The neuropsychological sequelae of on- and off-pump ... · The neuropsychological sequelae of on-...

The neuropsychological sequelae of on- and off-pump coronary artery

bypass graft surgery

Elizabeth Jane Vuletich

BSc (Hons)

School of Psychology

University of Western Australia

This thesis is presented for the degree of Doctor of Philosophy, and in partial

fulfilment of the requirements for Master of Psychology (Clinical Neuropsychology)

degree, of the University of Western Australia.

2011

i

Abstract

Post-operative neuropsychological decline is considered one of the major morbidity

outcomes following Coronary Artery Bypass Graft (CABG) surgery. Traditional CABG

uses the cardiopulmonary bypass machine to ensure a still operative field (on-pump

technique), but introduces microemboli and decreases perfusion in the brain. These can

potentially affect neurological integrity and compromise cognitive functioning.

Alternatively, performing CABG on the beating heart (off-pump method) allows normal

circulation to continue, which reduces cerebral emboli and hypoperfusion, and therefore the

risk of neurological damage. On this basis, it is argued that off-pump CABG should be less

detrimental to neuropsychological functioning than on-pump CABG. To date, research

findings have been inconsistent, largely due to substantial disagreement about what

constitutes meaningful post-CABG neuropsychological impairment. Consequently, the

relationship between on-pump CABG and cognitive dysfunction remains controversial.

Additionally, studies have not clearly established the candidate cognitive functions most at

risk during CABG surgery, or whether the effects are transient or persisting.

Methodological shortfalls, including differences in assessment times, use of control

samples, and failure to account for practice effects, measurement error and regression to the

mean, as well as varied and often arbitrary criteria used to define impairment, are likely to

blame for the lack of clarity within the literature. Using a longitudinal study, this thesis

aims to determine whether 1) pre-existing neuropsychological impairments occur in

candidates for CABG surgery, 2) CABG surgery is associated with neurocognitive

impairment, 3) neuropsychological function is differentially affected following on- versus

off-pump CABG and, therefore, whether the CPB is responsible for neurologic injury that

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manifests as neuropsychological impairment. In addition, this thesis investigates 4) which

areas of cognitive functioning or specific cognitive processes, if any, are at risk during

CABG surgery, and 5) whether changes are acute or persisting. The initial study of serial

cognitive assessment in a sample of healthy older adults (N = 46), confirmed that large

practice effects occurred when tests were repeated. Moreover, these effects varied across

cognitive domains and were not necessarily counteracted by use of alternate test versions.

These findings reaffirm the need to measure and control for practice effects in any

longitudinal study of cognitive change. Next, cognitive performance among a sample of

heart-diseased patients scheduled to undergo CABG surgery (n = 53) was compared to that

of age-matched healthy controls (n = 46). Presurgical impairments in verbal memory and

cognitive flexibility were revealed for CABG patients that could not be accounted for by

elevated stress, or mood disturbance. CABG patients were then randomly assigned to

receive either on-pump or off-pump CABG, and were assessed longitudinally at 1, 3 and 12

months after surgery. A novel statistical approach was applied to define cognitive

dysfunction using the data from age-matched controls assessed at the same intervals. This

approach simultaneously accounts for patient’s presurgical cognitive status, education,

gender, age, IQ, as well as differential rates of practice, test reliability and regression to the

mean. Impaired performances on measures of verbal fluency and processing speed were

found to be specific to the on-pump group, although only within the acute post-operative

follow-up. By 12 months there was no discernable difference in the cognitive performance

of patients who had received on- or off-pump CABG. The combined CABG sample,

however, did show widespread and persisting deficits across many of the tasks

administered at 12 months. Specifically, impairments were observed on two domains:

verbal learning and memory, and executive functioning. These findings suggest lasting

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deficits across a number of cognitive domains occur in coronary heart-diseased patients

who have undergone CABG irrespective of surgical technique. Differential patterns of

cognitive change, in the acute post-operative phase, emerged in favour of the off-pump

technique. The overall findings provided some support that on-pump CABG was related to

specific, but transient, cognitive deficits, and that these may be partially avoided through

the use of the off-pump technique. The results from the current series of studies suggest

that the aetiology of post-CABG cognitive impairment is multifactorial. In addition to the

effects related to CABG technique there appears to be an important contribution of factors

related to ischemic heart disease, as well as general effects of surgery. However, the

literature would suggest that factors other than cognition (e.g. rate of physical recovery,

comorbid medical conditions) are also important to consider when determining which

CABG procedure is the most appropriate.

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Table of Contents

Abstract ..................................................................................................................i

List of Tables......................................................................................................viii

List of Figures .....................................................................................................xii

List of Abbreviations..........................................................................................xiii

Acknowledgements ............................................................................................xiv

CHAPTER 1 : BLAME IT ON THE PUMP? ..................................................................1

Research Aims ......................................................................................................1

Background to Study.............................................................................................2

Thesis Aims and Approach ...................................................................................4

CHAPTER 2 : NEUROPSYCHOLOGICAL SEQUELAE, MECHANISMS AND

RELATION TO CABG SURGERY.................................................................................8

Link Between Vascular and Cerebral Integrity.....................................................8

Neuropathological Mechanisms for Cognitive Impairment................................14

Presurgical Neuropsychological Deficits in Candidates for CABG ...................23

Post-CABG Neuropsychological Dysfunction ...................................................25

On- Vs Off-pump Studies ...................................................................................30

CHAPTER 3 : METHODOLOGICAL CONSIDERATIONS .......................................39

Features of Study Design and Methodology.......................................................41

Regression to the Mean...........................................................................43

Practice Effects........................................................................................44

Definition of Impairment ........................................................................49

Predicted Versus Obtained Test Performances: A Novel Approach to Post-

CABG Neuropsychological Dysfunction............................................................54

Qualitative Neuropsychological Change Following CABG...............................57

Pathophysiological Mechanisms and Candidate Cognitive Functions ...............60

Neuropsychological Sequelae Following CABG................................................64

CHAPTER 4 : OBJECTIVES, HYPOTHESES AND GENERAL METHODOLOGY 65

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Thesis objectives .................................................................................................66

Hypotheses ..........................................................................................................68

Practice Effects in Healthy Older Adults ................................................68

Pre-surgical Neuropsychological Sequelae Among CABG Surgery

Patients ....................................................................................................69

Post-operative Neuropsychological Sequelae Among CABG Surgery

Patients ....................................................................................................69

Differentiation of Neuropsychological Impairments Across On versus

Off-pump CABG.....................................................................................70

Mood State and its Influence on Neuropsychological Performance in

CABG patients ........................................................................................71

Method ................................................................................................................71

Participants..............................................................................................71

Recruitment & Sample Size Calculation ................................................76

Materials..................................................................................................79

Neuropsychological Variables ................................................................80

Control Variables ..................................................................................100

Procedure...............................................................................................103

Data Analyses........................................................................................104

CHAPTER 5 : PRACTICE EFFECTS IN HEALTHY OLDER ADULTS .................110

Overview...............................................................................................110

Methodological Considerations for Assessing Cognitive Change........112

Practice Effects and Cognitive Decline.................................................123

Rationale and Aims ...............................................................................124

Hypothesis.............................................................................................125

Method ..............................................................................................................125

Sample Characteristics ..........................................................................126

Results ...............................................................................................................127

Practice Effects......................................................................................127

Test-retest Reliability ............................................................................129

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Inter-form Reliability ............................................................................131

Discussion .........................................................................................................134

CHAPTER 6 : PRE-SURGICAL NEUROPSYCHOLOGICAL SEQUELAE AMONG

CABG SURGERY PATIENTS ....................................................................................141

Overview...............................................................................................141

Background ...........................................................................................142

Hypothesis.............................................................................................145

Method ..............................................................................................................146

Results ...............................................................................................................148

Demographics and Covariates...............................................................148

Cognitive Performance..........................................................................150

Mood State and its Relationship to Cognitive Performance .................154

Discussion .........................................................................................................157

CHAPTER 7 : ACUTE NEUROPSYCHOLOGICAL SEQUELAE OF ON- VS. OFF-

PUMP CABG: A PROSPECTIVE RANDOMISED TRIAL.......................................163

Overview...............................................................................................163

Background ...........................................................................................163

Hypotheses ............................................................................................171

Method ..............................................................................................................172

Results ...............................................................................................................175

Control Data: Regression Analyses ......................................................175

Surgical Data: Screening.......................................................................178

Surgical data: One Month Follow-up....................................................179

Three Month Follow-up ........................................................................188


Discussion .........................................................................................................204

Post-operative Neuropsychological Sequelae: Differentiation of

Impairments Across On- versus Off-pump CABG...............................204

Post-operative Neuropsychological Sequelae: General CABG ............206

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Relationship Between Mood State and Post-operative

Neuropsychological Functioning in CABG Patients ............................207

Comparison of the Methods of Identifying Neuropsychological

Impairment. ...........................................................................................208

Methodological Strengths and Limitations ...........................................209

CHAPTER 8 : CHRONIC NEUROPSYCHOLOGICAL SEQUELAE OF ON- VS.

OFF-PUMP CABG .......................................................................................................219

Overview...............................................................................................219

Background ...........................................................................................219

Hypotheses ............................................................................................227

Method ..............................................................................................................228

Results ...............................................................................................................230

Sample Characteristics ..........................................................................230

Control Data: Regression Analyses ......................................................231

Surgical Data: Twelve Month Follow-up .............................................233


Discussion .........................................................................................................246

CHAPTER 9 : GENERAL DISCUSSION ...................................................................254

Outline...................................................................................................254

Rationale and Aims ...............................................................................254

Summary of Findings............................................................................257

Methodological Strengths and Limitations ...........................................262

Predicted Versus Obtained Test Performances: A Novel Approach to

Post-CABG Cognitive Dysfunction......................................................273

Mood and its Influence on Neuropsychological Test Performance ......275

Implications and Future Directions for Research..................................278

Conclusions ...........................................................................................285

References .........................................................................................................287

Appendix A .......................................................................................................317

viii

List of Tables

TABLE 4.1. .....................................................................................................................78

Sample size calculations based on standardised change from baseline to 1 month

for on- and off-pump groups. ..............................................................................78

TABLE 4.2. .....................................................................................................................99

Neuropsychological domains, tests, principal measures, and use of alternate

forms. ..................................................................................................................99

TABLE 5.1. ...................................................................................................................127

Demographic characteristics of healthy controls at each assessment. ..............127

TABLE 5.2. ...................................................................................................................130

Mean neuropsychological test performance at baseline, 1 month and 3 months.

