.4 Discussion A single exposure to general anesthesia did not impair spatial memory performance in young or old mice after learning had stabilized. General anesthesia repeated daily throughout behavioural training did not impair spatial or psychomotor learning and memory in mice young (3-month old), adult (6-month old), old (18-month old) or very old (27-month old) mice. During task acquisition, repeated general anesthesia appeared to facilitate spatial memory acquisition in the young and the 18-month old mice, but this effect was not observed in any of the psychomotor experiments. These results indicate that exposure to general anesthesia does not pose a risk of increased cognitive impairment in young or old mice. The absence of cognitive impairment on a pre-learned task following a single administration of general anesthesia is consistent with a similar study by van der Staay et al. (1988) but contrasts with the study by Culley ef al. (2003). Van der Staay ef al. (1988) tested the effects of general anesthesia on spatial working and reference memory in young (6-month) and old (30-month) rats, using a holeboard discrimination task. Working memory was defined as memory for the baited holes which had already been visited within a given trial. Reference memory was defined as memory for the holes that never contained food across different trials (i.e. the rats should avoid these holes if they remembered them). Clear age-related deficits in working and reference memory were found. In both memory tasks, asymptotic performance of the senescent rats was significantly worse than the young rats, although the rate of acquisition did not differ between the two age groups (in the working memory task). After performance had stabilized (after 22 days), the rats were anesthetized with halothane for 60 minutes. Behavioural testing resumed 24 hours later and continued for 5 days, without N.N. BUTTERFIELD 107 showing any impairment on spatial working or reference memory. The rats were subsequently anesthetized with thiopental, 25 mg/kg i.v.. Again, testing resumed 24 later and continued for 4 more days with no significant impairment observed. In contrast, Culley et al. (2003) reported that the detrimental effects of a single anesthetic administration may persist beyond 24 hours in aged rats. Young adult (6-month) and aged (18-month) rats were trained on a 12-arm radial maze task. The rats were trained until learning had stabilized to a standardized performance criteria, and subsequently anesthetized for 2 hours with 1.2% isoflurane in 70% nitrous oxide and 30% oxygen. The control group only inhaled air:oxygen for 2 hours. After a 24-hour recovery period, rats were re-tested over 6 consecutive days during the first and third weeks after anesthesia (or air). It was found that aged rats required 75% more training trials to meet the standardized performance criteria than the young adult rats and took longer to complete the 30-second and 2-hour delay trials. Although the performance of aged rats did not deteriorate from baseline for up to 3 weeks following anesthesia, it was still slower than that of young adult anesthetized rats. Furthermore, no significant improvement in performance was seen in the anesthetized aged rats during the first or third weeks after anesthesia. Specifically, in the third postanesthetic week, aged rats that received anesthesia took longer to complete the maze than aged rats that did not, suggesting that general anesthesia may have lasting effects on the aged brain. In short, anesthesia appeared to attenuate further improvement in performance in the aged mice compared to age-matched controls. The conflicting results may stem from differences in the sensitivity of behavioural task used in these studies; however, it is more likely that the effects of a single anesthetic are subtle, and large sample sizes are necessary to verify whether a single episode of anesthesia causes prolonged impairment in aged rodents. N.N. BUTTERFIELD 108 If the effects of a single anesthetic on spatial cognition are subtle, particularly after a task is already learned, we would expect that repeated general anesthesia will exaggerate the effects. After anesthetizing mice daily, 3 hours after each training session on the Barnes maze, there was no overall impairment in spatial reference memory performance in young, old mice or very old mice. In fact, anesthesia enhanced learning, compared to controls, during the acquisition period in the 3-month and 18-month old mice. This finding was unexpected, but has been reported before in young mice (Komatsu et al., 1998) and rats (Culley et al., 2003). One possible explanation for this effect may be that anesthesia enhances memory consolidation. Memory consolidation appears to peak around 2-3 hours after behavioural training, although some suggest that it is for this very reason that anesthetics administered in this period would actually cause cognitive impairment. Another possibility is that anesthesia decreases retroactive interference. Retroactive interference refers to the ability of a cognitive task to interfere with learning of earlier tasks (McGeoch, 1952). This is unlikely however, since there were no cognitively challenging tasks performed by the mice after the maze training. In any case, this result casts doubt on the assumption that general anesthesia impairs higher level cognitive functioning. This thesis study also found that overall psychomotor learning was not impaired by repeated general anesthesia with either isoflurane or propofol in young or old mice. This result is consistent with those obtained with the Barnes maze. In contrast to the maze experiments however, isoflurane anesthesia decreased rotarod performance in the 18-month old mice during the acquisition period. Although statistically significant, the result is strongly influenced by the unusually high rotarod performance on session 3 (Figure 15b), and was not observed in the propofol experiment (Figure 17b). The result of the serendipitous experiment in 6-month old mice further suggests that general N.N. BUTTERFIELD 109 anesthesia does not cause long-term cognitive impairment. Only one other study has previously investigated the relationship between repeated general anesthesia and cognitive impairment in aged rodents, in which the authors suggest that repeated general anesthesia is a biological factor that affects cognitive ageing (Blokland et al., 2001). In their study, rats 6 months of age were trained on a choice reaction time task, anesthetized for 2-3 hours (pentobarbital 20mg/kg i.p.), and tested two days later. This was repeated every 2 months until the age of 23.5 months. Although no significant impairment on motor time was detected, there was a decrease in mean reaction time and an increase in error rate in anesthetized rats at the last two test sessions, 23.5 and 26 months of age. Although their study design was very different from those conducted for this dissertation, it is not likely to account for the different conclusions reached. There are several caveats that limit interpretation of their results. Most importantly, control rats were not handled the same as treated rats. They did not receive sham injections, which is an important factor that can influence behaviour, particularly considering the very subtle differences observed in their study. Furthermore, the rats were not anesthetized prior to the last test session; therefore, the difference in behaviour observed in the last test session may be unrelated to anesthesia. Finally, a critical alpha value of 0.1 was chosen for statistical significance, indicating that the effects are small. In addition to the primary questions, the design of the repeated anesthesia experiments permits exploration of anterograde and retrograde effects of anesthesia. Anterograde amnesia is defined as impairment in the ability to acquire new information following a particular intervention. Retrograde amnesia is defined as impairment in the ability to retain or recall previously acquired information. Retrograde effects are stronger in the repeated anesthesia studies since anesthesia is produced 2-3 hours N.N. BUTTERFIELD 110 after each training session. The anterograde effects are considerably weaker since each testing session occurred 21-22 hours after anesthesia, allowing sufficient time for the anesthetic to be eliminated, and some have shown that behavioural training within 2 hours of anesthesia can cause anterograde amnesia, but not if training is delayed for 4 hours (Rosman et al., 1992). In the rotarod experiment, the psychomotor deficit produced by isoflurane anesthesia during task acquisition in the 18-month old mice, if it is a true effect, might be attributed to the retrograde amnestic effect of general anesthesia. My studies had some limitations and room for improvement. First, although the 18-month old mice used in the single anesthesia and rotarod experiments were impaired relative to the young mice, two batches of 18-month old mice used in the repeated anesthesia maze experiments did not demonstrate age-related impairment. One of the arguments supporting the hypothesis of increased risk of cognitive impairment in aged animals following anesthesia rests on the assumption that the aged brain is already impaired (Barnes, 1998). It is possible that this batch exhibited 'healthy aging' and that mice at more extremes of age may exhibit performance deficits following anesthesia. Thus far, there is no evidence for this, as the experiment with 27-month old mice and the previous study by van der Staay et al. (1988) with 30-month old rats both found significant age-related impairment, but no anesthetic related impairment in spatial memory. Second, general anesthesia was induced and maintained with a single inhalational agent, either isoflurane or propofol. Clinically, general anesthesia is commonly induced and maintained with a multitude of agents including induction agents, such as propofol or thiopental, nitrous oxide during maintenance, various opioids and benzodiazepines, as well as anticholinergic and antimuscarinic drugs. All N.N. BUTTERFIELD 111 of these may contribute to cognitive impairment, and the impact of combinations may be more significant than the drugs used in isolation. A caveat, which is a strength more than a limitation, was the use of equivalent doses of isoflurane in both the 3-month old and the 18-month old mice. The minimum alveoiar concentration requirements of inhalational anesthetics are reduced by approximately 17% in both elderly humans (Stevens etal., 1975) and aged rats (Loss, Jr. et al., 1989), suggesting that the dose of anesthetic was actually higher for the aged mice in our study. This would theoretically increase the chance of producing impairment. The dose was reduced to 1.2-1.3% atm. in the 27-month old mice. The main finding from these laboratory investigations is that general anesthesia does not contribute to long-term cognitive impairment in aged mice, even when mice were repeatedly anesthetized over 2 weeks. The consistency of results across all experimental conditions underscores the strength of this finding. In other words, regardless of the anesthetic agent used (propofol or isoflurane), regardless of the age cohort studied, and regardless of the cognitive task employed, general anesthesia did cause long-term cognitive impairment in mice. The fact that anesthesia may have even facilitated learning in some spatial memory tasks provides additional evidence against the role of anesthesia alone in causing long-term cognitive impairment. Taken together, these results suggest that anesthesia itself may not contribute to impairment in higher level cognitive function in the elderly surgical patient. 