...........................................................................................................................130

TABLE 5.3. ...................................................................................................................132

Test-retest reliability for cognitive battery across time.....................................132

TABLE 5.4. ...................................................................................................................133

Inter-form reliability: Pearson’s r and Spearman Rho (ρ) across parallel versions

of each task collapsed across time ....................................................................133

TABLE 6.1. ...................................................................................................................149

Demographic characteristics of the surgical and healthy control samples at initial

visit....................................................................................................................149

TABLE 6.2. ...................................................................................................................153

Results from ANCOVA. Relationship between demographic (covariates) and

independent variable (group) cognitive performance. ......................................153

TABLE 6.3. ...................................................................................................................156

Partial correlations between DASS scores and baseline cognitive scores in the

CABG group. ....................................................................................................156

TABLE 7.1. ...................................................................................................................176

Results of the regression analyses of controls at 1 month. ...............................176

TABLE 7.2. ...................................................................................................................177

Results of the regression analyses of controls at 3 months. ..............................177

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TABLE 7.3. ...................................................................................................................180

Demographic characteristics of the surgical and healthy control samples at 1

month. ...............................................................................................................180

TABLE 7.4. ...................................................................................................................181

Predicted-obtained difference scores for combined surgical group at 1 and 3

months. ..............................................................................................................181

TABLE 7.5. ...................................................................................................................183

Number (%) of CABG patients classified as impaired across two methods at 1

month. ...............................................................................................................183

TABLE 7.6. ...................................................................................................................185

Raw cognitive descriptive statistics at the 1 month follow-up. ........................185

TABLE 7.7. ...................................................................................................................187

Comparison of adjusted RCI method and Predicted-obtained method for

classifying patients as impaired at 1 month. .....................................................187

TABLE 7.8. ...................................................................................................................189

Demographic characteristics of the surgical and healthy control samples at 3

months. ..............................................................................................................189

TABLE 7.9. ...................................................................................................................191

Number (%) of CABG patients classified as impaired across two methods at

3months. ............................................................................................................191

TABLE 7.10..................................................................................................................193

Raw cognitive descriptive statistics at the 3 month follow-up. ........................193

TABLE 7.11..................................................................................................................194


classifying patients as impaired at 3 months.....................................................194

TABLE 7.12..................................................................................................................200

Partial correlations between DASS scores and 1 month post-operative cognitive

scores in the on-pump group. ............................................................................200

TABLE 7.13..................................................................................................................201


scores in the off-pump group. ...........................................................................201

TABLE 7.14..................................................................................................................202

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scores in the on-pump group. ............................................................................202

TABLE 7.15..................................................................................................................203


scores in the off-pump group. ...........................................................................203

TABLE 8.1. ...................................................................................................................230

Demographic characteristics of the surgical and healthy control samples. ......230

TABLE 8.2. ...................................................................................................................232

Results of the regression analyses of controls at 12 months. ............................232

TABLE 8.3. ...................................................................................................................234

Raw cognitive descriptive statistics at the 12 month follow-up .......................234

TABLE 8.4. ...................................................................................................................235

Predicted-obtained difference scores for combined surgical group at 12 month

...........................................................................................................................235

TABLE 8.5. ...................................................................................................................237

Repeated measures ANOVA for CABG and Controls from 3 to 12 months....237

TABLE 8.6. ...................................................................................................................238

Number (%) of CABG patients classified as impaired across two methods at 12

months. ..............................................................................................................238

TABLE 8.7. ...................................................................................................................239


classifying patients as impaired at 12 months...................................................239

TABLE 8.8. ...................................................................................................................244


scores in the on-pump group.............................................................................244

TABLE 8.9. ...................................................................................................................245


scores in the off-pump group ............................................................................245

TABLE A.1. ..................................................................................................................317

Test-retest reliability, Reliable change Cut-off, correction for practice effect, and

corrected RCI across measures at 1m. ..............................................................317

TABLE A.2. ..................................................................................................................318

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corrected RCI across measures at 3m. ..............................................................318

TABLE A.3. ..................................................................................................................319


corrected RCI across measures at 12m. ............................................................319

xii

List of Figures

Figure 3.1. Schematic representation of a model for assessing cognitive change

adapted from Barry et al. (2005). . .....................................................................54

Figure 4.1. Flow chart of study participation. ....................................................75

Figure 4.2. Schematic representation of the data analyses for practice effects

and the psychometric properties of the test battery...........................................107

Figure 4.3. Schematic representation of the approach to the analysis of post-

operative neuropsychological performance. .....................................................109

Figure 6.1. Flowchart of participation relevant to the study reported in the

current chapter...................................................................................................147

Figure 6.2. Group differences in verbal memory (RAVLT delayed recall) at

baseline..............................................................................................................151

Figure 6.3. Group differences in verbal learning (RAVLT total) at baseline...151

Figure 6.4. Group differences in cognitive flexibility (Trail Making Test ratio) at

baseline..............................................................................................................155

Figure 7.1. Flow chart of participation at baseline, 1 month and 3 months. ....173

Figure 7.3. Mean predicted-obtained discrepancy by group for verbal fluency

(COWAT ) at 1 month.. ....................................................................................186

Figure 7.4. Mean predicted-obtained discrepancy by group for verbal memory

(RAVLT delayed recall) at 1 month.. ...............................................................186

Figure 7.5. Mean predicted-obtained discrepancy for speed of processing (Part

A of the TMT), by surgical group.....................................................................192

Figure 8.1. Flow chart of participation at 12 months. ......................................229

xiii

List of Abbreviations

CABG Coronary Artery Bypass Graft

CHD Coronary heart disease

COWAT Controlled Oral Word Association Test

CPB Cardiopulmonary Bypass

DASS Depression Anxiety and Stress Scales

FSIQ Full Scale Intelligence Quotient

KHMT Kaufman Hand Movement Test

MCG Medical College of Georgia Complex Figures

NART National Adult Reading Test

PTCA Percutaneous Transluminal Coronary Angioplasty

RAVLT Rey Auditory Verbal Learning Test

RCI Reliable Change Index

RSPM Ravens Standard Progressive Matrices

RTM Regression to the mean

SDMT Symbol Digit Modalities Test

TMT Trail Making Test

xiv

Acknowledgements

Firstly, to my supervisors, Allison Fox & Mike Anderson, I thank you both for the

most important lessons I have learned through the process of preparing this thesis.

Your intellect and insight, ability to guide, challenge, encourage, offer thoughtful

perspectives on all aspects of my project, and provision of constructive criticism will

always be greatly appreciated.

This thesis would not have been possible were it not for the vision and superb skill of

Sir Charles Gairdner Hospital’s Cardiothoracic Surgeons, Mr Mark Newman and Mr

John Alvarez. Having witnessed Mr Newman in action, I can understand why many

participants referred to him as “the Messiah”. It was an honour and joy to work with

them both, and I thank them for providing me with the opportunity to conduct this

study. I sincerely thank the entire team at the Heart Research Institute, Sir Charles

Gairdner Hospital, for their never-ending support, encouragement, and patience. In

particular, I would like to thank Professor Peter Thompson, for continuing to believe

in me at times when I did not, and Dr Pam Bradshaw, Nola Mammatt & Jo Crittenden

for their friendship, guidance, and practical support throughout my candidature. My

colleagues, and in particular Dr Carmela Connor, at the Neurosciences Unit have also

been instrumental in providing me with encouragement, support, and flexibility

during the final stages of the thesis. For that, I am eternally grateful. Thank you also

to Professor Geoff Hammond, for supporting and quietly encouraging me along my

academic path. I would also like to acknowledge the participants who graciously

provided their time, effort and commitment to take part in this project.

A huge thank you goes to my ever supportive and encouraging family and friends

who kept me happy, balanced and grounded through the PhD journey. Sare & Lach,

who, late in the journey, provided invaluable encouragement, critical review, fun, and

conviction. I especially thank Mum, who always had time to talk through ideas, read

drafts, file hundreds of references, share laughs and wipe away tears. Finally, to Vuly,

I thank you for your absolute patience and faith, and for continuing to be the best

piece of sunshine in my life.

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CHAPTER 1 : BLAME IT ON THE PUMP?

With recent improvements to cardiac surgery procedures, mortality rates following

coronary artery bypass grafting (CABG) have decreased dramatically. As a consequence,

interest has shifted to morbidity outcomes rather than mortality following heart surgery.

One such outcome of interest is the impact that heart surgery, in particular CABG, has on

cerebral integrity and the resultant neuropsychological sequelae. With cardiovascular

surgery one of the most frequently performed surgeries in industrialised medicine, such

outcomes are potentially a major health concern and understanding the impact of these

procedures will better inform treatment decisions and patient education.

Although research has shown that patients who have undergone CABG surgery experience

cognitive dysfunction, it is not known whether these reported difficulties are a consequence

of physiological changes associated with the CABG procedure or some other factor. The

prevailing view seems to be that utilising cardiopulmonary bypass (CPB) during on-pump

CABG compromises cerebral functioning and affects cognition. However, existence of

cognitive impairment following bypass has not been unanimously supported by the

research data, and the relationship between on-pump CABG and cognitive decline is yet to

be demonstrated.

Research Aims

The main aim of the current research was to provide further understanding of

neuropsychological function following CABG. Specifically, this thesis aims to address

2

several unanswered questions regarding the neuropsychological sequelae associated with

CABG surgery, namely:

1. Is there pre-existing neuropsychological impairment among candidates for CABG

surgery?

2. Is CABG surgery associated with a risk for neurocognitive impairment?

3. Is neuropsychological function differentially affected following two types of CABG

surgery, traditional on-pump (i.e. using CPB) and off-pump; and therefore is the

CPB responsible for neurologic injury manifest as neuropsychological impairment?

4. Which areas of cognitive functioning or specific cognitive processes, if any, are at

risk during CABG surgery?

5. If CABG-related deterioration does occur, are changes acute or do they lead to long-

term cognitive impairment?

A better understanding of the relationship between CABG surgery and neurocognitive

outcomes will provide health professionals, caring for patients with coronary artery disease,

information that can inform treatment decisions and the advice and education given to

patients.

Background to Study

The first surgical re-vascularisation for coronary artery disease was performed – on the

beating heart – by Alexis Carrel in 1910 (Newman & Harrison, 2000). Some 50 years later

the CPB technique advanced the discipline by providing surgeons with a still and bloodless

3

operative field, and enabling intra-cardiac procedures to be performed (Mack, 2000).

Cardiopulmonary bypass became the universally accepted ‘gold standard’ method for

cardiac surgery. However, more recent interest in less invasive methods of intervention

fuelled a revival of beating heart surgery for coronary artery grafting (off-pump CABG).

The reintroduction of the off-pump method as a viable alternative to the traditional on-

pump technique prompted researchers to explore whether the mortality and morbidity

outcomes of these forms of surgery differ. Of current interest is the neurologic and

consequent neuropsychological decline that is believed to occur following CABG surgery.

If bypassing the cardiopulmonary system during surgery (on-pump) leads to cognitive

decline, performing surgery on the beating heart (off-pump) should reduce the risk of

neurological, and neuropsychological, dysfunction. Thus, a comparison of cognitive

performance among patients who undergo CABG either on-pump or off-pump would

enable us to determine the effect of using CPB on neuropsychological functioning. To date,

well-controlled studies that have investigated whether cognitive dysfunction can, in fact, be

attributed to the ‘pump’ are limited and have yielded inconsistent results. Chapter 2 is

dedicated to a more detailed discussion of this literature.

The reasons for this persisting confusion about whether on-pump CABG actually causes

neuropsychological impairment are numerous, although they centre around both theoretical

and methodological shortcomings within the research to date. Firstly, the definition of

cognitive impairment or decline has typically been arbitrary and often inconsistent with

neuropsychological theory. Secondly, there are fundamental methodological issues

associated with this type of research that must be considered and addressed before sensible

4

interpretation of the findings can be offered. These methodological limitations to existing

literature will be examined in greater detail within chapter 3.

Thesis Aims and Approach

The main aim of the current research was to further our understanding of the

neuropsychological sequelae of CABG by employing two sophisticated and defensible

statistical approaches to the measurement of cognitive change. Specifically, the studies in

this thesis were designed to examine the effect of two alternative methods of CABG

surgery - traditional on-pump, and off-pump technique - on cognitive outcome prior to, and

1, 3, and 12 months after surgery. In addition, this thesis examined whether all, or specific,

cognitive domains are affected, and the trajectory of any changes over a 12 month period.

To date, numerous methodological factors and disagreement regarding the measurement of

post-CABG neuropsychological impairment have complicated the research findings. The

most salient of these relate to issues of repeat neuropsychological assessment, and what

constitutes meaningful cognitive decline. The potential compounding effect of

psychological distress on poor test performance has also been largely ignored. As such, it

was necessary to examine and control for these influences in the design and analysis.

This thesis will address some of the methodological shortfalls by employing the Reliable

Change Index (RCI) and a regression-based approach that compares predicted with

obtained test performances.

5

The Reliable Change Index, first advocated for use within the CABG literature by

Kneebone et al. (1998), set the scene for the need to address important and complex

measurement issues. This approach sets limits around a measured value based on the

known, and imperfect, reliability of a given task. Follow-up scores that fall beyond these

limits are statistically unlikely the result of measurement error alone. The second

approach attempts to take this technique one step further by using regression to

simultaneously account for the influences of test-reliability, regression to the mean, and

individual rates of practice. Chapter 3 will address these approaches in detail.

Importantly, both approaches are conservative and well considered methods for examining

cognitive change that account for some of the significant problems associated with serial

neuropsychological assessment. By employing these methods this thesis will provide a

more controlled investigation of the effects specific to the surgical intervention. This will

enable us to answer, with greater certainty, whether traditional on-pump CABG produces

meaningful cognitive deficits and whether the alternative approach (off-pump) is

neuroprotective. That is, whether avoiding the use of CPB, by employing the off-pump

technique, will lessen the neurologic consequences and associated neuropsychological

impairments.

The thesis begins with a consideration of the current literature, including the cognitive

processes that appear to be at risk following CABG surgery and discussion of the

pathophysiological mechanisms that might underpin these changes (chapter 2). Chapter 2

also examines the relationship between CABG surgery and cognitive dysfunction and

addresses the existing research findings in studies that have specifically compared cognitive

6

changes following both on- and off-pump CABG. Chapter 3 will include a discussion of

the complex methodological issues impacting the measurement and definition of

neuropsychological impairment. The thesis objectives and hypotheses, and overall study

design and methodology will then be described in chapter 4. The four studies that form the

body of this thesis, which attempt to address some of these methodological shortcomings to

examine the neuropsychological sequelae of on-pump and off-pump CABG, will be

presented across chapters 5 to 8.

Chapter 5 will evaluate the pattern of practice effects and psychometric properties of the

selected neuropsychological test battery. Data from the repeat assessments of a sample of

healthy older adults, examining the psychometric properties of the neuropsychological test

battery and the rates of practice effects across cognitive domains and measures will be

presented.

Chapter 6 is dedicated to the investigation of pre-surgical deficits among candidates of

CABG, including the role of emotional distress variables on cognitive test performance

among this sample. The findings of post-operative neuropsychological sequelae will be

presented across the following two chapters (7 and 8) to delineate the acute and chronic

neuropsychological outcomes.

Chapters 7 and 8 will test whether CABG surgery results in cognitive impairment, and

specifically whether there are any appreciable differences in neuropsychological outcomes

following off-pump and on-pump technique. Determine which cognitive processes/domains

are at risk during CABG surgery. More specifically, in this chapter, I will determine

7

whether the performance decline is general, or is specific to certain cognitive processes.

Determine whether the neurocognitive effects of CABG are acute and resolvable, or lead to

chronic alterations in cognitive function. Finally, the overarching findings and implications

will be presented and discussed in chapter 9.

8

CHAPTER 2 : Neuropsychological Sequelae, Mechanisms and Relation to CABG Surgery

A proportion of patients report cognitive changes following CABG that is believed to be the

consequence of some neuropathological effects associated with the procedure. Before

reviewing the literature regarding these cognitive changes, it is important to establish why

cognitive dysfunction would be expected, and which candidate cognitive functions are

potentially at risk, following CABG surgery. In order to do this, the following section will

briefly summarise the intrinsic link between the vascular system, the brain, and cognition

before outlining the proposed specific pathophysiological mechanisms for cerebral injury

during CABG surgery. Discussion of these mechanisms will include evidence for differences

between on-pump and off-pump CABG, as well as the likely resultant cognitive deficits.

Following this, the literature on CABG-related cognitive dysfunction will be reviewed

culminating in a discussion of the evidence from randomised controlled studies of on- and off-

pump CABG. This review will highlight the major methodological issues that have made it

difficult to draw unequivocal conclusions from the literature to date.

Link Between Vascular and Cerebral Integrity

The fundamental premise in neuropsychology is that mental processes are mediated within the

brain. Associated with this is the understanding that compromised brain or neural functioning

will result in reduced mental or cognitive capacity. In turn, impaired cognition may therefore

signpost structural neurological changes within the brain. From a neuropsychological

standpoint, it is necessary to understand basic neurophysiological functioning, and the

influences of pathophysiological changes on the brain in order to predict ways in which

9

cognition may be affected. From this perspective, any procedure that may damage the brain’s

structure or function may manifest as neuropsychological dysfunction.

Relative to its small size, the brain consumes a disproportionate percentage of the body’s total

oxygen (Magistretti, 1999). To meet this metabolic demand, the brain is dependent on

continued and uninterrupted supply of both oxygen and nutrients via the bloodstream; a need

that is reflected in the extensive cerebral vasculature throughout the brain’s white, and

particularly grey matter (Zigmond, Bloom, Landis, Roberts, & Squire, 1999).

Paradoxically, the brain cannot store oxygen and, because of its considerable energy demands,

it is highly vulnerable to disturbances in energy metabolism and therefore cerebral vascular

changes (Bigler & Alfano, 1988; Scholey, 2001; Takano et al., 2007). Even a 20% reduction

in normal blood flow will result in loss of consciousness within 10 seconds, and by 30 seconds,

mitochondrial functions necessary for cellular respiration fail, rendering neural metabolism

inactive. This can have the effect of decreasing the threshold at which synaptic activity ceases

(Takano et al., 2007). Unless rapid and full reperfusion of oxygen occurs morphological

changes such as cell damage, dendritic spine loss, neuronal swelling, and necrosis can occur

(Angevine & Cotman, 1981; Takano et al., 2007). Consistent with this, even minor

fluctuations in the brain’s blood-supply can alter neural metabolism, influencing brain

function and thereby modulating cognitive ability.

Disruption to neural hemodynamic and metabolism can occur in a number of ways including

reduced blood flow and vessel blockage. Both of these mechanisms have the potential to limit

oxygen supply causing cerebral ischemia, hypoxia or anoxia and compromise neural

10

processing. Consequently, factors that affect the integrity of the broader vascular system will

potentially compromise blood supply to the metabolically vulnerable brain. As such, there

exists an important intrinsic relationship between the integrity of the brain and the functioning

of the vascular system.

Coronary Heart Disease

Coronary Heart Disease (CHD) is a vascular pathology affecting the blood supply and

functioning of the heart that has recently received much attention within the

neuropsychological literature. Whilst there are other vascular conditions, such as carotid

atherosclerosis and cerebrovascular disease, that are known to affect cerebral and cognitive

functioning, this thesis is primarily concerned with the neuropsychological outcomes

associated with the surgical treatment for severe CHD. For information on the other vascular

conditions and neuropsychological functioning the readers are directed to Johnston and

colleagues (2004), Moser et al. (2007), and Vingerhoets, Van Nooten, and Jannes (1996).