1 Some studies suggest that a chamber or pipe be used as an escape home for the mouse. Both were tried with limited success. A surgical tray painted black (except for the section directly underneath the hole) was finally tried and used in these experiments, as suggested by Dr. Gerard B. Fox (2001, personal communication). N.N. BUTTERFIELD 112 2 A CLOSED SYSTEM ANESTHETIC CHAMBER FOR MICE INTRODUCTION Specialised anesthesia systems for rodents have been described, as commercially available anesthesia equipment is generally not designed for small rodents. However, these semi-open and semi-closed systems are elaborate in their construction (Smith et al., 1973; Norris and Miles, 1982) require expensive anesthetic vaporisers (Smith et al., 1973; Norris et al., 1982; Ventrone et al., 1982) and cause pollution from excess anesthetic delivery (Ventrone et al., 1982). Closed systems that do not require an anesthetic vaporiser have also previously been reported, but gas monitors have not been used to study their efficiency. For example, Mulder and Brown (1972) designed a closed chamber with an internal fan to circulate exhaled air over C 0 2 absorbent. Their mechanical method of air mixing was later modified to a manual pump; however, this simplification necessitated a separate induction chamber (Mulder and Hauser, 1984). As the development of these chambers predated the widespread availability of respiratory and anesthetic gas monitors, sufficient oxygen levels, adequate C 0 2 absorption and precise anesthetic concentrations were not assessed. I designed and tested a simple and inexpensive closed chamber system that would allow precise control of the inspired anesthetic concentration without using a vaporiser, induction and maintenance for 30 minutes within the same closed chamber, and minimal anesthetic waste and pollution. METHODS The anesthetic chamber was assembled using a 750 ml airtight Tupperware™ container (Figure 19). Inflow and exhaust ports were cut to a diameter of 8 mm and N.N. BUTTERFIELD 113 fitted with intravenous-type three-way stopcocks (held in place by rubber stoppers) for the attachment of gas lines. The chamber was constructed as follows (from bottom to top): aluminium mesh over which soda lime (94 % calcium hydroxide, 5 % sodium hydroxide, 1 % potassium hydroxide) was distributed to absorb exhaled CO2; a second layer of aluminium mesh with a gauze pad on top to hold the liquid anesthetic; and a third layer of aluminium mesh to support the mouse and prevent direct contact with the caustic soda lime. Following approval from the ethics committee on animal care, two anesthetic concentrations were tested in two separate mouse groups. Mice were placed individually in the chamber, which was closed and flushed with 100 % 0 2 . Isoflurane (volume calculated using the Universal Gas Law (PV=nRT); Table 7) was then injected through one of the portals onto the gauze. The onset of anesthesia was defined as loss of the righting reflex, which was tested by gently rolling the mouse on its back inside the chamber. Recovery from anesthesia was defined as return of the righting reflex. RESULTS In group 1 {n - 19), the injection of 0.05 ml liquid isoflurane, calculated to give 1.3 %, resulted in a measured concentration of 1.3 ± 0.1 % (mean ± SD). The measured concentration decreased to 1.1 ± 0.1 % after 30 minutes. In group 2 (n = 15), the injection of 0.06 ml isoflurane, calculated to give 1.6 %, resulted in a measured gas concentration of 1.6 ± 0.1 %. The measured concentration decreased to 1.4 ± 0.1 % after 30 minutes. Oxygen concentrations at the start of anesthesia for Groups 1 and 2 were 95.6 ± 0.8 and 93.7 + 1.8 %, respectively; at the end of anesthesia oxygen concentrations were 91.2 ± 1.7 and 91.8 ± 1.5 %, respectively. N.N. BUTTERFIELD 114 C 0 2 concentrations at the start of anesthesia were 2.1 ± 0.5 (Group 1) and 2.3 ± 1.0 mmHg (Group 2) and increased to 2.5 ± 0.5 (Group 1) and 2.5 ± 0.5 mmHg (Group 2) after 30 minutes, suggesting that CO2 did not accumulate. The temperature in the chamber did not change throughout the course of anesthesia. All animals recovered within 3-4 minutes. DISCUSSION This inexpensive, closed chamber system allowed the successful induction and maintenance of anesthesia with isoflurane for up to 30 minutes in mice. The well-described advantages of a closed system, including decreased anesthetic waste and pollution, decreased costs, hydration of the inhaled gases and conservation of body heat, were confirmed. This system allowed precise and accurate control of anesthesia and prevented the limitations of closed chamber anesthesia systems including anoxia and C 0 2 build-up. Precise determination of the amount of liquid anesthetic needed to induce and maintain anesthesia, using gas law principles, allowed us to minimise anesthetic waste and pollution. Volumes of isoflurane as little as 0.05 ml were needed to maintain anesthesia at MAC levels (1.3 %) for up to 30 minutes per mouse. In contrast, vaporisers require continuous gas flow to maintain precise and accurate anesthetic concentrations, which produces greater waste. Flushing the chamber with 100% O2 provided a well-oxygenated environment throughout the duration of anesthesia. C 0 2 build-up was insignificant after 30 minutes of anesthesia, suggesting that a mouse's respiration is sufficient to circulate the gas past the soda lime granules in a chamber this size. Without absorbent, CO2 levels may rise up to 60 mmHg after 30 minutes (unpublished observations). N.N. BUTTERFIELD 115 Although a gas analyser was used to validate the concentration of anesthesia and verify low concentration of atmospheric CO2, is not essential for laboratories that do not have access to one. An ethyl violet dye is activated once the soda lime granules are saturated with C 0 2 . This provides a simple indicator of when C 0 2 will begin to accumulate in the chamber. We confirmed that C 0 2 levels were acceptable while the soda lime granules remained white. Investigators using this technique should be aware that the granules may turn white in ultraviolet light, even when saturated. This easily constructed anesthetic chamber provides an economical, environmental and simple answer for laboratories that require anesthesia for the study of anesthetic agents and to provide safe anesthesia for short surgical procedures. Aluminium; Mesh 0 0 0 0 0 0 0 0 0 0 0 / Rubber Stoppe r .3-way Stop-cock Gauze Pad Soda Lime Granules Figure 19. Anesthetic chamber for a single mouse. The concentration of isoflurane, 0 2 and CO2 was sampled at the start and end of anesthesia (30 minutes) using a Datex Ohmeda gas analyser (200 ml/min sampling rate). The sample gas outflow was recirculated into the chamber. N.N. BUTTERFIELD 116 Table 7. Method of calculating the volume of isoflurane required for closed chamber anesthesia Isoflurane m.w. = 184.5 g/mol Specific gravity =1.5 g/ml Barometric pressure = 760 mmHg Room Temperature = 62 Kelvin To obtain the desired concentration in the chamber with a specific quantity of anaesthetic, use the Universal Gas Law (Barker and Tremper, 1992). PV=nRT P = partial pressure; V= volume of chamber; n = moles of isoflurane; R = rate constant; T = temperature in Kelvins Step 1. Determine the partial pressure needed for the desired concentration:Pp (Partial pressure) = desired concentration x Barometric (Atmospheric) pressure To obtain a concentration 1.3% isoflurane ... Pp = 0.013 (760 mmHg) Pp = 15.2 mmHg Step 2. Determine the moles isoflurane necessary to obtain the Pp(9.88 mmHg)(0.75L) = n(62)(298K) n = 0.0004 moles Step 3. Determine the weight of Isoflurane neededO.0004 mol x 184.5 g/mol = 0.07 g of Isoflurane Step 4. Calculate a volume of liquid anesthetic needed to inject into the chamber 0.07g /1 5g/ml = 0.05 ml of isoflurane N.N. BUTTERFIELD 117 CHAPTER 5: GENERAL DISCUSSION N.N. BUTTERFIELD 118 Chapter 5. General Discussion The goal of this thesis was to investigate the relationship between postoperative/postanesthetic cognitive impairment in high-risk groups. Because of the complex nature of this topic, this work focused on two specific aspects of postoperative cognitive impairment. The clinical component included two trials that investigated whether anesthetics with rapid elimination properties would improve early cognitive recovery in high-risk patients who would receive substantial benefit from rapid recovery. Accordingly, we tested whether propofol would reduce the cognitive impairment compared to thiopental, after ECT. We also tested whether desflurane would reduce cognitive impairment compared to isoflurane in elderly patients after carotid endarterectomy. The laboratory component included behavioural studies in young and aged mice to help understand whether anesthesia itself has a role in precipitating prolonged cognitive deficits, and age increases the risk of long-term postanesthetic impairment, if it indeed exists. The animal studies assessed cognitive function approximately 24 hours after anesthesia, over approximately 2 weeks (in the repeated anesthesia experiments). The main questions addressed in this thesis were: 1. What is the relationship between the pharmacokinetic properties of the general anesthetics and short-term cognitive impairment in high-risk patient populations? a. Does the type of inhalational general anesthetic used influence short-term cognitive recovery in a high-risk patient population—elderly vascular patients undergoing carotid endarterectomy? b. Does the type of intravenous general anesthetic used influence short-N.N. BUTTERFIELD 119 term cognitive recovery in a high-risk patient population—depressed patients receiving electroconvulsive therapy? 2. What is the relationship between anesthesia, aging, and long-term postanesthetic cognitive impairment in mice? a. Does a single episode of isoflurane general anesthesia lead to a long-term impairment in a prelearned spatial memory task and is the effect greater in aged mice? b. Does repeated general anesthesia, with isoflurane or propofol, impair spatial learning and memory, and is the effect greater in aged mice? c. Does repeated general anesthesia, with isoflurane or propofol, impair psychomotor learning and memory, and is the effect greater in aged mice? A. SUMMARY OF FINDINGS AND CONTRIBUTIONS OF THE CLINICAL STUDIES The first component of this thesis focussed on patients considered to be at high risk of developing postoperative cognitive impairment who would particularly benefit from early cognitive recovery. Carotid endarterectomy patients were identified based on their preoperative risk factors, including advanced age, presence of cerebrovascular disease, in many cases preexisting cognitive impairment, intraoperative risk factors, such as transient carotid artery occlusion and potential embolic events (Wilke et al., 1996). Quick recovery to enable early neurologic assessment is an important requirement in these patients (Wilke etal., 1996; Jenkins etal., 1987). The main finding from the carotid endarterectomy study was that there was no overall difference between desflurane and isoflurane in cognitive recovery within the first 24 hours following carotid endarterectomy. There was no significant difference in N.N. BUTTERFIELD 120 emergence time or short-term cognitive recovery (15 minutes or four hours postoperatively) between each anesthetic. Four hours after anesthesia, patients from both groups were impaired on the Simple and Choice Reaction tasks and on the delayed recall trial of the RAVLT, but not on the Finger Tapping or the Trail Making Test. The following day prior to discharge (~24 hours), performance on all the neuropsychological tasks returned to baseline in both groups, with the exception of RAVLT delayed recall in the isoflurane group and choice reaction task in the desflurane group, both of which remained significantly impaired compared to baseline. This