Coronary heart disease is a major health issue in western countries such as Australia. The

prevalence of angina and ischemic heart disease in Australia is around 2% of the total

population (National Heart Foundation of Australia, 2005). Males are more likely than

females to suffer from ischemic heart disease or angina, and the risk of chronic circulatory

conditions, such as coronary heart disease, increases dramatically with advancing age.

11

As the leading cause of mortality and morbidity in the industrialised world, CHD is a major

health burden. In Australia, it is the largest single cause of death (AIHW, 2008) and the single

most costly condition carrying over 20% of the total burden of all illness and injury (National

Heart Foundation of Australia, 2005). In 2003 it was the leading single cause of disease

burden in men, and the second leading cause of disease burden in women (Begg et al., 2007).

As such, those with cardiovascular conditions utilise health services 1.7 times more frequently

than patients with other conditions. Although CHD-related mortality rates are declining in

Australia (AIHW, 2008), there is a continued excessive morbidity burden which remains a

serious concern for the individual, their families, and for the health system. Effective ways of

maximising outcomes and minimising such morbidity are therefore critical.

Treatment for ischemic heart disease can be via either pharmacotherapy or revascularisation,

depending on the extent of disease. There are two main methods for revascularisation;

percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting

(CABG) which carry equivalent long-term outcomes in terms of reducing the main symptom

of heart disease, angina pectoris (Pockock et al., 1995). This thesis will focus on the CABG

method, and readers are referred to Hlatky et al. (1997) for a review on neuropsychological

sequelae associated with other revascularisation procedures.

Coronary Artery Bypass Graft Surgery (CABG)

CABG surgery involves the grafting of healthier vessels taken from elsewhere in the body (i.e.

leg, chest wall) to the cardiac vasculature to circumvent the diseased or blocked coronary

12

artery and re-establish blood supply to the heart muscles. It is an effective, life-saving

treatment for ischemic heart disease that improves patients’ quality of life and life expectancy.

Traditionally, CABG utilises a surgical technique known as cardiopulmonary bypass (CPB) to

enable surgery to be performed on the arrested heart. Because the heart is no longer beating,

the blood is not being circulated through the pulmonary arteries for essential oxygenation prior

to recirculation through the body. Rather, while under CPB, blood is bypassed through a

heart-lung machine, which enables oxygenation and circulation of the blood. A recently re-

introduced alternative technique to CPB is off-pump surgery, where grafts are placed on the

stabilized, yet beating, heart. This method negates the need for the cardiopulmonary bypass

and allows normal circulation to continue. The use of the off-pump procedure has increased

and while it is routinely performed in many hospitals, the frequency of use varies across

institutions and individual surgeons (Mack, 2000). As mentioned above, off-pump bypass is

not a new technique; in fact it preceded the development and introduction of the

cardiopulmonary bypass (Mack, 2000; Raja & Dreyfus, 2004). It has recently come back into

vogue, underpinned by the drive to reduce post-operative morbidity and, in particular,

neurological complications following bypass.

Paralleling the increase in ischemic heart disease, the frequency of cardiac revascularisations

has risen dramatically over the last few decades. Specifically, CABG surgery is one of the

most commonly performed surgical procedures in western medicine, with around 16000-

17000 operations performed each year in Australia alone (Australian Institute of Health and

Welfare, 2003).

13

With improvements in surgical technique, perioperative care, anaesthesia, and post-operative

management of patients, CABG can now be performed on more elderly, frail individuals, and

those presenting with co-morbid risk factors. Paradoxically, despite this increase in the “risk”

profile of the CABG population, the incidence of stroke and mortality resulting from cardiac

surgery has declined (Estafanous et al., 1998). Overall mortality estimates range from 1-5%

(Hannan et al., 2009; Taggart, 2002), and estimates of stroke range from 1-6.1% (Hannan et

al., 2009; Puskas et al., 2000; Roach et al., 1996; Schmitz et al., 2002; Taggart, 2002; Van

Dijk et al., 2002; van Wermeskerken et al., 2000). Consequently, the interest has shifted to the

less severe morbidity outcomes following CABG surgery.

Morbidity following CABG is reportedly common, with around 43% of patients experiencing

some complication following surgery. Morbidity can manifest in a number of ways including

renal failure, inflammation, damage to the heart, wound infection, bleeding, gastrointestinal

complications as well as cerebral injury and resultant cognitive impairments. The latter of

these complications are the leading cause of morbidity following CABG and are of current

concern within the CABG literature (Taggart & Westaby, 2001).

Over the last decade, a dedicated literature has emerged which explores the nature of these

cognitive changes over time and attempts to unravel the question of whether performing

CABG surgery using cardiopulmonary bypass (on-pump) specifically, causes cognitive

dysfunction. Before this can be addressed, it is necessary to review the proposed mechanisms

for neurological damage during bypass surgery. This will lead on to a discussion about the

likelihood of anatomical, and cognitive, specificity of such damage, before a more targeted

review of the literature addressing the cognitive sequelae of CABG surgery.

14

Neuropathological Mechanisms for Cognitive Impairment

The basic pathophysiological mechanism underlying the potential for neurological damage

with CABG is believed to be hypoxia (Browne, Halligan, Wade, & Taggart, 2003; Mutch et

al., 1997; O'Dwyer, Prough, & Johnston, 1996; Taggart & Westaby, 2001). Support for this

comes from studies reporting correlations between jugular venous oxygen desaturation and

functional neuroimaging markers of increased brain hypoxia during bypass (Mutch et al.,

1997), as well as correlations between hypoxia and cognitive impairment (Browne et al.,

2003). Essentially two processes - decreased flow (hypoperfusion) or vessel blockage due to

cerebral emboli can reduce cerebral blood flow and metabolism.

The use of artificial circulation in traditional CABG aims to mimic the body’s physiological

processes, while ensuring that the operative field remains motionless and free of blood

(Taggart, 2002). Despite sophisticated filtration, the CPB is a known source of emboli, can

reduce cerebral perfusion, and can alter important physiological states in ways which may

affect cerebral function (Abu-Omar, Cifelli, Matthews, & Taggart, 2004; Blauth, 1995; Moody

et al., 1995; Sylivris et al., 1998; Wan, LeClerc, & Vincent, 1997).

CPB has remained the central candidate in the mechanisms underpinning the cognitive

changes observed in CABG patients for two main reasons. Firstly, thrombotic or gaseous

micro and macro emboli are introduced to cerebral circulation through recannulation,

oxygenation, and disturbance of plaques and atheromatous material during the procedures

required for extracorporeal circulation (Benedict, 1994). The CPB itself can, and does,

produce a variety of debris such as bubbles, clotted blood, plaque, particles of tubing, glove

powder - that may cause blockages once reintroduced to systemic circulation. Secondly, blood

15

flow or cerebral hemodynamics may be altered through the use of the pump (M. J. G. Harrison,

1995; O'Dwyer et al., 1996). Specifically, CPB is associated with reduced cerebral blood flow

and a sustained decline in arterial pressure which could be associated with altered metabolism

and compromised cerebral functioning (Bigler & Alfano, 1988). Both of these mechanisms

(reduced blood flow, and emboli) may result in ischemic changes and tissue starvation (Aly et

al., 2003; Martin et al., 2009), which can manifest as cognitive impairment.

In contrast, the off-pump technique is rarely associated with embolisation (Abu-Omar et al.,

2004; BhaskerRao et al., 1998; Bowles et al., 2001; Diegler et al., 2000; Lee et al., 2003; Lund

et al., 2003; Motellebzadeh, 2007), and cerebral perfusion remains largely uncompromised

during and after this procedure (Chernov, Efimova, Efimova, Akmedov, & Lishmanov, 2005;

Diegler et al., 2000; Lee et al., 2003).

Emboli

There is considerable evidence to support the increased presence of embolic materials in the

cerebral vasculature during CABG surgery (Abu-Omar et al., 2004; Blauth, 1995; Brooker et

al., 1998; Fearn et al., 2001; Lee et al., 2003; Lund et al., 2003; Moody et al., 1995;

Motellebzadeh, 2007; Sylivris et al., 1998). Emboli can take the form of gaseous or

particulate matter. There are several potential sources of emboli during the bypass procedure,

such as atheromatous material dislodged from the aorta, thrombotic material released from the

left ventricle of the heart, or microemboli of lipids, platelet aggregates, air, or other particulate

matter arising from cardiotomy suction, manipulation of major vessels, cannulation,

16

defibrillation at the completion of surgery, or from the pump itself (BhaskerRao et al., 1998;

Brooker et al., 1998; Fearn et al., 2001; Lund et al., 2003). Consistent with the idea that the

CPB is the major source of emboli, studies using Transcranial Doppler Ultrasound, have

demonstrated significantly greater number of microemboli during on-pump CABG than in the

absence of CPB (off-pump) (Abu-Omar et al., 2004; BhaskerRao et al., 1998; Bowles et al.,

2001; Diegler et al., 2000; Lee et al., 2003; Liu et al., 2009; Lund et al., 2003; Motellebzadeh,

2007).

Importantly, there is evidence that these microembolic events cause morphological changes

within the brain. For example, neuronal loss, vacuolation, and gliosis have been demonstrated

to occur at the sites of embolic occlusions (Moody et al., 1995) suggesting that these emboli

cause tissue damage. The permeability of the blood-brain barrier is altered (Haggag, Russell,

Walday, Skiphamn, & Torvik, 1998; Lee & Olszewski, 1959) and histopathologically

identifiable microinfarctions are littered throughout the brain following CPB (Haggag et al.,

1998; Moody et al., 1995). Changes are also evident on neuroimaging (Abu-Omar et al., 2004;

Lee et al., 2003) although some authors have failed to demonstrate a relationship between

embolic load and structural changes within the human brain (Lund et al., 2003) and a direct

causal link remains controversial. These latter findings raise some doubt as to whether, or to

what extent, increased embolic load during on-pump CABG can cause neurological damage

that is significant enough to affect cognition.