suggests that the despite the differences in elimination kinetics in young healthy individuals, the combination of age, cerebrovascular disease, and preexisting cognitive impairment as well as other comorbidities such as decreased pulmonary function, and hypertension "overshadow" these potential benefits. ECT patients were identified based on the presence of depression, pre-existing cognitive impairment (often secondary to the depression), as well as the known cognitive impairment induced by the treatment itself (American Psychiatric Association, 2001). The most important side effect limiting the use of electroconvulsive therapy is the cognitive side effects. Frequent postictal cognitive impairment can be distressing to family members. Furthermore, cognitive impairment can increase the risk of patients having accidents and can delay patient discharge from the recovery room. Finally, severe cognitive impairment that occurs frequently after ECT may necessitate discontinuation of this important treatment for depression. The main finding from the electroconvulsive study was that, compared to thiopental, propofol results in decreased cognitive impairment shortly after ECT in clinically depressed patients. Few studies have assessed the influence of anesthesia on cognitive impairment following ECT (Table 4.), and they have generally concluded N.N. BUTTERFIELD 121 that the type of anesthetic does not significantly contribute to post-ictal recovery. This study is the first to show that the choice of anesthetic influences cognitive recovery. This was also the first study to use of a battery of sensitive neuropsychological tests in the early postictal period. Previous studies used simple orientation questionnaires that indicated nearly 100% recovery within 30 minutes (Fredman et al., 1994; Avramov et al., 1995). This study also benefited from the multiple crossover design. There were multiple assessments per patient during consecutive ECTs (three with each anesthetic). Since there is high interpatient variability in postictal cognitive impairment in ECT patients, which could mask differences between anesthetics, the multiple within patient assessments helps reduce the impact of this variability on the cognitive outcome measures. A strength of both of the clinical studies in this thesis was the choice of psychometric tests. Jones (1989) and Zuurmond et al. (1989) pointed out that many of the tests used in assessing postoperative cognitive dysfunction are not standardized, and target much too broad a range of cognitive functions, from low level sensory perceptual processes to high level knowledge and semantic memory retrieval processes. Use of such a wide range of tests, particularly when test selection is not guided within a framework or theory of cognition, makes it difficult to interpret the specific cognitive processes that may be impaired by anesthesia. Furthermore, cognitive tests frequently used in the anesthetic literature were designed as diagnostic tools in neurologic patients rather than to evaluate the more subtle effects of drugs on cognitive impairment (Dijkstra, 1997). With these considerations in mind, the tests selected for my clinical research studies were standardized tests that focussed on core or fundamental functions essential for perception and cognition. They were based on known sensitivity to speed N.N. BUTTERFIELD 122 of processing, established sensitivity to CNS drugs, and sensitivity to age-related cognitive impairment. Slowed processing speed has been theorized to account for many of the deficits in high level cognitive processes in the elderly (Salthouse, 1996), as well as those with clinical depression (Nebes et al., 1992; Flint et al., 1993). Furthermore, tests of speed of processing have been amongst the most sensitive and reliable tests used in psychopharmacology and anesthesia studies (Zuurmond et al., 1989; Dijkstra, 1997). Taken together, the clinical studies support existing evidence that general anesthesia can impair cognitive function shortly after emergence. However, the use of the more rapidly eliminated anesthetic agents, does not automatically translate into more rapid postoperative cognitive recovery. Although the short-acting anesthetic propofol reduced cognitive impairment in ECT patients, desflurane, another short-acting anesthetic, did not produce more rapid cognitive recovery in carotid endarterectomy patients. Factors other than the choice of inhalational agent may have had a greater influence on the speed of cognitive recovery in my study (such as age and cardiovascular and cerebrovascular diseases). However, faster emergence with desflurane (compared to isoflurane) has been shown in carotid endarterectomy cases of longer duration (Umbrain ef al., 2000). Even a desflurane based general anesthesia may be improved with the use of short-acting opioids such as remifentanil (Wilhelm ef al., 2001). Therefore, it is suggested that anesthetics with faster recovery profiles should still be used when a potential benefit has been identified, as is the case in carotid patients. B. SUMMARY OF FINDINGS AND CONTRIBUTIONS OF THE ANIMAL STUDIES The animal studies presented in Chapter 4 were designed to address the role of N.N. BUTTERFIELD 123 general anesthesia in precipitating long-term cognitive dysfunction, of which advanced age is an important risk factor, while at the same time avoiding the limitation of clinical research. C57BL/6 mice were chosen because of the wealth of literature on this species and because of their well-defined ability to learn both spatial memory (Fox et al., 1998; Fox et al., 1999) and psychomotor tasks (Forster et al., 1999). Isoflurane and propofol were studied because they are commonly used inhalational and parenteral anesthetics, respectively. The mouse studies showed that general anesthesia does not to lead to prolonged spatial memory or psychomotor impairment in aged mice. Interestingly, isoflurane and propofol anesthesia appeared to improve spatial memory acquisition in both young and aged (18-month old) mice, although this trend was not significant and was not observed in the 27-month old mice, or in the propofol rotarod experiments. Improved spatial memory following anesthesia has been observed in young rodents (Komatsu et al., 1998; Culley et al., 2003). Although the mechanism for this is not completely understood enhanced memory consolidation by anesthesia has been suggested (Komatsu et al., 1998). Unspecified effects on other aspects of memory, such as gene expression, protein synthesis, or structural changes to the neurons has also been suggested (Culley et al., 2003). One of the strengths of the animal studies was the choice of the Barnes maze to test spatial memory, a technique not previously reported in the anesthesia literature. Behavioural paradigms that rely on hunger to motivate behaviour, including delayed matching to sample, radial arm maze, T-maze, Skinner's box and the elevated plus maze, may be negatively influenced by an effect of anesthetics on food consumption (Flecknell and Liles, 1991). For example, rats anesthetized with halothane, have been shown to consume significantly less food than control rats (Flecknell et al., 1991; Liles N.N. BUTTERFIELD 124 and Flecknell, 1992). If anesthesia reduces food intake, performance on tasks that require hunger to motivate behaviour may suffer. Although this effect may be specific to halothane, behavioural tasks that do not require hunger as a motivating factor may be better suited for testing postanesthetic cognitive function. Another strength of the animal experiments was repeatedly anesthetizing mice throughout behavioural training. This is the first series of experiments that has initiated repeated anesthesia at 24-hour intervals throughout training in aged animals. This design has a number of advantages over studies that have included only a single anesthetic episode. For instance, the effect of a single episode of anesthesia may be difficult to detect early in the training period because of the high degree of variability in performance (even in laboratory animals that are supposedly genetically uniform). Alternatively, the effect of a single anesthetic may be too subtle to cause a consistent impairment in the plateau or asymptotic portion of the learning curve, possibly resulting in conflicting literature (van der Staay et al., 1988; Culley et al., 2003). Determining an optimal time to administer an anesthetic might circumvent these issues, but that would be difficult. If anesthesia does indeed cause prolonged cognitive impairment, it is reasonable to assume that multiple administrations would increase the chance of detecting an impairment. Multiple administrations of anesthesia spread over the lifespan have been implicated in increasing cognitive impairment in both aged humans (Houx and Jolles, 1993) and rats (Blokland et al., 2001). C. AREAS FOR FUTURE CLINICAL RESEARCH Clinically, there are endless combinations of anesthetics that can be administered. The choice of agent(s) is based on availability, as well as on the appropriateness for the patients. Accordingly, more studies should be conducted in patients that may N.N. BUTTERFIELD 125 specifically benefit from more rapid cognitive recovery. Long-term cognitive impairment does appear to exist, but a causal relationship with general anesthesia remains unclear. Some authors have concluded that there are many other factors likely to influence long-term cognitive impairment, independently of anesthesia (Ritchie et al., 1997; Dijkstra et al., 1999). Future research should concentrate on non-anesthetic influences on long-term postoperative cognitive function, such as progression of previously undetected mild cognitive impairment. For instance, the authors of a recent study on vascular dementia suggest that many of the patients that suffered long-term postoperative cognitive impairment in the ISPOCD study may have had undetected vascular dementia (Roman, 2002). Better methods of detecting mild cognitive impairment in elderly patients may indeed show that postoperative cognitive impairment represents a continuing decline in cognitive function, rather than a specific change because of surgery and anesthesia. D. AREAS FOR FUTURE LABORATORY RESEARCH Duration of anesthesia may be important in determining the extent of cognitive impairment (Moller et al., 1998). Though it is difficult to make conclusions about longer duration of anesthesia in humans, particularly since longer durations of anesthesia generally follow from longer durations of surgery, this would be amenable to laboratory studies. For example, is the effect of a 2-hour anesthetic the same as an 8-hour anesthetic? Is the effect of one 8-hour anesthetic equivalent to eight consecutive 1-hour anesthetics? Differences in durations of anesthesia exist across different studies, but the results are mixed, and a systematic study would be useful. More studies should be conducted with rodents close to the 50% survivability age, which is when a rodent can truly be considered old (Walford, 1976). For the N.N. BUTTERFIELD 126 C57BL/6 mouse, this is near 24 months of age (Walford, 1976). Unfortunately, at this age, mice become extremely expensive, and as indicated, 50% will die of natural causes, which occurred with the animals used in this thesis work. Although these limitations make experimentation less practical in these old mice, they may be a more suitable for studying the relationship between age-related impairments and general anesthesia. A separation of good learners and poor learners may parallel the effects of normal and cognitively impaired humans, whereby increased postoperative cognitive impairment is seen in the cognitively impaired individuals. Such an attempt was made by Valzelli et al. (1988), who compare the effects