If emboli are harmful to neuronal tissue (Haggag et al., 1998; Moody et al., 1995) they might

be expected to influence cognitive functioning. However, studies that have correlated embolic

load and cognitive change have produced mixed findings (Martin et al., 2009). For example,

17

Lund et al. (2003), Selnes and colleagues (1999), and more recently Liu et al. (2009) reported

no relationship between increased levels of cerebral microemboli and neuropsychological

functioning. However, Selnes et al. (1999) did not directly measure emboli, but used

subjective report by the surgeons of the probability of emboli, which may have produced

inaccurate data. It was not clear what cognitive measure (at 3 months) Lund et al. used to

correlate with the number of emboli, and Liu et al.’s logistic regression analyses may have

been confounded by a significant degree of variability in the number of emboli detected during

surgery as well as the criteria used to define post-operative cognitive impairment. Positive

correlations between perioperative emboli and post-operative cognitive decline have been

reported at discharge (Diegler et al., 2000), 1 week (Fearn et al., 2001) and 5 years after

surgery (Stygall et al., 2003).

The nature of these neuropsychological effects will depend on the location, size, extent and

composition of these microemboli (Jacobs et al., 1998; Selnes, Goldsborough, Borowicz,

Enger, et al., 1999). Unfortunately, most studies have correlated microembolic load with a

single measure of cognitive impairment (Diegler et al., 2000; Lund et al., 2003; Stygall et al.,

2003), rather than across specific tasks or cognitive domains (Fearn et al., 2001; Jacobs et al.,

1998). Additionally, many have not specifically examined the concordance between

microembolisation and cognitive decline (BhaskerRao et al., 1998; Lee et al., 2003). Within

the literature reviewed, memory and working memory deficits appear the most commonly

associated with elevated microembolic events (Abu-Omar et al., 2004; Selnes, Goldsborough,

Borowicz, Enger, et al., 1999). This indicates that certain anatomical regions or networks are

vulnerable to the effects of embolic showers during CABG surgery.

18

Large emboli typically occlude larger vessels such as the middle cerebral artery (MCA), while

small emboli travel to smaller vessels and often end up in border zones or watershed regions

(Harrison, 1995; Knipp et al., 2008; Moody, Bell, & Challa, 1990; Moody, Bell, Challa,

Johnston, & Prough, 1990). In studies using bilateral Transcranial Doppler Ultrasound, there

is controversy over whether emboli favour the pathway leading from the right brachiocephalic

trunk. For example rates of embolisation have been reported as greater over the left middle

cerebral artery (Lee et al., 2003) and the right (Jacobs et al., 1998). Why these differences

across studies occur is unclear, although inspection of individual patient data reported by

Jacob et al. indicates that the pattern and number of emboli are highly variable. Moreover,

differences in Doppler techniques and instruments can produce quite different estimates of

embolisation, which makes it difficult to compare across studies (Martin et al., 2009).

However, neuroimaging and histopathological findings do not support any hemispheric

preference or clear regional anatomical selectivity (Knipp et al., 2008), although there is some

evidence for a higher prevalence of embolic dilations in more densely vascularised areas such

as the cortex and deep grey matter (Moody et al., 1995). Inspection of data presented by Knipp

et al. suggests that the bilateral frontal lobes appear most vulnerable to new ischemic lesions.

While the distribution of emboli may not be selective, the vulnerability of brain regions to

ischemic events is (Moody, Bell, & Challa, 1990; Small & Buchan, 1996). Understanding of

the potential anatomic specificity of embolisation, or at least the neuronal damage caused by

embolic events, can provide insights into the likely neuropsychological deficits that occur

following on-pump CABG. This will be expanded following discussion of the perfusion

changes in CABG surgery.

19

Hypoperfusion

A reduction in blood flow or hypoperfusion is also a common consequence of

cardiopulmonary bypass, and has been cited as one of the other major potential mechanisms

for cerebral injury following CABG. As with emboli, hypoperfusion has the potential to cause

cerebral ischemia, and deprive the brain tissue of necessary nutrients and oxygen. Perfusion

need only fall below resting metabolic demand for a few minutes for ischemia to occur

(O'Dwyer et al., 1996).

Within the CABG literature, significant changes in cerebral hemodynamics have been reported

during CPB (Chernov et al., 2005; Fearn et al., 2001; Gottesman et al., 2007; Lee et al., 2003).

As with increased emboli, this reduction in cerebral blood flow and metabolism is observed in

on-pump, but not off-pump CABG (Chernov et al.; Lee et al.). In particular, reduced

perfusion following on-pump CABG appears to be both regional and scattered multifocal,

affecting bilateral occipital and cerebellar lobes, precunei and thalami, and the left temporal

lobe (Lee et al.). To the contrary, there seems to be some controversy over whether such

hemodynamic changes occur during off-pump For example Lee et al. report no such decline,

while others (Chernov et al.) have noted significant improvement in cerebral perfusion within

frontal, parietal, and occipital regions following the off-pump procedure.

Comparing jugular oxygenation, Diephius et al. (Diephuis et al., 2005) reported significantly

lower levels of saturation among patients randomised to off-pump over traditional CPB CABG.

Whilst jugular oxygen desaturation has been previously associated with lower cerebral blood

flow and reduced mean arterial pressure (Croughwell et al., 1992), the precise nature of the

20

relationship between these variables and cognition remains uncertain (Martin et al., 2009) and

the cause of apparent associations is speculative.

Recovery of cerebral perfusion and oxygenation appears to be quite protracted, with hypoxia

evident in the majority of CPB patients two days after surgery (Browne et al., 2003) and

regional cerebral blood flow levels failing to return to baseline levels even 6 months post-

operatively (Chernov et al., 2005). These findings demonstrate that cerebral perfusion and

oxygenation are chronically affected as a consequence of on-pump CABG. Whether such

hypoperfusion translates into true ischemic damage is unclear (Kohn, 2002; Simonson et al.,

1994).

Even less clear is whether such cerebral disruption in on-pump CABG causes cognitive

dysfunction. Studies of the relationship between hypoperfusion or low intra- or post-operative

oxygen saturation and cognitive functioning following bypass have yielded inconsistent results.

On the one hand, some works suggest that these factors are unrelated to cognitive impairment

(Newman et al., 1995; Robson et al., 2000) while others (Browne et al., 2003; Chernov et al.,

2005; Fearn et al., 2001) have shown a clear relationship between cerebrovascular reactivity

variables (such as perfusion and oxygen saturation) and changes in overall cognitive

performance.

For example, reduced mean arterial pressure has been shown to correlate moderately with

measures of attention (Fearn et al., 2001), while reduced cerebral perfusion in the right

posterior parietal region correlated with deterioration in delayed nonverbal memory (Chernov

et al., 2005). Although reduced mean arterial pressure was not a significant predictor of

21

overall cognitive decline in Newman et al.’s study (1995), it correlated with a circumscribed

deficit on a digit-symbol substitution task among elderly patients. Collectively, these findings

would suggest that hypoperfusion, arising from the pump, is an important factor in post-

operative cognitive dysfunction.

In summary, multiple microemboli and hypoperfusion are the most likely mechanisms for

neuropsychological changes following on-pump CABG as both of these mechanisms have the

potential to reduce cerebral metabolism and cause hypoxic or ischemic injury. The evidence

suggests that these factors are likely to cause some degree of neurological damage, although is

more compelling for emboli composed of lipid or particulate matter, than hypoperfusion. In

reality, it is likely that the combination of hypoperfusion and emboli arising from the

traditional CABG procedure will increase the risk of hypoxia and related neural damage

(Caplan & Hennerici, 1998).

Anatomical Specificity of Ischemia and Hypoxia

Complete cessation of blood supply (as we might expect with blockage from particulate

emboli) can produce focal lesions, while reduced blood flow is more likely to produce mild

ischemic changes in the watershed regions or border zone (i.e. boundary regions the farthest

from major vessels and supplied by smaller capillaries) (Harrison, 1995; Moody, Bell, &

Challa, 1990). While the distribution of emboli is not selective (Moody, Bell, Challa, et al.,

1990) certain brain regions are more vulnerable to anoxic events than others (Moody, Bell, &

Challa, 1990; Small & Buchan, 1996). The brain regions that are highly susceptible to

22

metabolic changes include the basal ganglia, cerebellum, hippocampus, and the

parietotemporal cortex. In particular, research has highlighted a vulnerability of mesial

temporal (particularly hippocampal) and frontal regions to ischemia and anoxia, in addition to

diffuse damage (Bigler & Alfano, 1988; Cummings, Tomiyasu, Read, & Benson, 1984; Petito,

1987). Diffuse white matter changes (Filley, 1998) can also occur; disrupting important neural

networks involved in higher-level thought (Cummings, 1993, 1995; Reed, 2006; Tekin &

Cummings, 2002). This might lead us to hypothesize that hypoxia or ischemia, from

hypoperfusion, and or embolic showers, would produce circumscribed, focal deficits in

addition to more global changes.

In examining the broader neuropsychological literature, we find evidence that this is the case

(Bigler & Alfano, 1988; Kelly, Claypoole, & Coppel, 1990). For example, Bigler and Alfano

(1988) investigated neuropsychological correlates of severe anoxic injury versus closed head

trauma. They reported a global deficit (across most measures) in their anoxic, but not their

head injured sample, although the greatest impairments were identified in general memory

functioning. They concluded that anoxia produces diffuse, non-specific deficits, with memory

function the most predominantly affected cognitive domain.

The on-pump method induces embolisation and persisting hypoperfusion, which are known to

cause multiple microinfarctions and generalised ischemic damage within the brain. By

comparison, the off-pump method does not. On this basis, the use of the CPB (on-pump)

remains the likely candidate for neurological damage (Mack, 2000). Whether such

neurological insult, arising from on-pump CABG, translates into lasting, meaningful cognitive

23

deficits remains controversial and there are other potential factors that may contribute to the

cognitive difficulties observed following this type of surgery.

The following section will review the literature of the cognitive deficits associated with

traditional on-pump CABG, before outlining the research that has directly compared the

relative neuropsychological outcomes after on-pump or off-pump surgery.

Presurgical Neuropsychological Deficits in Candidates for CABG

As the CPB is the proposed candidate for disrupted cerebral hemodynamics and metabolism,

the literature has predominantly focused on the post-surgical cognitive deficits. It is also

plausible that alteration of cerebral blood flow and metabolism also occur with severe

cardiovascular disease. Severe hypertension that is common among patients with significant

coronary artery disease is associated with hemodynamic instability, cerebral ischemia, white

matter damage and lacunaes (Adams et al., 1993; Fisher, 1982; Mäntylä et al., 1999). Such

structural compromise can give rise to functional impairments including cognitive dysfunction

(Jokinen et al., 2006; Kramer, 2002; Longstreth et al., 1996; Reed, 2006; Ylikoski et al., 1993).

On this basis, it might be expected that individuals with severe cardiac illness (such as those

scheduled for CABG surgery) would show neuropsychological impairments.

Indeed, cognitive dysfunction has also been reported in candidates for CABG (Christine. S.

Ernest, Murphy, et al., 2006; Keith et al., 2002; Rankin, Kochamba, Boone, Petitti, &

Buckwalter, 2003; Vingerhoets, Van Nooten, & Jannes, 1997), raising the question that the

24

cardiovascular disease process may be a causative factor (Selnes et al., 2003; Vingerhoets,

Van Nooten, & Jannes, 1997).

Selnes and colleagues (2009) have tracked the trajectory of cognitive change among

cardiovascular diseased patients who underwent CABG, or were managed without surgical

intervention. Their results suggested that, compared to healthy controls and irrespective of

whether patients were due for surgery, significant and generalised cognitive impairments

occurred.

Consistent with such findings, disease-related factors (such as hypertension, impaired

ventricular function, atherosclerosis, history of cardiac arrhythmia, cardiac arrest, or acute

myocardial infarction, and poor ejection fraction) are associated with poor cognitive

performance (Vidal et al., 2010; Vingerhoets, Van Nooten, & Jannes, 1997; Zuccalà et al.,

1997).

In addition, candidates may show reduced cognitive performance because of elevated anxiety

and emotional distress (Brown, Scott, Bench, & Dolan, 1994; Duits et al., 1998; Keith et al.,

2002). Not surprisingly, CABG patients have been shown to be significantly more anxious,

compared with non-surgical healthy controls prior surgery (Andrew, Baker, Kneebone, &

Knight, 2000; Keith et al., 2002; Tsushima, Johnson, Lee, Matsukawa, & Fast, 2005).

However, correlations between pre-surgical depression, anxiety, and cognitive dysfunction

have been negligible (Andrew et al., 2000; Tsushima et al., 2005), with the exception of one

study (McKhann, Borowicz , Goldsborough, Enger, & Selnes, 1997) that reported better

25

cognitive performance among non-depressed compared to depressed patients after controlling

for age.

Post-CABG Neuropsychological Dysfunction

Observations of CABG patients over the last few decades indicate that many patients suffer

from post-operative cognitive decline, which has been historically attributed to the use of CPB.

The incidence of cognitive impairment following CABG, however, varies dramatically across

studies and post-operative follow-up times. For example, the greatest incidence is claimed to

occur around the time of discharge, although estimates range from 3-96% (Mahanna et al.,

1996; Newman et al., 2001; Rasmussen, Christiansen, Hansen, & Moller, 1999; Roach et al.,

1996; Vingerhoets, Van Nooten, Vermassen, De Soete, & Jannes, 1997). Estimates are

between 13.8-50% at 6 to 12 weeks, 8-55% at 6 months, and 8 to 42% at 3-5 years (Ho et al.,

2004; Müllges, Babin-Ebell, Reents, & Toyka, 2002; Newman et al., 2001; Rasmussen et al.,

1999; Roach et al., 1996; Selnes, Goldsborough, Borowicz, Enger, et al., 1999; Diederik. van

Dijk et al., 2000; Vanninen et al., 1998; Vingerhoets, Van Nooten, Vermassen, et al., 1997;

Zamvar et al., 2002). Differences in follow-up times, measurement tools, and definitions of

impairment are thought to be responsible for these diverse findings (Mahanna et al., 1996;

Roach et al., 1996; Diederik. van Dijk et al., 2000).

In addition to the inconsistency in the reported incidence of dysfunction, there is a variety of

patterns of change reported over time. Specifically, there are reports of both deterioration

(Bendszus, Reents, Franke, Müllges, & al., 2002; Jacobs et al., 1998; McKhann,

Goldsborough, et al., 1997; Stygall et al., 2003; Taggart, Browne, Halligan, & Wade, 1999),

26

and improvement (Bendszus et al., 2002; Jacobs et al., 1998; Selnes et al., 2001; Taggart et al.,

1999) in test performance over time. There are also reports of a proportion of CABG patients

showing no changes from pre-operative levels, or an absence of impairment at follow-up

(McKhann, Goldsborough, et al., 1997).

A pattern of early transient post-operative neuropsychological decline, followed by recovery

has been reported by a number of researchers (Bendszus et al., 2002; Browne et al., 2003;

Jacobs et al., 1998; Knipp et al., 2008; Mahanna et al., 1996; McKhann, Goldsborough, et al.,

1997; Newman et al., 2001; Rasmussen et al., 1999; Selnes et al., 2001; Stygall et al., 2003;

Taggart et al., 1999). Others, however, reported an absence of cognitive impairment (Kilo et

al., 2001; Vingerhoets, Van Nooten, Vermassen, et al., 1997) and even improvement from

baseline scores following CABG surgery (McKhann et al., 2005; Selnes et al., 2003).

In terms of chronic, or persisting changes (exceeding 3 months), findings are mixed.

Consistent with the proposed pattern of early deterioration and recovery, many studies report

improvement in test performance, and a lower incidence of impairment beyond 3 months

(Mahanna et al., 1996; McKhann, Goldsborough, et al., 1997; Müllges et al., 2002; Newman

et al., 2001; Selnes et al., 2001). Four studies, however, reported an additional “late” decline

following a pattern of decline at discharge and subsequent recovery within the acute phase

(Knipp et al., 2008; Newman et al., 2001; Selnes et al., 2009; Selnes et al., 2001; Stygall et al.,

2003), while another study showed continued improvement from baseline cognitive test

performance after 4.5 years (Müllges et al., 2002).

27

The trajectory of change over time also varies considerably across cognitive domains and

individual tests. That is, even within individual studies, different patterns of deterioration in

improvement have been reported across different measures over time. Transient declines in

performance have been reported for measures of verbal and visuospatial memory (Jacobs et al.,

1998; McKhann, Goldsborough, et al., 1997; Stygall et al., 2003), language (McKhann,

Goldsborough, et al., 1997), visuoconstruction (Selnes et al., 2001), attention and working

(Knipp et al., 2008; Stygall et al., 2003), and speed of processing (Jacobs et al., 1998; Selnes

et al., 2001). Subsequent improvement has also been reported by some investigators for many

of these domains, namely; verbal memory (Jacobs et al., 1998; McKhann, Goldsborough, et al.,

1997), visuospatial memory (Jacobs et al., 1998), language (McKhann, Goldsborough, et al.,

1997), and speed of information processing (Jacobs et al., 1998). In contrast, persisting

decline has been reported by others for visuospatial memory (McKhann, Goldsborough, et al.,

1997; Selnes et al., 2009), attention (Stygall et al., 2003), and executive functioning (Selnes et

al., 2009). Improvement, either where there is an absence of decline or where performance

exceeds pre-surgical levels, has been observed for measures of executive functioning (Selnes

et al., 2001; Townes et al., 1989), memory (Jacobs et al., 1998; Townes et al., 1989),

concentration and attention (Jacobs et al., 1998; Townes et al., 1989). The lack of uniformity

in the trajectory of change, both across and within cognitive domains, makes it difficult to

conclude which cognitive domains are affected and their rates of recovery.

Collectively, the findings within the general CABG literature do appear to show a pattern of

performance decline followed by improvement that, authors have concluded, reflects early

post-operative dysfunction and subsequent recovery following CPB. While this pattern might

be interpreted as evidence for a transient cognitive dysfunction, there are alternate

28

explanations for these results. Specifically, scores can vary purely as a result of measurement

error, regression to the mean, or practice in the absence of change that can be attributed to the

procedure itself (Browne, Halligan, Wade, & al., 1999; Kneebone, Andrew, Baker, & Knight,

1998; Rabbitt, Diggle, Holland, & Mc Innes, 2004; Rabbitt, Diggle, Smith, Holland, & Mc

Innes, 2001; Rabbitt, Lunn, Wong, & Cobain, 2008). Moreover, given the potential

confounding factors, attributing the cause of any reported cognitive changes to the use of CPB

is speculative in the absence of an adequate control group.

Control samples are necessary when attempting to infer a causal relationship between

variables. They provide researchers with greater confidence that the effect of interest is due to

the difference between the control group and experimental group. Without a well-matched

control sample, we cannot be confident that any observed changes in cognition are related to

the CABG procedure.

Within the CABG literature, even when control samples are included the evidence for CPB-

related impairment is also far from convincing. A pattern of impaired performance among

CABG patients relative to controls, is observed at discharge (Bruggemans, Van Dijk, &

Huysmans, 1995; Kilo et al., 2001; Kneebone et al., 1998; Townes et al., 1989), although

evidence for subsequent recovery is somewhat inconclusive. Many studies reported an

improvement in cognitive scores over time (Kilo et al., 2001; McKhann et al., 2005; Selnes et

al., 2003; Townes et al., 1989), or no difference in pattern of cognitive change between CABG

and controls (McKhann et al., 2005; Selnes et al., 2003; Vingerhoets, Van Nooten, Vermassen,

et al., 1997). Additionally, some report persisting deficits, absence of improvement, or

29

attenuated practice effects in their CABG group, which may reflect residual cognitive

weakness (Fearn et al., 2001; Kilo et al., 2001; Selnes et al., 2009; Vanninen et al., 1998).