of various anesthetic agents on memory and exploration in CD-1 mice aged 5-7 weeks, though results were mixed. Mice were trained in a classic shuttle box until learning had stabilized. After a 9-day interval, mice were administered one of several anesthetic agents (chloroform, pentobarbital, choral hydrate, and ketamine) 2.5 hours prior to the first retention testing. Retention testing continued for 4 more days. Pentobarbital and chloral hydrate treated mice showed impairment on the fourth and fifth day only, while chloroform treated mice showed impairment on the first and second day only. The only agent used clinically (in special circumstances), ketamine, did not cause significant impairment. CD-1 mice in general are not strong learners however, which might have accounted for the variability observed. Administering anesthetics to animals that have been developed to model cerebrovascular or cardiovascular disease may help researchers understand the relationship between these diseases, general anesthesia and cognitive impairment. Furthermore, a wider range of experiments that systematically control for a surgical N.N. BUTTERFIELD 127 insult compared to anesthesia alone may help elucidate the impact of the surgical stress response. Finally, a fundamental issue that remains unresolved is the discrepancy between studies that suggest anesthetics may be neuroprotective (Jevtovic-Todorovic et al., 1997; Sarraf-Yazdi et al., 1998; Ito ef al., 1999; Mantz, 1999; Yano ef al., 2000; Jevtovic-Todorovic ef al., 2001b; Ergun ef al., 2002; Bickler ef al., 2003), and those studies that suggest anesthetics are neurotoxic (Spahr-Schopfer ef al., 2000; Jevtovic-Todorovic ef al., 2001a; Jevtovic-Todorovic ef al., 2003). Most studies that have found neurotoxic effects were conducted in very young rodents (Olney ef al., 2002; Jevtovic-Todorovic ef al., 2003), in which there is rapid neurogeneration and synaptogenesis (Jevtovic-Todorovic ef al., 2003). Recent work however, has shown that neurotoxicity from nitrous oxide and ketamine is in fact more severe in aged than young rats (Beals ef al., 2003). Future research should continue to attempt to consolidate these discrepancies. N.N. BUTTERFIELD 128 Appendix I: Related research The influence of choice of anesthetic on ictal EEG A. INTRODUCTION Traditionally, seizure duration was used as a measure of adequate electroconvulsive therapy (ECT) treatment, but lack of supporting evidence has led to the search for alternative markers. The ictal electroencephalogram (EEG) has been widely accepted as a marker of ECT efficacy (American Psychiatric Association, 2001). Its clinical utility, however, requires an understanding of the variance imposed by treatment-related parameters. Although anesthetic choice is known to influence the seizure duration, the effect on ictal EEG configuration is not well understood. Previously, comparison between propofol and methohexital found no difference in postictal suppression index or mean integrated amplitude, despite significant differences in seizure duration (Geretsegger ef al., 1998). In contrast, ketamine has been shown to increase mid-ictal slow-wave amplitude compared to methohexital (Krystal ef al., 2003). B. METHODS We recently reported a crossover-design clinical trial in which short-term cognitive recovery was improved following right unilateral electroconvulsive therapy (ECT) with propofol versus thiopental anesthesia (Butterfield et al., 2003). ECT was administered at three times above threshold (using a Thymatron; Somatics Inc., Lake Bluff, IL apparatus). Fifty-four ictal EEG traces were available from 11 patients (27 per anesthetic). Although not planned in the original protocol, a psychiatrist manually rated each ictal EEG based on five previously reported criteria (Nobler ef al., 1993; Krystal ef N.N. BUTTERFIELD 129 al., 1998). The rater was blinded to all patient and treatment information. C. RESULTS Compared to thiopental, treatments with propofol consistently resulted in ictal EEGs with a significantly shorter slow wave phase (18.2 ±11.9 vs. 36.4 ± 16.2 seconds*), reduced peak slow wave amplitude (9.2 ± 4.0 vs. 12.8 ± 4.7 mm*), and reduced global seizure patterning or stereotypy (3.0 ± 1.5 vs. 4.4 ± 1.5, 7-point Likert scale*). The effect of anesthetic type on the time to onset of the slow wave phase and on postictal suppression was inconsistent. Propofol reduced slow-wave onset time in 45% of the patients, and increased onset in the 36%. Propofol reduced the degree of postictal suppression in 45% of patients while increasing suppression in 18%. Seizure duration was shorter with propofol treatments (33 ± 15 vs. 49 ± 19 seconds*). *Mean ± SD, P < 0.05, repeated measures ANOVA. D. DISCUSSION Our results suggest that propofol may not only influence seizure duration, but also ictal EEG configuration. We believe this has potential implications for the interpretation of EEG quality measures with propofol anesthesia and requires further prospective studies which include measures of clinical outcome. In the meantime, we would like to suggest that methods used to evaluate the quality of the EEG should take into account the choice of anesthetic used. N.N. BUTTERFIELD 131 To compare how each anaesthetic affects my ability to concentrate, pay attention and remember, I will be asked to perform a series of very simple tasks shortly after each ECT. The first task is Finger Tapping; I will be asked to tap with my index fingers, first one then the other, as fast as I can for 10 seconds. The second task is called Simple Reactions; for which I will have to stop a clock with a finger tap as fast as I can when I see a star flash onto a computer display-screen. For the third task, Trail Making, I will receive a sheet of paper with numbers on it, and I must follow the numbers by drawing a line from the first to the second, to the third etc.. The fourth task is Choice Reactions where I will be asked to differentiate between 2 letter on the computer screen. The last computer task is called Card Sorting, where I will have to decide whether a playing card that is flashed on a computer screen has the letter A or B on it. The next task is Word Memory, and for this one I will learn a series of words and then attempt to recollect them from memory after a brief moment. In many ways, these tasks are like the puzzles and mazes that are often printed in magazines and newspapers, and for this reason, they are only as challenging or as fun as I choose to make them. I will be given these tasks about 45 minutes after I have had my ECT. I will receive the same tests (different versions for some) after each of six ECT treatments. The results will help to determine whether there are any lasting effects of the anaesthetic that affect my ability to concentrate, pay attention, and remember. Exclusions I understand that I am only being asked to volunteer in this study. Thus, if I do not give written consent that I completely understand the purpose, procedure and all other aspects of this study, I will not be a participant. Not participating in this study will not affect my continued medical care in any way. I may be excluded for other reasons as well: if I am unwilling to perform the memory and attention tasks; if I have any known or possible allergies to any of the medications to be used; if I am receiving ECT for any other reason than depression; if I have uncorrected visual impairment; or if I am not fluent in the English language. Risks Thiopentone and propofol have similar properties. Thus the risks are similar, but very minimal, particularly because such a small amount is given. These minimal risks have been or will be discussed by my anaesthetist (the doctor who puts me to sleep). Both agents are standard general anaesthetics. The only difference in this study from current practice is the means of choosing which anaesthetic agent will be used. The risks of ECT have been explained to me by my psychiatrist. Benefits This study will give information about the differences in recovery that may be produced by propofol and thiopentone general anaesthetics. It is expected that an anaesthetic with less effects on memory and concentration may be better for patients receiving ECT. This information will help in the choice of anesthetic for patients receiving general anesthetics for other types of surgery as well. N.N. BUTTERFIELD 134 If I participate in the study I will be assigned by chance into one of two groups: one group will receive an isoflurane general anaesthesia while the other group will receive desflurane general anaesthesia. Both of these are standard anaesthetics. I will be given a local anaesthetic (bupivacaine, a standard hospital drug). To compare how each anaesthetic affects post-operative confusion, I will be asked to carry out a series of simple attention and memory tasks. The first task is Finger Tapping; I will be asked to tap with my index fingers, first one then the other, as fast as I can for 10 seconds. The second task is called Simple Reactions; for which I will have to stop a clock with a finger tap as fast as I can when I see a star flash onto a computer display-screen. For the third task, Trail Making, I will receive a sheet of paper with numbers on it, and I must follow the numbers by drawing a line from the first to the second, to the third etc.. The fourth task is Choice Reactions; and here I will have to decide whether a playing card that is flashed on a computer screen has the letter A or B on it. The final task is Word Memory, and for this one I will learn a series of words and then attempt to recollect them from memory after a brief moment. In many ways, these tasks are like the picture puzzles and mazes that are often printed in magazines and newspapers, and for this reason, they are only as challenging or as fun as I choose to make them. I will be given these tasks about two weeks before the day of surgery, to get baseline data. This will be done at the time of my routine visit to the pre-admission clinic in the hospital. The tests will be repeated four hours and 24 hours after the surgery. The results will help to determine whether I have any residual effects of the anaesthetic. Exclusions I will be excluded from this study if I am under 65, unable to fully understand and give written permission to participate in this study, or if I am unwilling to cooperate with the psychological testing. Risks I understand that there are no risks due to the study. The only difference from present practice is the means of choosing which general anesthetic agent will be used. Both agents are used at this hospital at this time. The risks of carotid surgery have been explained to me by my surgeon. Benefits This study will give information about the differences in recovery that may be produced by desflurane and isoflurane general anaesthetics. It is expected that earlier recovery time will lead to faster recovery and less post-operative confusion. This will help in the choice of anesthetic for older patients receiving general anesthetics for other types of surgery. Withdrawal I understand that I may withdraw from the study at anytime, and this will not in any way affect the quality of my treatment. N.N. BUTTERFIELD 136 Bibliography A task force report of the American Psychiatric Association. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging, Second ed.2001. Washington, DC: American Psychiatric Association. Alexinsky T, Chapouthier G. Halothane anaesthesia and DMS performance in rats: memory impairment or avoidance behaviour? Physiol Behav 1979;22:99-105. Ancelin ML, de Roquefeuil G, Ledesert B, Bonnel F, Cheminal JC, Ritchie K. Exposure to anaesthetic agents, cognitive functioning and depressive symptomatology in the elderly. Br J Psychiatry 2001; 178:360-366. Avramov MN, Husain MM, White PF. The comparative effects of methohexital, propofol, and etomidate for electroconvulsive therapy. Anesth Analg 1995;81:596-602. Azad SS, Bartkowski RR, Witkowski TA, Marr AT, Lessin JB, Seltzer JL. A comparison of desflurane and isoflurane in prolonged surgery. Journal of Clinical Anesthesia 1993;5:122-28. Bach ME, Barad M, Son H, Zhuo M, Lu YF, Shih R, Mansuy I et al. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci USA^ 999;96:5280-5285. Baker BR, Duckworth T, Wilkes E. Mental state and other prognostic factors in femoral fractures of the elderly. J R Coll Gen Pract 1978;28:557-59. Barker SJ, Tremper KK. Physics applied to anesthesia. In Barash PG, Cullen BF, Stoelting RK, eds. Clinical Anesthesia.1992. Philadelphia: J.B. Lippincott Company, 141-81. Barnes CA. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 1979;93:74-104. Barnes CA. Memory changes during normal aging: neurobiological correlates. In Martinez J, Kesner R, eds. Neurobiology of learning and memory. 1998. San Diego: Academic Press, 247-87. Barnes CA, Nadel L, Honig WK. Spatial memory deficit in senescent rats. Can J Psychol 1980;34:29-39. Bartus RT, Dean RL, Pontecorvo MJ, Flicker C. The cholinergic hypothesis: a historical overview, current perspective, and future directions. Ann N Y Acad Sci 1985;444:332-58. N.N. BUTTERFIELD 137 Beals JK, Carter LB, Jevtovic-Todorovic V. Neurotoxicity of nitrous oxide and ketamine is more severe in aged than in young rat brain. Ann N Y Acad Sci 2003;993:115-4. Beattie C. History and principles of anesthesiology. In Hardman JG, Limbird LE, Gilman AG, eds. Goodman & Gilman's The pharmacological basis of therapeutics.2001. New York: McGraw-Hill, 321-35. Beatty WW, Shavalia DA. Spatial memory in rats: time course of working memory and effect of anesthetics. Behav Neural Biol 1980;28:454-62. Beaussier M, Decorps A, Tilleul P, Megnigbeto A, Bahadur P, Lienhart A. Desflurane improves the throughput of patients in the PACU. A cost-effectiveness comparison with isoflurane. Can J Anaesth 2002;49:339-46. Bedford PD. Adverse cerebral effects of anaesthesia in old people. Lancet 1955;259-63. Bell ML. Postoperative pain management for the cognitively impaired older adult. Semin PerioperNurs 1997;6:37-41. Benke T, Neussl D, Aichner F. Neuropsychological deficits in asymptomatic carotid artery stenosis. Acta Neurol Scand 1991 ;83:378-81. Bennett JA, Lingaraju N, Horrow JC, McElrath T, Keykhah MM. Elderly patients recover more rapidly from desflurane than from isoflurane anesthesia. J Clin Anesth 1992;4:378-81. Benzel EC, Hadden TA, Nossaman BD, Lancon L, Kesterson L. Does sufantanil exacerbate marginal neurological dysfunction. J Neurosurg Anesthesiol 1990;2:50-52. Berggren D, Gustafson Y, Eriksson B, Bucht G, Hansson LI, Reiz S, Winblad B. Postoperative confusion after anesthesia in elderly patients with femoral neck fractures. Anesth Analg 1987;66:497-504. Bernstein D, Olton DS, Ingram DK, Waller SB, Reynolds MA, London ED. Radial maze performance in young and aged mice: neurochemical correlates. Pharmacol Biochem Behav 1985;22:301-7. Bickler PE, Warner DS, Stratmann G, Schuyler JA. gamma-Aminobutyric Acid-A Receptors Contribute to Isoflurane Neuroprotection in Organotypic Hippocampal Cultures. Anesth Analg 2003;97:564-71. Bigler D, Adelhoj B, Petring OU, Pederson NO, Busch P, Kalhke P. Mental function and morbidity after acute hip surgery during spinal and general anaesthesia. Anaesthesia 1985;40:672-76. Black S, Enneking FK, Cucchiara RF. Failure to awaken after general anesthesia due to cerebrovascular events. J Neurosurg Anesthesiol 1998;10:10-15. N.N. BUTTERFIELD 138 Blokland A, Honig W, Jolles J. Long-term consequences of repeated pentobarbital anaesthesia on choice reaction time performance in ageing rats. Br J Anaesth 2001;87:781-83. Boey WK, Lai FO. Comparison of propofol and thiopentone as anaesthetic agents for electroconvulsive therapy. Anaesthesia 1990;45:623-28. Boldt J , Jaun N, Kumle B, Heck M, Mund K. Economic considerations of the use of new anesthetics: a comparison of propofol, sevoflurane, desflurane, and isoflurane. Anesth Analg 1998;86:504-9. Bone ME, Wilkins CJ, Lew JK. A comparison of propofol and methohexitone as anaesthetic agents for electroconvulsive therapy. Eur J Anaesthesiol 1988;5:279-86. Boysen K, Sanchez R, Krintel JJ, Hansen M, Haar PM, Dyrberg V. Induction and recovery characteristics of propofol, thiopental and etomidate. Acta Anaesthesiologica Scandinavica 1989;33:689-92. Bruce DL, Bach MJ, Arbit J. Trace anesthetic effects on perceptual, cognitive, and motor skills. Anesthesiology 1974;40:453-58. Burker EJ, Blumenthal JA, Feldman M, Thyrum E, Mahanna E, White W, Smith LR et al. The Mini Mental State Exam as a predictor of neuropsychological functioning after cardiac surgery. Int J Psychiatry Med 1995;25:263-76. Butterfield NN, Graf P, Ries CR, Macleod BA. The effect of repeated isoflurane anesthesia on spatial and psychomotor performance in young and aged mice. Anesth Analg (in press). Butterfield NN, Graf P, Macleod BA, Ries CR, Zis AP. Propofol reduces cognitive impairment after electroconvulsive therapy. J ECT (in press). Butterfield NN, Kim EY, Schwarz, SKW, Ries CR, Franciosi LG, and Macleod BA. Comparison of isoflurane and desflurane for short ambulatory anesthesia: drug cost and recovery profiles. Anesth Analg 94[2S], S-118. 2002. Butterfield NN, Ries CR, Macleod BA. An inexpensive, calibrated closed system to induce and maintain anesthesia in mice. Proc West Pharmacol Soc 2001 ;44:7-8. Cheam EW, Dob DP, Skelly AM, Lockwood GG. The effect of nitrous oxide on the performance of psychomotor tests. A dose-response study. Anaesthesia 1995;50:764-68. Chen X, Zhao M, White PF, Li S, Tang J, Wender RH, Sloninsky A et al. The recovery of cognitive function after general anesthesia in elderly patients: a comparison of desflurane and sevoflurane. Anesth Analg 2001;93:1489-94, table. Chung F, Meier R, Lautenschlager E, Carmichael FJ, Chung A. General or spinal anesthesia: which is better in the elderly? Anesthesiology 1987;67:422-27. N.N. BUTTERFIELD 139 Chung F, Seyone C, Dyck B, Chung A, Ong D, Taylor A, Stone R. Age-related cognitive recovery after general anesthesia. Anesth Analg 1990;71:217-24. Chung FF, Chung A, Meier RH, Lautenschlaeger E, Seyone C. Comparison of perioperative mental function after general anaesthesia and spinal anaesthesia with intravenous sedation. Can J Anaesth 1989;36:382-87. Croughwell ND, Newman MF, Blumenthal JA, White WD, Lewis JB, Frasco PE, Smith LR et al. Jugular bulb saturation and cognitive dysfunction after cardiopulmonary bypass. Ann Thorac Surg 1994;58:1702-8. Crul BJ, Hulstijn W, Burger IC. Influence of the type of anaesthesia on post-operative subjective physical well-being and mental function in elderly patients. Acta Anaesthesiol Scand 1992;36:615-20. Cryns AG, Gorey KM, Goldstein MZ. Effects of surgery on the mental status of older persons. A meta-analytic review. J Geriatr Psychiatry Neurol 1990;3:184-91. Csiza CK, McMartin DN. Apparent acaridal dermatitis in a C57BL/6 Nya mouse colony. LabAnim Sci 1976;26:781-87. Culley DJ, Baxter MG, Yukhhananov R, Crosby G. The memory effects of general anesthesia persist for weeks in young and aged rats. Anesth Analg 2003;96:1004-9. Curtis D, Stevens WC. Recovery from general anesthesia. Int Anesthesiol Clin 1991;29:1-11. Davison LA, Steinhelber JC, Eger El, Stevens WC. Psychological eff-cts of halothane and isoflurane anesthesia. Anesthesiology 1975;43:313-24. de Jager CA, Milwain E, Budge M. Early detection of isolated memory deficits in the elderly: the need for more sensitive neuropsychological tests. Psychol Med 2002;32:483-91. Dean RL, III, Scozzafava J, Goas JA, Regan B, Beer B, Bartus RT. Age-related differences in behavior across the life span of the C57BL/6J mouse. Exp Aging Res 1981;7:427-51. Delacour J. A central activation role fo rthe hippocampus: a viewpoint. Neurosci Res Commun 1995;16:1-10. Delacour J. Neurobiology of consciousness: an overview. Behav Brain Res 1997;85:127-41. Dexter F, Tinker JH. Comparisons between desflurane and isoflurane or propofol on time to following commands and time to discharge. A metaanalysis. Anesthesiology 1995;83:77-82. N.N. BUTTERFIELD 140 Dijkstra JB. The influence of surgery on cognitive functioning. An operation under general anaesthesia and cognitive ageing. 1997. The Netherlands: Neuropsych Publishers Maastricht, 13-44. Dijkstra JB, Houx PJ, Jolles J. Cognition after major surgery in the elderly: test performance and complaints. BrJAnaesth 1999;82:867-74. Dijkstra JB, Jolles J. Postoperative cognitive dysfunction versus complaints: a discrepancy in long-term findings. Neuropsychol Rev 2002;12:1-14. Dodds C, Allison J. Postoperative cognitive deficit in the elderly surgical patient. Br J Anaesth 1998;81:449-62. Duffy CM, Matta BF. Sevoflurane and anesthesia for neurosurgery: a review. J Neurosurg Anesthesiol 2000; 12:128-40. Duggleby W, Lander J . Cognitive status and postoperative pain: older adults. J Pain Symptom Manage 1994;9:19-27. Dupont J , Tavernier B, Ghosez Y, Durinck L, Thevenot A, Moktadir-Chalons N, Ruyffelaere-Moises L ef al. Recovery after anaesthesia for pulmonary surgery: desflurane, sevoflurane and isoflurane. Br J Anaesth 1999;82:355-59. Dwyer R, McCaughey W, Lavery J, McCarthy G, Dundee JW. Comparison of propofol and methohexitone as anaesthetic agents for electroconvulsive therapy. Anaesthesia 1988;43:459-62. Dyer CB, Ashton CM, Teasdale TA. Postoperative delirium. A review of 80 primary data-collection studies. Arch Intern Med 1995;155:461-65. Eagle KA, Brundage BH, Chaitman BR, Ewy GA, Fleisher LA, Hertzer NR, Leppo JA ef al. Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery. Circulation 1996;93:1278-317. Easton C, MacKenzie F. Sensory-perceptual alterations: delirium in the intensive care unit. Heart Lung 1988;17:229-37. Eckenhoff RG. Do specific or nonspecific interactions with proteins underlie inhalational anesthetic action? Mol Pharmacol 1998;54:610-615. Edmonds CR, Barbut D, Hager D, Sharrock NE. Intraoperative cerebral arterial embolization during total hip arthroplasty. Anesthesiology 2000;93:315-18. Edwards H, Rose EA, Schorow M, King TC. Postoperative deterioration in psychomotor function. JAMA 1981;245:1342-43. N.N. BUTTERFIELD 141 Egbert AM, Parks LH, Short LM, Burnett ML. Randomized trial of postoperative patient-controlled analgesia vs intramuscular narcotics in frail elderly men. Arch Intern Med 1990;150:1897-903. Eger El, II. Isoflurane (Forane): a compendium and reference. 1981. Madison, Wisconsin: Ohio Medical Products. Eger El, Bowland T, lonescu P, Laster MJ, Fang Z, Gong D, Sonner J et al. Recovery and kinetic characteristics of desflurane and sevoflurane in volunteers after 8-h exposure, including kinetics of degradation products. Anesthesiology 1997;87:517-26. Ellis BW, Dudley HA. Some aspects of sleep research in surgical stress. J Psychosom Res 1976;20:303-8. Engeland CG, Vanderwolf CH, Gelb AW. Rats show unimpaired learning within minutes after recovery from single bolus propofol anesthesia. Can J Anaesth 1999;46:586-92. Ergun R, Akdemir G, Sen S, Tasci A, Ergungor F. Neuroprotective effects of propofol following global cerebral ischemia in rats. Neurosurg Rev 2002;25:95-98. Evers AS, Crowder CM. General anesthetics. In Hardman JG, Limbird LE, Gilman AG, eds. Goodman & Gilman's The pharmacological basis of therapeutics.2001. New York: McGraw-Hill, 337-65. Fear CF, Littlejohns CS, Rouse E, McQuail P. Propofol anaesthesia in electroconvulsive therapy. Reduced seizure duration may not be relevant. Br J Psychiatry 1994; 165:506-9. Feldt KS, Ryden MB, Miles S. Treatment of pain in cognitively impaired compared with cognitively intact older patients with hip-fracture. J Am GeriatrSoc 1998;46:1079-85. Figiel GS, Hassen MA, Zorumski C, Krishnan KR, Doraiswamy PM, Jarvis MR, Smith DS. ECT-induced delirium in depressed patients with Parkinson's disease. J Neuropsychiatry Clin Neurosci 1991;3:405-11. Flatt JR, Birrell PC, Hobbes A. Effects of anaesthesia on some aspects of mental functioning of surgical patients. Anaesth Intensive Care 1984;12:315-24. Flecknell PA, Liles JH. The effects of surgical procedures, halothane anaesthesia and nalbuphine on locomotor activity and food and water consumption in rats. Lab Anim 1991;25:50-60. Fletcher JE, Sebel PS, Murphy MR, Smith CA, Mick SA, Flister MP. Psychomotor performance after desflurane anesthesia: a comparison with isoflurane. Anesth Analg 1991;73:260-265. Flint AJ, Black SE, Campbell-Taylor I, Gailey GF, Levinton C. Abnormal speech articulation, psychomotor retardation, and subcortical dysfunction in major depression. J Psychiatr Res 1993;27:309-19. N.N. BUTTERFIELD 142 Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98. Forster MJ, Dubey A, Dawson KM, Stutts WA, Lai H, Sohal RS. Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc Natl Acad Sci USA 1996;93:4765-69. Forster MJ, Lai H. Estimating age-related changes in psychomotor function: influence of practice and of level of caloric intake in different genotypes. Neurobiol Aging 1999;20:167-76. Fox GB, Fan L, LeVasseur RA, Faden Al. Effect of traumatic brain injury on mouse spatial and nonspatial learning in the Barnes circular maze. J Neurotrauma 1998;15:1037-46. Fox GB, LeVasseur RA, Faden Al. Behavioral responses of C57BL/6, FVB/N, and 129/SvEMS mouse strains to traumatic brain injury: implications for gene targeting approaches to neurotrauma. J Neurotrauma 1999;16:377-89. Franco K, Litaker D, Locala J, Bronson D. The cost of delirium in the surgical patient. Psychosomatics 2001 ;42:68-73. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994;367:607-14. Franks NP, Lieb WR. Background K+ channels: an important target for volatile anesthetics? Nat Neurosci 1999;2:395-96. Fredman B, Husain MM, White PF. Anaesthesia for electroconvulsive therapy: use of propofol revisited. Eur J Anaesthesiol 1994; 11:423-25. Fredman B, Lahav M, Zohar E, Golod M, Paruta I, Jedeikin R. The effect of midazolam premedication on mental and psychomotor recovery in geriatric patients undergoing brief surgical procedures. Anesth Analg 1999;89:1161-66. Fredman B, Sheffer O, Zohar E, Paruta I, Richter S, Jedeikin R, White PF. Fast-track eligibility of geriatric patients undergoing short urologic surgery procedures. Anesth Analg 2002;94:560-564. Galanakis P, Bickel H, Gradinger R, Von Gumppenberg S, Forstl H. Acute confusional state in the elderly following hip surgery: incidence, risk factors and complications. Int J Geriatr Psychiatry 2001 ;16:349-55. Galinkin JL, Janiszewski D, Young CJ, Klafta JM, Klock PA, Coalson DW, Apfelbaum JL ef al. Subjective, psychomotor, cognitive, and analgesic effects of subanesthetic concentrations of sevoflurane and nitrous oxide. Anesthesiology 1997;87:1082-88. Gallagher M, Rapp PR. The use of animal models to study the effects of aging on cognition. Annu Rev Psychol 1997;48:339-70. N.N. BUTTERFIELD 143 Garrioch MA, Fitch W. Anaesthesia for carotid artery surgery. Br J Anaesth 1993;71:569-79. Geretsegger C, Rochowanski E, Kartnig C, Unterrainer AF. Propofol and methohexital as anesthetic agents for electroconvulsive therapy (ECT): a comparison of seizure-quality measures and vital signs. J ECT 1998;14:28-35. Ghoneim MM, Dhanaraj J , Choi WW. Comparison of four opioid analgesics as supplements to nitrous oxide anesthesia. Anesth Analg 1984;63:405-12. Ghoneim MM, Hinrichs JV, O'Hara MW, Mehta MP, Pathak D, Kumar V, Clark et al. Comparison of psychologic and cognitive functions after general or regional anesthesia. Anesthesiology 1988;69:507-15. Ghouri AF, Bodner M, White PF. Recovery profile after desflurane-nitrous oxide versus isoflurane-nitrous oxide in outpatients. Anesthesiology 1991;74:419-24. Goldstein MZ. He/she was never the same after surgery. Newsletter of the American Association of Geriatric Psychiatry 1990; 11:13. Goldstein MZ, Young BL, Fogel BS, Benedict RH. Occurrence and predictors of short-term mental and functional changes in older adults undergoing elective surgery under general anesthesia. Am J Geriatr Psychiatry 1998;6:42-52. Grichnik KP, Ijsselmuiden AJ, D'Amico TA, Harpole DH, Jr., White WD, Blumenthal JA, Newman MF. Cognitive decline after major noncardiac operations: a preliminary prospective study. Ann Thorac Surg 1999;68:1786-91. Grounds RM, Moore M, Morgan M. The relative potencies of thiopentone and propofol. Eur J Anaesthesiol 1986;3:11 -17. Gustafson Y, Berggren D, Brannstrom B, Bucht G, Norberg A, Hansson LI, Winblad B. Acute confusional states in elderly patients treated for femoral neck fracture. J Am Geriatr Soc 1988;36:525-30. Gustafson Y, Brannstrom B, Berggren D, Ragnarsson Jl , Sigaard J, Bucht G, Reiz S et al. A geriatric-anesthesiologic program to reduce acute confusional states in elderly patients treated for femoral neck fractures. J Am Geriatr Soc 1991;39:655-62. Haavisto E, Kauranen K. Psychomotor performance after short-term anaesthesia. Eur J Anaesthesiol 2002;19:436-41. Hadzic A, Glab K, Sanborn KV, Thys DM. Severe neurologic deficit after nitrous oxide anesthesia. Anesthesiology 1995;83:863-66. Hammon JW, Jr., Stump DA, Kon ND, Cordell AR, Hudspeth AS, Oaks TE, Brooker RF et al. Risk factors and solutions for the development of neurobehavioral changes after coronary artery bypass grafting. Ann Thorac Surg 1997;63:1613-18. N.N. BUTTERFIELD 144 Hauber W, Schmidt WJ. Acquisition, but not retrieval of delayed alternation is impaired by ketamine. Research Communications in Psychology, Psychiatry and Behavior 1990;15:17-29. Hendrickx HH, Safar P, Miller A. Delayed recovery of behavior after anesthesia in rats. Resuscitation 1984; 12:213-21. Henriksson BA, Carlsson P, Hallen B, Hagerdal M, Lundberg D, Ponten J. Propofol vs thiopentone as anaesthetic agents for short operative procedures. Acta Anaesthesiol Scand 1987;31:63-66. Herbert M. The duration of post-anaesthetic mental impairment. In Hindmarch I, Jones JG, Moss E, eds. Aspects of recovery from anaesthesia.1987. Chichester: John Wiley &Sons, 103-12. Heyer EJ, Sharma R, Winfree CJ, Mocco J, McMahon DJ, McCormick PA, Quest DO et al. Severe pain confounds neuropsychological test performance. J Clin Exp Neuropsychol 2000;22:633-39. Hindmarch I, Bhatti JZ. Recovery of cognitive and psychomotor funciton following anaesthesia. A review. In Hindmarch I, Jones JG, Moss E, eds. Aspects of recovery from anaesthesia.1987. London: John Wiley, 113-70. Hintze, J. NCSS and PASS. Number Cruncher Statistical Systems. 2001. Kaysville, Utah, www.ncss.com. Hobson RW, Weiss DG, Fields WS, Goldstone J, Moore WS, Towne JB, Wright CB. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group. N Engl J Med 1993;328:221-27. Hole A, Terjesen T, Breivik H. Epidural versus general anaesthesia for total hip arthroplasty in elderly patients. Acta Anaesthesiol Scand 1980;24:279-87. Houx PJ, Jolles J. Age-related decline of psychomotor speed: effects of age, brain health, sex, and education. Percept Mot Skills 1993;76:195-211. Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992;76:334-41. Ingram DK. Complex maze learning in rodents as a model of age-related memory impairment. Neurobiol Aging 1988;9:475-85. Ingram DK, Jucker M. Developing mouse models of aging: a consideration of strain differences in age-related behavioral and neural parameters. Neurobiol Aging 1999;20:137-45. Ito H, Watanabe Y, Isshiki A, Uchino H. Neuroprotective properties of propofol and midazolam, but not pentobarbital, on neuronal damage induced by forebrain ischemia, based on the GABAA receptors. Acta Anaesthesiol Scand 1999;43:153-62. N.N. BUTTERFIELD 145 Jacobson DM, Terrence CF, Reinmuth OM. The neurologic manifestations of fat embolism. Neurology 1986;36:847-51. Jenkins LC, Wong DHW. Anaesthetic management of carotid endarterectomy. 1987. London: Lloyd-Luke (Medical Books). Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876-82. Jevtovic-Todorovic V, Kirby CO, Olney JW. Isoflurane and propofol block neurotoxicity caused by MK-801 in the rat posterior cingulate/retrosplenial cortex. J Cereb Blood FlowMetab 1997;17:168-74. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF ef al. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med 1998;4:460-463. Jevtovic-Todorovic V, Wozniak DF, Benshoff ND, Olney JW. A comparative evaluation of the neurotoxic properties of ketamine and nitrous oxide. Brain Res 2001a;895:264-67. Jevtovic-Todorovic V, Wozniak DF, Powell S, Olney JW. Propofol and sodium thiopental protect against MK-801-induced neuronal necrosis in the posterior cingulate/retrosplenial cortex. Brain Res 2001b;913:185-89. Johnson T, Monk T, Rasmussen LS, Abildstrom H, Houx P, Korttila K, Kuipers HM ef al. Postoperative cognitive dysfunction in middle-aged patients. Anesthesiology 2002;96:1351-57. Jones AG, Hunter JM. Anaesthesia in the elderly. Special considerations. Drugs Aging 1996;9:319-31. Jones BJ, Roberts DJ. The quantitative measurement of motor inco-ordination in naive mice using an accelerating rotarod. J Pharm Pharmacol 1968;20:302-4. Jones MJ. The influence of anesthetic methods on mental function. Acta Chir Scand Suppl 1989;550:169-75. Jones MJ, Piggott SE, Vaughan RS, Bayer AJ, Newcombe RG, Twining TC, Pathy J ef al. Cognitive and functional competence after anaesthesia in patients aged over 60: controlled trial of general and regional anaesthesia for elective hip or knee replacement. BMJ 1990;300:1683-87. Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F, Zaugg M ef al. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J 2003;17:250-252. N.N. BUTTERFIELD 146 Juvin P, Servin F, Giraud O, Desmonts JM. Emergence of elderly patients from prolonged desflurane, isoflurane, or propofol anesthesia. Anesth Analg 1997;85:647-51-Kaneko T, Takahashi S, Naka T, Hirooka Y, Inoue Y, Kaibara N. Postoperative delirium following gastrointestinal surgery in elderly patients. Surg Today 1997;27:107-11. Kendig JJ, Maclver MB, Roth SH. Anesthetic actions in the hippocampal formation. Ann N Y Acad Sci 1991;625:37-53. Kirkby KC, Beckett WG, Matters RM, King TE. Comparison of propofol and methohexitone in anaesthesia for ECT: effect on seizure duration and outcome. Aust N Z J Psychiatry 1995;29:299-303. Kluger A, Gianutsos JG, Golomb J, Ferris SH, Reisberg B. Motor/psychomotor dysfunction in normal aging, mild cognitive decline, and early Alzheimer's disease: diagnostic and differential diagnostic features. Int Psychogeriatr 1997;9 Suppl 1:307-16. Knill RL. Clinical research in anaesthesia. Past accomplishments and a future horizon. Anaesthesia 1990;45:271-72. Komatsu H, Nogaya J, Anabuki D, Yokono S, Kinoshita H, Shirakawa Y, Ogli K. Memory facilitation by posttraining exposure to halothane, enflurane, and isoflurane in ddN mice. Anesth Analg 1993;76:609-12. Komatsu H, Nogaya J, Kuratani N, Ueki M, Yokono S, Ogli K. Psychomotor performance during initial stage of exposure to halothane, enflurane, isoflurane and sevoflurane in mice. Clin Exp Pharmacol Physiol 1997;24:706-9. Komatsu H, Nogaya J, Kuratani N, Ueki M, Yokono S, Ogli K. Repetitive post-training exposure to enflurane modifies spatial memory in mice. Anesthesiology 1998;89:1184-90. Korttila K. Recovery from outpatient anaesthesia. Factors affecting outcome. Anaesthesia 1995;50 Suppl:22-28. Korttila K. Postanesthetic cognitive and psychomotor impairment. Int Anesthesiol Clin 1986;24:59-74. Korttila K. Recovery from day case anaesthesia. Best Pract Res Clin Anesthesiol 1990;4:713-32. Korttila K, Linnoila M, Ertama P, Hakkinen S. Recovery and simulated driving after intravenous anesthesia with thiopental, methohexital, propanidid, or alphadione. Anesthesiology 