Interestingly, whilst performance appears impaired relative to healthy controls (Bruggemans et

al., 1995; Kneebone et al., 1998; McKhann et al., 2005; Townes et al., 1989), cognitive

impairments are also reported among coronary artery diseased, other vascular, or urological

surgery controls (Selnes et al., 2003; Townes et al., 1989; Vingerhoets, Van Nooten,

Vermassen, et al., 1997). Though this may suggest that deficits are not specific to CABG, this

pattern is not universal (Bruggemans, Van Dijk, & Huysmans, 1995; Townes et al., 1989). In

addition, few studies have directly compared the magnitude or pattern of change between

CABG and controls. Failing to do this, by examining only the presence or absence of

impairment ignores an important possibility. That is, that systematic and relevant group

differences - such as attenuated practice effects- may have occurred (Fearn et al., 2001;

Müllges, Berg, Schmidtke, Weinacker, & Toyka, 2000; Vanninen et al., 1998) .

To summarise, the reported incidence of impairment varies considerably, and has resulted in

confusion about whether, and to what extent, CABG is associated with cognitive impairment.

Studies without control groups seem to point to a pattern of early decline, most pronounced

around the time of discharge, followed by improvement. This improvement has been

considered evidence for “recovery” of functioning despite the absence of adequate control

samples to tease out the effects of other influences on test performance including practice

effects, regression to the mean, test-reliability and changes in mood. Within the controlled

studies, early impairment is also observed, however, there is conflicting evidence regarding

subsequent recovery.

30

Given the dramatic range in reported incidence and nature of impairment, and the caveats on

interpreting the changes in neuropsychological test scores over time, it would be difficult to

conclude that CABG surgery causes neuropsychological dysfunction. Consequently, the

incidence, severity and temporal nature of these neuropsychological drawbacks continue to be

the focus of ongoing debate.

To determine whether the CPB is the cause of cognitive deterioration, the ideal control group

would only differ on the use of CPB during the surgical intervention. That is, they would be

identical to patients undergoing on-pump CABG in terms of demographic features, coronary

artery pathology, anaesthetic regimen, and they would undergo a similar surgical intervention

without CPB. Fortunately, the re-emergence and popularisation of the off-pump CABG

technique has provided such a group, and has enabled researchers to compare the

neuropsychological outcomes of these procedures.

On- Vs Off-pump Studies

Observational Studies

If CPB is deleterious to neurological and neuropsychological functioning, then avoiding the

use of CPB during surgery should reduce the risk of cognitive deterioration. Since the re-

introduction of off-pump surgery as a practicable and less invasive alternative to on-pump

CABG, several observational studies have assessed the cognitive outcomes following these

two procedures (BhaskerRao et al., 1998; Browne et al., 2003; Chernov et al., 2005; Kilo et al.,

2001; Malherios et al., 1995; Schmitz et al., 2002; Stroobant, Van Nooten, Van Belleghem, &

31

Vingerhoets, 2002; Taggart et al., 1999). However, findings across these studies have been

mixed, and have failed to clarify whether performing CABG on-pump causes cognitive

impairment and whether the off-pump method results in better cognitive outcome.

Specifically, some studies have reported no differences between these techniques (Malherios

et al., 1995; Stroobant et al., 2002), while others have reported results in favour of the off-

pump procedure (BhaskerRao et al., 1998; Chernov et al., 2005).

For example, an early study by Malheiros et al. (1995) examined the frequency of neurological

and neuropsychological abnormalities among 81 CABG patients at discharge. Aside from

shorter operative times and fewer vessels requiring grafting, off-pump patients (n= 33) were

reasonably well matched with the remaining patients who underwent on-pump CABG. Post-

operatively, there was a similar incidence of frank neurological abnormalities between both

groups. In terms of cognition, there were no detectable group differences in the pre- and post-

operative difference scores on any of the neuropsychological measures. Both groups showed

similar magnitudes of deterioration in attention and speed of information processing, and

equivalent improvements on measures of memory, leading the authors to conclude that the

pump may not be the single cause of neurological morbidity in patients following CABG

surgery.

In a much larger study (N=322), BhaskerRao et al. (1998) also evaluated cognitive

performance around the time of discharge. Despite a clear selection bias resulting from the

decision to perform off-pump surgery on patients with severe co-morbidity (n=17), their

results strongly favour the off-pump method. They reported a striking dissociation between

the two groups on an antisaccadic eye movement task, with 94% of off-pump and only 35.4%

32

of on-pump patients producing intact performances. Moreover, none of the off-pump group,

compared to 28% of the on-pump patients, completely failed this task. These findings

indicated to the authors surgical technique was indeed an important factor in cognitive decline,

with clear impairments following on-pump CABG.

Whilst Taggart, Browne, Halligan and Wade (1999) concluded that the profiles of cognitive

change were similar across both CABG procedures, closer inspection of their data shows a

selective and significant deterioration in verbal memory in their on-pump group. Moreover,

the on-pump patients in this study failed to improve at the same rate as those in the off-pump

group on a visual search task after 3 months that, the authors concede might also reflect

impairment. While this finding is complicated by the apparent selection bias resulting from

less-severely diseased individuals receiving off-pump surgery, it does highlight an important

outcome of longitudinal studies; that is the absence of improvement may be a relevant

indicator of acquired cognitive impairment.

Similarly, while the incidence of impairment did not differ between the on-pump and off-

pump methods in Stroobant et al.’s (2002) study, patients in the off-pump group showed

significantly better performance on the Judgement of Line Orientation Test relative to the on-

pump group at follow-up.

In examining the relationship between changes in cerebral perfusion and neuropsychological

test performances before and after on- and off-pump CABG Chernov, Efimova, Efimova,

Akmedov, and Lishmanov (2005) observed a similar pattern of change across the two groups

However there were significant differences in the magnitude of decline, with results in favour

33

of the off-pump method. Both groups showed deteriorations in processing speed, attention,

learning and memory, and declines were most pronounced at the two-week follow-up.

Thereafter, there was some improvement at 6 months, although both learning and memory

remained affected. Again, performance was poorer among the on-pump patients, though

group differences were no longer significant at the 6-month follow-up. Using a criterion of

20% decline from baseline scores on at least two measures, there was a greater frequency of

impairment in on-pump patients compared to the off-pump patients at two-weeks and at 6

months post-surgery.

More recently, Selnes et al. (2009) evaluated the longitudinal changes in on-pump, off-pump,

non-surgical cardiac patients, and healthy controls on a range of cognitive measures.

Collectively, their results showed only marginal benefit from performing CABG off-pump,

with all cardiac groups demonstrating cognitive decline from baseline to 72 months

postoperatively. Inspection of their data, however, revealed a greater number of domains

affected following on-pump versus off-pump and no surgery.

Important differences between on- and off-pump CABG have also been observed using highly

sensitive electrophysiological measures of brain function (Event Related Potentials (ERP):

Kilo et al., 2001). In Kilo et al.’s (2001) study, 224 patients who underwent on-pump CABG

produced a significantly prolonged P300 waveform 7 days after surgery, whereas those who

received the off-pump method (n = 84) showed an improvement on this measure. Post CABG

cognitive impairment, and the apparent superiority of the off-pump method were not, however,

reflected in cognitive test performance on two basic screening measures (Kilo et al.). Mean

34

scores on the Mini Mental State Examination, and on alternate versions of the Trail Making

Test, remained unchanged from baseline to follow-up.

That some scores appear to deteriorate following off-pump, as well as on-pump CABG

(Browne et al., 2003; Taggart et al., 1999) has lead to the hypothesis that the pump may not be

the sole factor in the aetiology of post-CABG cognitive decline (Taggart & Westaby, 2001).

This raises the possibility that off-pump CABG may itself induce separate pathophysiological

changes that manifest as cognitive dysfunction. Unfortunately, observational studies

comparing neuropsychological outcomes after on-pump and off-pump CABG have been

unable to offer any firm resolution to the debate about whether off-pump CABG offers a

distinct cognitive advantage, or whether the neuropsychological outcome is similar to the on-

pump method (Selke et al., 2005).

While observational studies have encouraged discussion about the potential benefits of

performing CABG surgery without the use of CPB, the weight of their findings is limited by

the potential influence of selection biases (Ferrer, Salthouse, Stewart, & Schwartz, 2004;

Rabbitt, Watson, Donlan, Bent, & McInnes, 1994) and other, often unmeasured, confounding

variables, on neuropsychological outcome.

For example, differences in estimated premorbid IQ were apparent in Stroobant et al.’s (2002)

study, which might account for the different observed rates of test improvement at follow-up

(Lowe & Rabbitt, 1998; Rabbitt et al., 2004; Rabbitt et al., 2001; Rabbitt et al., 2008).

Additionally, several studies have reported significantly fewer number of grafts (Browne et al.,

2003; Malherios et al., 1995; Taggart et al., 1999) and shorter time under anaesthesia (Browne

35

et al., 2003; Malherios et al., 1995; Taggart et al., 1999) in off-pump compared to on-pump

CABG. It is plausible that these reflect less advanced disease, and therefore better general

vascular (including cerebrovascular) health, among patients who were selected to receive off-

pump CABG. The number of grafts has been shown to correlate positively with cognitive

dysfunction (Kilo et al., 2001).

Conversely, off-pump surgery has been selected for patients with more severe co-morbid

illnesses, such as chronic obstructive pulmonary disease, history of transient ischemic attacks

or stroke, AIDS, uncontrolled diabetes mellitus and morbid obesity (BhaskerRao et al., 1998).

Many of these co-morbidities have known neuropsychological sequelae (Kelly et al., 1990;

Verhaeghen, 2003), and therefore might be expected to increase patients’ vulnerability to

potentially deleterious effects of surgery .

Many of the observational studies that have concluded no group differences have also based

their findings on the presence or absence of impairment. Dichotomising cognitive outcomes

in this way has been criticised because it fails to acknowledge, or account for, the possibility

that rates of improvement on cognitive test scores may differ systematically across these

groups. Classifying patients as either impaired or not, without considering these factors, can

obscure other very relevant patterns of change and grossly mislead our interpretation of the

data. Indeed, equally relevant information can be derived from a reduction or relative absence

of improvement in test performance within one group. Unfortunately, when cognitive data are

examined as continuous variables, the findings remain inconclusive.