1975;43:291-99. Korttila K, Nuotto EJ, Lichtor JL, Ostman PL, Apfelbaum J, Rupani G. Clinical recovery and psychomotor function after brief anesthesia with propofol or thiopental. Anesthesiology 1992;76:676-81. N.N. BUTTERFIELD 147 Korttila K, Tammisto T, Ertama P, Pfaffli P, Blomgren E, Hakkinen S. Recovery, psychomotor skills, and simulated driving after brief inhalational anesthesia with halothane or enflurane combined with nitrous oxide and oxygen. Anesthesiology 1977;46:20-27. Krystal AD, Weiner RD, Dean MD, Lindahl VH, Tramontozzi LA, III, Falcone G, Coffey CE. Comparison of seizure duration, ictal EEG, and cognitive effects of ketamine and methohexital anesthesia with ECT. J Neuropsychiatry Clin Neurosci 2003;15:27-34. Krystal AD, Coffey CE, Weiner RD, Holsinger T. Changes in seizure threshold over the course of electroconvulsive therapy affect therapeutic response and are detected by ictal EEG ratings. J Neuropsychiatry Clin Neurosci 1998;10:178-86. Krystal AD, Weiner RD, Coffey CE. The ictal EEG as a marker of adequate stimulus intensity with unilateral ECT. J Neuropsychiatry Clin Neurosci 1995;7:295-303. La Marca S, Lozito RJ, Dunn RW. Cognitive and EEG recovery following bolus intravenous administration of anesthetic agents. Psychopharmacology 1995; 120:426-32. Lee C, Kwan WF, Tsai SK, Chen BJ, Cheng M. A clinical assessment of desflurane anaesthesia and comparison with isoflurane. Can J Anaesth 1993;40:487-94. Lerer B, Shapira B, Calev A, Tubi N, Drexler H, Kindler S, Lidsky D ef al. Antidepressant and cognitive effects of twice- versus three-times-weekly ECT. Am J Psychiatry 1995;152:564-70. Lezak MD. Neuropsychological assessment, 3rd ed ed.1995. New York: Oxford University Press. Liles JH, Flecknell PA. The effects of buprenorphine, nalbuphine and butorphanol alone or following halothane anaesthesia on food and water consumption and locomotor movement in rats. Lab Anim 1992;26:180-189. Lipowski ZJ. Delirium (acute confusional states). JAMA 1987;258:1789-92. Lisanby SH, Maddox JH, Prudic J, Devanand DP, Sackeim HA. The effects of electroconvulsive therapy on memory of autobiographical and public events. Arch Gen Psychiatry 2000;57:581-90. Litaker D, Locala J , Franco K, Bronson DL, Tannous Z. Preoperative risk factors for postoperative delirium. Gen Hosp Psychiatry 2001 ;23:84-89. Loss GE, Jr., Seifen E, Kennedy RH, Seifen AB. Aging: effects on minimum alveolar concentration (MAC) for halothane in Fischer-344 rats. Anesth Analg 1989;68:359-62. Lynch EP, Lazor MA, Gellis JE, Orav J, Goldman L, Marcantonio ER. The impact of postoperative pain on the development of postoperative delirium. Anesth Analg 1998;86:781-85. N.N. BUTTERFIELD 148 Ma J, Shen B, Stewart LS, Herrick IA, Leung LS. The septohippocampal system participates in general anesthesia. J Neurosci 2002;22:RC200. Mackenzie N, Grant IS. Comparison of the new emulsion formulation of propofol with methohexitone and thiopentone for induction of anaesthesia in day cases. Br J Anaesth 1985;57:725-31. Malsch E, Gratz I, Mani S, Backup C, Levy S, Allen E. Efficacy of electroconvulsive therapy after propofol and methohexital anesthesia. Convuls Ther 1994;10:212-19. Mann RA, Bisset Wl. Anaesthesia for lower limb amputation. A comparison of spinal analgesia and general anaesthesia in the elderly. Anaesthesia 1983;38:1185-91. Mantz J. Neuroprotective effects of anesthetics. Ann Fr Anesth Reanim 1999; 18:588-92. Marcantonio ER, Goldman L, Mangione CM, Ludwig LE, Muraca B, Haslauer CM, Donaldson MC et al. A clinical prediction rule for delirium after elective noncardiac surgery. JAMA 1994;271:134-39. Martensson B, Bartfai A, Hallen B, Hellstrom C, Junthe T, Olander M. A comparison of propofol and methohexital as anesthetic agents for ECT: effects on seizure duration, therapeutic outcome, and memory. Biol Psychiatry 1994;35:179-89. Matsuoka H, Watanabe Y, Isshiki A, Quock RM. Increased production of nitric oxide metabolites in the hippocampus under isoflurane anaesthesia in rats. Eur J Anaesthesiol 1999;16:216-24. Matters RM, Beckett WG, Kirkby KC, King TE. Recovery after electroconvulsive therapy: comparison of propofol with methohexitone anaesthesia. Br J Anaesth 1995;75:297-300. McCall WV, Cohen W, Reboussin B, Lawton P. Pretreatment differences in specific symptoms and quality of life among depressed inpatients who do and do not receive electroconvulsive therapy: a hypothesis regarding why the elderly are more likely to receive ECT. J ECT 1999;15:193-201. McCann DJ, Rabin RA, Winter JC. Interactions of clonidine with phencyclidine and ketamine: studies of radial maze performance and righting reflex in rats. Pharmacol Biochem Behav 1987;26:23-28. McElhiney MC, Moody BJ, Steif BL. Autobiographical memory and mood: effects of electroconvulsive therapy. Neuropsychology 1995;9:501-17. McGeoch JA. The psychology of human learning, 2nd ed.1952. New York: Longmans, Green. McLeskey CH. Geriatric anesthesiology'.1997'. Baltimore, Md: Williams & Wilkins. N . N . B U T T E R F I E L D 149 Mecca RS. Postoperative Recovery. In Barash PG, Cullen BF, Stoelting RK, eds. Pharmacology and physiology in anesthetic practice. 1999. Philadelphia: Lippincott-Raven, 1515-46. Millar K. The effects of Anaesthetic and Analgesic Drugs. Handbook of Human Performance.1992. Academic Press Ltd., 337-85. Millar K, Asbury AJ, Murray GD. Pre-existing cognitive impairment as a factor influencing outcome after cardiac surgery. Br J Anaesth 2001 ;86:63-67. Miller AL, Faber RA, Hatch JP, Alexander HE. Factors affecting amnesia, seizure duration, and efficacy in ECT. Am J Psychiatry 1985;142:692-96. Miller PS, Richardson JS, Jyu CA, Lemay JS, Hiscock M, Keegan DL. Association of low serum anticholinergic levels and cognitive impairment in elderly presurgical patients. Am J Psychiatry 1988;145:342-45. Mills SA. Risk factors for cerebral injury and cardiac surgery. Ann Thorac Surg 1995;59:1296-99. Mitchell P, Hickie I, Torda T. Propofol and ECT. Br J Psychiatry 1992;161:861-62. Mitchell P, Torda T, Hickie I, Burke C. Propofol as an anaesthetic agent for ECT: effect on outcome and length of course. Aust NZJ Psychiatry 1991 ;25:255-61. Miu P, Puil E. Isoflurane-induced impairment of synaptic transmission in hippocampal neurons. Exp Brain Res 1989;75:354-60. Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J , Rabbitt P et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancer 1998;351:857-61. Moller JT, Svennild I, Johannessen NW, Jensen PF, Espersen K, Gravenstein JS, Cooper JB et al. Perioperative monitoring with pulse oximetry and late postoperative cognitive dysfunction. Br J Anaesth 1993;71:340-347. Morrison RS, Magaziner J , Gilbert M, Koval KJ, McLaughlin MA, Orosz G, Strauss E et al. Relationship between pain and opioid analgesics on the development of delirium following hip fracture. J Gerontol A Biol Sci Med Sci 2003;58:76-81. Mulder JB, Brown RV. An anesthetic unit for small laboratory animals. Lab Anim Sci 1972;22:422-23. Mulder JB, Hauser JJ. A closed anesthetic system for small laboratory animals. Lab Anim Sci 1984;34:77-78. Mulsant BH, Rosen J, Thornton JE, Zubenko GS. A prospective naturalistic study of electroconvulsive therapy in late-life depression. J Geriatr Psychiatry Neurol 1991 ;4:3-13. N.N. BUTTERFIELD 150 Murkin JM. The role of CPB management in neurobehavioral outcomes after cardiac surgery. Ann Thorac Surg 1995;59:1308-11. Murkin JM, Newman SP, Stump DA, Blumenthal JA. Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery. Ann Thorac Surg 1995;59:1289-95. Murphy TM. Somatic blockade of the head and neck. In Cousins MJ, Bridenbaugh PO, eds. Neural Blockade. 1988. Philadelphia, PA: Lippincott, 550. Nadelson T. The psychiatrist in the surgical intensive care unit. I. Postoperative delirium. Arch Surg 1976;111:113-17. NASCET. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991 ;325:445-53. Nathanson MH, Fredman B, Smith I, White PF. Sevoflurane versus desflurane for outpatient anesthesia: a comparison of maintenance and recovery profiles. Anesth Analg 1995;81:1186-90. Naylor AR. Regarding "high embolic rate early after carotid endarterectomy is associated with early cerebrovascular complications, especially in women". J Vase Surg 2002;36:408-9. Nebes RD, Brady CB, Reynolds CF, III. Cognitive slowing in Alzheimer's disease and geriatric depression. J Gerontol 1992;47:331-36. Nebes RD, Butters MA, Mulsant BH, Pollock BG, Zmuda MD, Houck PR, Reynolds CF, III. Decreased working memory and processing speed mediate cognitive impairment in geriatric depression. Psychol Med 2000;30:679-91. Nobler MS, Sackeim HA, Solomou M, Luber B, Devanand DP, Prudic J. EEG manifestations during ECT: effects of electrode placement and stimulus intensity. Biol Psychiatry 1993;34:321-30. Norris ML, Miles P. An improved, portable machine designed to induce and maintain surgical anaesthesia in small laboratory rodents. Lab Anim 1982;16:227-30. O'Gorman DA, O'Connell AW, Murphy KJ, Moriarty DC, Shiotani T, Regan CM. Nefiracetam prevents propofol-induced anterograde and retrograde amnesia in the rodent without compromising quality of anesthesia. Anesthesiology 1998;89:699-706. O'Keeffe ST, Ni CA. Postoperative delirium in the elderly. Br J Anaesth 1994;73:673-87. Olney JW, Wozniak DF, Jevtovic-Todorovic V, Farber NB, Bittigau P, Ikonomidou C. Drug-induced apoptotic neurodegeneration in the developing brain. Brain Pathol 2002;12:488-98. N.N. BUTTERFIELD 151 Pang R, Quartermain D, Rosman E, Turndorf H. Effect of propofol on memory in mice. Pharmacol Biochem Behav 1993;44:145-51. Parikh SS, Chung F. Postoperative delirium in the elderly. Anesth Analg 1995;80:1223-32. Patel SS, Goa KL. Desflurane. A review of its pharmacodynamic and pharmacokinetic properties and its efficacy in general anaesthesia. Drugs 1995;50:742-67. Perlmutter M, Metzger R, Nezworski T, Miller K. Spatial and temporal memory in 20 to 60 year olds. J Gerontol 1981 ;36:59-65. Perry E. Cholinergic mechanisms and cognitive decline. Eur J Anaesthesiol 1998;15:768-73. Platzer H. Post-operative confusion in the elderly--a literature review. Int J Nurs Stud 1989;26:369-79. Pollard BJ, Elliott RA, Moore EW. Anaesthetic agents in adult day case surgery. Eur J Anaesthesiol 2003;20:1-9. Porter J , Lynch L, Hart S, Keohane C. Unexpected neurological deficits following recovery from anaesthesia. Can J Anaesth 1994;41:317-20. Prior FN, Chander P. Air as a vaporizing gas. Cognitive functions in elderly patients undergoing anaesthesia. Br J Anaesth 1982;54:1207-12. Pugsley W, Klinger L, Paschalis C, Treasure T, Harrison M, Newman S. The impact of microemboli during cardiopulmonary bypass on neuropsychological functioning. Stroke 1994;25:1393-99. Rabbitt PM. An age decrement in the ability to ignore irrelevant information. J Gerentology 1965;20:233-38. Rampton AJ, Griffin RM, Stuart CS, Durcan JJ, Huddy NC, Abbott MA. Comparison of methohexital and propofol for electroconvulsive therapy: effects on hemodynamic responses and seizure duration. Anesthesiology 1989;70:412-17. Rasmussen, L. S. Cognitive dysfunction after anesthesia and surgery. Acta Anaesthesiol.Scand. 45[Suppl. 115], 27. 2001. Rasmussen LS, Steentoft A, Rasmussen H, Kristensen PA, Moller JT. Benzodiazepines and postoperative cognitive dysfunction in the elderly. ISPOCD Group. International Study of Postoperative Cognitive Dysfunction. Br J Anaesth 1999;83:585-89. Ries CR, Puil E. Ionic mechanism of isoflurane's actions on thalamocortical neurons. J Neurophysiol 1999a;81:1802-9. Ries CR, Puil E. Mechanism of anesthesia revealed by shunting actions of isoflurane on thalamocortical neurons. J Neurophysiol 1999b;81:1795-801. N.N. BUTTERFIELD 152 Ritchie K, Polge C, de Roquefeuil G, Djakovic M, Ledesert B. Impact of anesthesia on the cognitive functioning of the elderly. Int Psychogeriatr 1997;9:309-26. Rogers MP, Liang MH, Daltroy LH, Eaton H, Peteet J, Wright E, Albert M. Delirium after elective orthopedic surgery: risk factors and natural history. Int J Psychiatry Med 1989;19:109-21. Rollason WN, Robertson GS, Cordiner CM, Hall DJ. A comparison of mental function in relation to hypotensive and normotensive anaesthesia in the elderly. Br J Anaesth 1971;43:561-66. Roman GC. Vascular dementia may be the most common form of dementia in the elderly. J A/euro/ Sci 2002;203-204:7-10. Rooke, G. E. What makes the older patient more difficult? Supplement to Anesthesia & Analgesia July 2003, 23-26. 2003. Society for Ambulatory Anesthesia 2003 Annual Meeting Lectures. Rosenberg, J. and Kehlet, H. Postoperative mental confusion - association with postoperative hypoxemia. Anesthesiology 77, 315. 1992. Rosman E, Quartermain D, Pang R, Turndorf H. Halothane anesthesia causes state-dependent retrieval failure in mice. Physiology & Behavior 1992;52:449-53. Rouse EC. Propofol for electroconvulsive therapy. A comparison with methohexitone. Preliminary report. Anaesthesia 1988;43 Suppl:61-64. Russell D. Cerebral microemboli and cognitive impairment. J Neurol Sci 2002;203-204:211-14. Sackeim HA, Portnoy S, Neeley P, Steif BL, Decina P, Malitz S. Cognitive consequences of low-dosage electroconvulsive therapy. Ann N Y Acad Sci 1986;462:326-40. Sackeim HA, Prudic J, Devanand DP, Kiersky JE, Fitzsimons L, Moody BJ, McElhiney MC et al. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. N Engl J Med 1993;328:839-46. Sackeim HA, Prudic J , Devanand DP, Nobler MS, Lisanby SH, Peyser S, Fitzsimons L et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry 2000;57:425-34. Sakamoto A, Hoshino T, Suzuki N, Suzuki H, Kimura M, Ogawa R. Effects of propofol anesthesia on cognitive recovery of patients undergoing electroconvulsive therapy. Psychiatry Clin Neurosci 1999;53:655-60. Salthouse TA. The processing-speed theory of adult age differences in cognition. Psychol Rev 1996;103:403-28. N.N. BUTTERFIELD 153 Salthouse TA. Aging and measures of processing speed. Biol Psychol 2000;54:35-54. Salthouse TA, Hancock HE, Meinz EJ, Hambrick DZ. Interrelations of age, visual acuity, and cognitive functioning. J Gerontol B Psychol Sci Soc Sci 1996;51:317-30. Sarraf-Yazdi S, Sheng H, Miura Y, McFarlane C, Dexter F, Pearlstein R, Warner DS. Relative neuroprotective effects of dizocilpine and isoflurane during focal cerebral ischemia in the rat. Anesth Analg 1998;87:72-78. Savageau JA, Stanton BA, Jenkins CD, Frater RW. Neuropsychological dysfunction following elective cardiac operation. II. A six-month reassessment. J Thorac Cardiovasc Surg 1982;84:595-600. Schor JD, Levkoff SE, Lipsitz LA, Reilly CH, Cleary PD, Rowe JW, Evans DA. Risk factors for delirium in hospitalized elderly. JAMA 1992;267:827-31. Scott WA, Whitwam JG, Wilkinson RT. Choice reaction time. A method of measuring postoperative psychomotor performance decrements. Anaesthesia 1983;38:1162-68. Shukitt-Hale B, Mouzakis G, Joseph JA. Psychomotor and spatial memory performance in aging male Fischer 344 rats. Exp Gerontol 1998;33:615-24. Simon W, Hapfelmeier G, Kochs E, Zieglgansberger W, Rammes G. Isoflurane blocks synaptic plasticity in the mouse hippocampus. Anesthesiology 2001;94:1058-65. Simpson KH, Halsall PJ, Carr CM, Stewart KG. Propofol reduces seizure duration in patients having anaesthesia for electroconvulsive therapy. Br J Anaesth 1988;61:343-44. Smiley RM, Ornstein E, Matteo RS, Pantuck EJ, Pantuck CB. Desflurane and isoflurane in surgical patients: comparison of emergence time. Anesthesiology 1991;74:425-28. Smith C, Carter M, Sebel P, Yate P. Mental function after general anaesthesia for transurethral procedures. Br J Anaesth 1991;67:262-68. Smith DM, Goddard KM, Wilson RB, Newberne PM. An apparatus for anesthetizing small laboratory rodents. Lab Anim Sci 1973;23:869-71. Smith I, Taylor E, White PF. Comparison of tracheal extubation in patients deeply anesthetized with desflurane or isoflurane. Anesth Analg 1994;79:642-45. Smith MA, Stoops WW. Sensitivity to the effects of sedative-hypnotics on motor performance: influence of task difficulty and chronic phenobarbital administration. Behav Pharmacol 2001; 12:125-34. Smith RJ, Roberts NM, Rodgers RJ, Bennett S. Adverse cognitive effects of general anaesthesia in young and elderly patients. Int Clin Psychopharmacol 1986;1:253-59. Sobin C, Sackeim HA, Prudic J, Devanand DP, Moody BJ, McElhiney MC. Predictors of retrograde amnesia following ECT. Am J Psychiatry 1995;152:995-1001. N.N. BUTTERFIELD 154 Solca M, Salvo I, Russo R, Fiori R, Veschi G. Anaesthesia with desflurane-nitrous oxide in elderly patients. Comparison with isoflurane-nitrous oxide. Minerva Anestesiol 2000;66:621-26. Sonner JM, Gong D, Li J , Eger El, Laster MJ. Mouse strain modestly influences minimum alveolar anesthetic concentration and convulsivity of inhaled compounds. Anesth Analg 1999;89:1030-1034. Spahr-Schopfer I, Vutskits L, Toni N, Buchs PA, Parisi L, Muller D. Differential neurotoxic effects of propofol on dissociated cortical cells and organotypic hippocampal cultures. Anesthesiology 2000;92:1408-17. Spreen O, Strauss E. A compendium of neuropsychological tests administration, norms, and commentary, 2nd ed ed.1998. New York: Oxford University Press. Squire LR, Shimamura AP, Graf P. Independence of recognition memory and priming effects: a neuropsychological analysis. J Exp Psychol Learn Mem Cogn 1985;11:37-44. Stevens WC, Dolan WM, Gibbons RT, White A, Eger El, Miller RD, DeJong RH et al. Minimum alveolar concentrations (MAC) of isoflurande with and without nitrous oxide in patients of various ages. Anesthesiology 1975;42:197-200. Stoelting RK, Eger El. The effects of ventilation and anesthetic solubility on recovery from anesthesia: an in vivo and analog analysis before and after equilibrium. Anesthesiology 1969;30:290-296. Stoelting RK. Pharmacology and physiology in anesthetic practice, 3rd ed ed.1999. Philadelphia: Lippincott-Raven. Strauss B, Paulsen G, Strenge H, Graetz S, Regensburger D, Speidel H. Preoperative and late postoperative psychosocial state following coronary artery bypass surgery. Thorac Cardiovasc Surg 1992;40:59-64. Stromberg L, Ohlen G, Nordin C, Lindgren U, Svensson O. Postoperative mental impairment in hip fracture patients. A randomized study of reorientation measures in 223 patients. Acta Orthop Scand 1999;70:250-255. Thompson GE, Miller RD, Stevens WC, Murray WR. Hypotensive anesthesia for total hip arthroplasty: a study of blood loss and organ function (brain, heart, liver, and kidney). Anesthesiology 1978;48:91-96. Townes BD, Dikmen SS, Bledsoe SW, Hornbein TF, Martin DC, Janesheski JA. Neuropsychological changes in a young, healthy population after controlled hypotensive anesthesia. Anesth Analg 1986;65:955-59. Tsai SK, Lee C, Kwan WF, Chen BJ. Recovery of cognitive functions after anaesthesia with desflurane or isoflurane and nitrous oxide. Br J Anaesth 1992;69:255-58. N.N. BUTTERFIELD 155 Tsourtos G, Thompson JC, Stough C. Evidence of an early information processing speed deficit in unipolar major depression. Psychol Med 2002;32:259-65. Tu JV, Hannan EL, Anderson GM, Iron K, Wu K, Vranizan K, Popp AJ et al. The fall and rise of carotid endarterectomy in the United States and Canada. N Engl J Med 1998;339:1441-47. Tune LE, Damlouji NF, Holland A, Gardner TJ, Folstein MF, Coyle JT. Association of postoperative delirium with raised serum levels of anticholinergic drugs. Lancet 1981;2:651-53. Tzabar Y, Asbury AJ, Millar K. Cognitive failures after general anaesthesia for day-case surgery. Br J Anaesth 1996;76:194-97. Uchihashi Y, Kuribara H, Isa Y, Morita T, Sato T. The disruptive effects of ketamine on passive avoidance learning in mice: involvement of dopaminergic mechanism. Psychopharmacology (Berl) 1994; 116:40-44. Umbrain V, Keeris J , D'Haese J, Verborgh C, Debing E, Van den Brande P, Camu F. Isoflurane, desflurane and sevoflurane for carotid endarterectomy. Anaesthesia 2000;55:1052-57. Uttl B, Graf P. Episodic spatial memory in adulthood. Psychol Aging 1993;8:257-73. Uttl B, Graf P, Cosentino S. Exacting assessments: do older adults fatigue more quickly? J Clin Exp Neuropsychol 2000;22:496-507 Valzelli L, Kozak W, Skorupska M. Effect of some anesthetics on memory and exploration. Methods Find Exp Clin Pharmacol 1988;10:239-42. van der Staay FJ, Raaijmakers WGM, Sakkee AN, van Bezooijen CFA. Spatial working and reference memory of adult and senescent rats after thiopental anaesthesia. Neurosci Res Commun 1988;3:55-61. Ventrone R, Baan E, Coggins CR. Novel inhalation device for the simultaneous anaesthesia of several laboratory rodents. Lab Anim 1982;16:231-33. Villalonga A, Bernardo M, Gomar C, Fita G, Escobar R, Pacheco M. Cardiovascular Response and Anesthetic Recovery in Electroconvulsive Therapy with Propofol or Thiopental. Convuls Ther 1993;9:108-11. Walford RL. Letter: When is a mouse "old"? J Immunol 1976;117:352. Warner DS. Isoflurane neuroprotection: a passing fantasy, again? Anesthesiology 2000;92:1226-28. Weightman WM, Zacharias M. Comparison of propofol and thiopentone anaesthesia (with special reference to recovery characteristics). Anaesth Intensive Care 1987;15:389-93. N.N. BUTTERFIELD 156 Weiner RD, Rogers HJ, Davidson JR, Kahn EM. Effects of electroconvulsive therapy upon brain electrical activity. Ann N YAcad Sci 1986a;462:270-281. Weiner RD, Rogers HJ, Davidson JR, Squire LR. Effects of stimulus parameters on cognitive side effects. Ann N Y Acad Sci 1986b;462:315-25. Wenger GR, Dews PB. The effects of phencyclidine, ketamine, delta-amphetamine and pentobarbital on schedule-controlled behavior in the mouse. J Pharmacol Exp Ther 1976;196:616-24. Wilhelm W, Schlaich N, Harrer J , Kleinschmidt S, Muller M, Larsen R. Recovery and neurological examination after remifentanil-desflurane or fentanyl-desflurane anaesthesia for carotid artery surgery. Br J Anaesth 2001;86:44-49. Wilke HJ2, Ellis JE, McKinsey JF. Carotid endarterectomy: perioperative and anesthetic considerations. J Cardiothorac Vase Anesth 1996;10:928-49. Williams-Russo P, Sharrock NE, Mattis S, Liguori GA, Mancuso C, Peterson MG, Hollenberg J et al. Randomized trial of hypotensive epidural anesthesia in older adults. Anesthesiology 1999;91:926-35. Williams-Russo P, Sharrock NE, Mattis S, Szatrowski TP, Charlson ME. Cognitive effects after epidural vs general anesthesia in older adults. A randomized trial. JAMA 1995;274:44-50. Williams-Russo P, Urquhart BL, Sharrock NE, Charlson ME. Post-operative delirium: predictors and prognosis in elderly orthopedic patients. J Am Geriatr Soc 1992;40:759-67. Winawer N. Postoperative delirium. Med Clin North Am 2001;85:1229-39. Yamakura T, Bertaccini E, Trudell JR, Harris RA. Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol 2001 ;41:23-51. Yamakura T, Harris RA. Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol. Anesthesiology 2000;93:1095-101. Yano T, Nakayama R, Ushijima K. Intracerebroventricular propofol is neuroprotective against transient global ischemia in rats: extracellular glutamate level is not a major determinant. Brain Res 2000;883:69-76. Yoshizumi J, Marshall RW, Sanders LD, Vickers MD. Effects of small concentrations of isoflurane on some psychometric measurements. Br J Anaesth 1993;71:839-44. Zacny JP, Lichtor JL, Korttila K. Psychological and neurological disturbances related to anaesthesia. Best Pract Res Clin Anesthesiol 1992;6:645-61. Zaidi NA, Khan FA. Comparison of thiopentone sodium and propofol for electro convulsive therapy (ECT). J Pak Med Assoc 2000;50:60-63. N.N. BUTTERFIELD 157 Zuurmond WW, Balk VA, van Dis H, van Leeuwen L, Paul EA. Multidimensionality of psychological recovery from anaesthesia. Analysing six recovery tests. Anaesthesia 1989;44:889-92. 

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