36

Randomised Controlled Trials

Randomly allocating participants to experimental group is a useful technique to eliminate or

reduce potential sample biases and confounds. However, to date there have been few

published fully randomised clinical trials assessing the neurocognitive outcomes of on- and

off-pump CABG surgery, and reported findings have been fairly heterogeneous (Takagi,

Tanabashi, Kawai, & Umemoto, 2007a, 2007b). Of these, several studies report no significant

group differences between on- and off-pump surgery (Baker, Andrew, Ross, & Knight, 2000;

Hernandez et al., 2007; Jensen, Hughes, Rasmussen, Pedersen, & Steinbruchel, 2006; Lloyd et

al., 2000; Lund et al., 2003; Tully, Baker, Kneebone, & Knight, 2008) while others

demonstrate superiority of the off-pump procedure (Chernov et al., 2005; Diegler et al., 2000;

Christine. S. Ernest, Worcester, et al., 2006; Zamvar et al., 2002). Others have reported no

difference in the incidence of dysfunction but greater improvement in cognitive performance

following the off- pump technique (Lee et al., 2003; Van Dijk et al., 2002) and one study

reported better rates of improvement following on-pump relative to off-pump CABG (Rankin

et al., 2003).

Within the last few years, two meta-analyses comparing on- and off-pump CABG have been

published (Marasco, Sharwood, & Abramson, 2008; Takagi, Kawai, & Umemoto, 2008;

Takagi et al., 2007a) with somewhat conflicting conclusions. Both analyses by Takagi and

colleagues provided partial support for reduced impairment following off-pump CABG, with

significantly better neuropsychological outcomes at 1 to 3 months in the six included studies.

These authors, however, found non-significant or negligible effects either in the very early

post-operative period or after 6 months. In an analysis of eight randomised controlled trials,

Marasco et al. (2008) reported only one significant difference from five neuropsychological

37

measures; Trail Making Test Part A. Based on the pooled findings, performance on this task

improved in the off-pump but not the on-pump group at both acute and longitudinal follow-up

times.

Although off-pump surgery is considered to reduce the risk of neuropsychological morbidity,

it is difficult to strongly conclude this based on the few sizeable, fully randomised studies

conducted to date, and given the methodological inconsistencies throughout the literature. In

addition, most studies have not attempted to evaluate which cognitive domains may be

compromised during CPB, and whether these are impaired as a result of the physiological

changes caused by on-pump surgery, or whether there are other methodological explanations

for any observed changes. In particular, only three of the reviewed studies into the long-term

outcomes of CABG have attempted to address the issues arising from practice effects (Ernest,

Worcester, et al., 2006; Kneebone et al., 1998; Tully et al., 2008). Failure to do so in other

studies has impeded the definition of meaningful cognitive decline, and the identification of

the cognitive processes that are at risk during cerebral insult stemming from CABG surgery.

Additionally, major potentially life-threatening surgery can induce stress, anxiety and

depression which in turn may influence neurocognitive functioning (Biringer et al., 2005;

Brown et al., 1994; Kizilbash, 2002; McKhann, Borowicz , et al., 1997). Despite this, few of

the studies above have acknowledged, or accounted for, the known impact of mood on

cognitive performance (Lloyd et al., 2000; McKhann, Borowicz , et al., 1997; Townes et al.,

1989). This might be important for pre- and early post-operative assessments (Townes et al.,

1989), although findings have not yet fully supported the presence of an association between

post-CABG dysfunction and mood (Andrew et al., 2000; Ernest et al., 2007; Tsushima et al.,

38

2005). While these limitations are not adequately dealt with, the question as to whether

changes in cognitive performance can be attributed to the CABG procedure, and whether these

changes affect all, or select cognitive domains, remain.

In sum, the assessment of post-operative cognitive changes has been complicated by

methodological differences in follow-up times and neuropsychological tests. Additionally,

complex factors associated with serial assessment have impeded the definition of meaningful

decline. Collectively, these factors have made it difficult to compare across studies, and to

identify the cognitive processes, if any, that are at risk during CABG, and whether deficits are

transient or persisting.

The following chapter will explore how study design and methodological differences have

contributed to the inconsistencies within the research findings to date. Discussion will centre

around what constitutes meaningful neuropsychological impairment, and the importance of

addressing the complex factors associated with repeat neuropsychological assessment in the

measurement of cognitive change. The methodology used in the study presented in this thesis

will then be outlined followed by a discussion of the proposed pathophysiological mechanisms

and associated neuropsychological consequences following CABG surgery. Chapter 3 will

conclude with the objectives and specific hypothesis of the current research.

39

CHAPTER 3 : Methodological Considerations

Post-operative neuropsychological decline is considered one of the major morbidity outcomes

following CABG (BhaskerRao et al., 1998; Fearn et al., 2001; Mack, Mitchell, & Dewey,

2001; Malherios, Massaro, & Buffolo, 2002; Müllges et al., 2000; Taggart, 2002; Taggart et

al., 1999). It remains uncertain whether the reported impairments following CABG are a

result of the physiological changes associated with bypassing the blood via the heart-lung

machine (on-pump), or are due to non-specific effects of surgery.

In chapter 2 it was established that post-operative cognitive dysfunction after CABG is not a

consistent or compelling finding across the literature. Collectively, general CABG studies,

observational research comparing on- and off-pump methods, and randomised trials have

yielded inconsistent results. Observational studies of CABG appear to show a pattern of acute

performance decline followed by improvement, which is typically interpreted as transient

dysfunction and recovery. Within the controlled studies, early impairment is also observed;

however, there is conflicting evidence regarding subsequent recovery.

The reintroduction of a technique to perform coronary revascularisation without the need for

cardiopulmonary bypass (off-pump) has provided an ideal comparison group to compare the

neuropsychological sequelae with traditional on-pump CABG. Compared to on-pump, off-

pump CABG is associated with reduced embolic activity (Abu-Omar et al., 2004; BhaskerRao

et al., 1998; Lund et al., 2003; Motellebzadeh, 2007) and more adequate cerebral perfusion

and oxygenation (Chernov et al., 2005; Fearn et al., 2001); both of which are allied with

decreased risk of neuropathology. This has led authors to argue that CABG performed off-

40

pump, at least on a group level, should invariably result in a better cognitive outcome than the

traditional on-pump procedure.

Although it is established that off-pump surgery provides better perfusion and reduced

embolisation, it is unclear whether these translate to measurable neuropsychological advantage

over on-pump surgery. Inconsistency across findings is largely due to methodological

differences and limitations, including;

1. Cross-section versus longitudinal design.

2. Use of control samples and random allocation to groups.

3. Consideration of the impact of potential confounds such as mood on

neuropsychological test performance.

4. Statistical artefacts such as regression to the mean stemming from imperfect test

reliability.

5. Failure to account for differential practice effects across measures and individuals.

6. Differences in follow-up times.

7. Arbitrary definitions of cognitive dysfunction.

Additionally, studies have largely been unable to establish which cognitive domains are most

at risk and the temporal changes in cognitive functioning over time. It is unclear whether any

potential impairment associated with on-pump CABG reflects dysfunctional processing in

specific cognitive domains or a more global decline in all cognitive functions. Such

information will potentially guide our understanding of the likely brain regions affected and

give a better indication of the neuropathophysiological mechanisms at play: Information that

will be valuable in shaping future treatments to minimise morbidity after CABG surgery.

41

The aims of this chapter are twofold. Firstly, it will specifically address the methodological

weaknesses that have made it difficult to draw sensible conclusions from the existing literature.

An alternative methodological approach will be proposed which considers these factors when

attempting to evaluate meaningful changes in cognitive function following a potential

neurological insult.

The second aim of this chapter is to examine the nature of the cognitive functions potentially

at risk during CABG. Building on concepts introduced in chapter 1, the pathophysiological

damage associated with on-pump CABG and the likely neuropsychological effects of this will

be discussed. Finally, the neuropsychological test battery to be employed in this thesis to

determine whether all (global), or specific functions are affected following on- and off-pump

bypass, will be outlined.

Features of Study Design and Methodology

Study design plays a critical role in informing us of the strengths and weaknesses of the

research in terms of being able to address the questions of interest. Across the literature

reviewed, the methodology has varied in important ways, and collectively has limited

conclusions that could be drawn from the existing research in this field. These factors include

sampling features and potential confounds, statistical artefacts such as regression to the mean

(Browne et al., 1999; Kneebone et al., 1998), issues of repeat assessment (Rabbitt et al., 2004;

Rabbitt et al., 2001; Rabbitt et al., 2008), and definition and measurement of impairment or

cognitive decline (Kneebone et al., 1998; Mahanna et al., 1996). Furthermore, most studies

have failed to include adequate, healthy control samples to address such issues. Additionally,

42

the cognitive domains, and neuropsychological measures vary across research studies, making

it difficult to make comparisons, or draw conclusions about the likely candidate cognitive

domains at risk from CABG.

Sampling features such as selection bias and subject attrition are an important consideration

when examining neuropsychological changes over time (Ferrer et al., 2004; Rabbitt et al.,

1994). Non-random allocation to the independent variable of interest (i.e. CABG method) can

potentially introduce important confounds that exert influence on cognitive test change. For

example, differences in presurgical cognitive ability, disease severity, existence of co-morbid

illness, or levels of anxiety and depression, have each influenced post-operative changes in

cognition (Browne et al., 2003; Malherios et al., 1995; Stroobant, & Vingerhoets, 2008;

Stroobant et al., 2002; Taggart et al., 1999). When other such explanations for observed

changes exist, it is difficult to give causal credit to the effect of interest. These nuisance

variables can be neutralised by holding them constant across samples or conditions in the

study (e.g. matching samples on particular characteristics), or more preferably, through

random allocation to groups. In addition, participants tend not to dropout of longitudinal

studies in a random fashion. Rather, those who dropout tend to be more cognitively

compromised than individuals who complete study follow-up (Blumenthal et al., 1995; Levin,

Katzen, Klein, & Llabre, 2000; Rabbitt, Lunn, & Wong, 2007). Assessment of post-operative

function that is reliant on those who complete the study may therefore result in an

underestimation of the true incidence of dysfunction.

Serial neuropsychological assessment is necessary when examining changes over time. Intra-

individual change is a more methodologically sound tool than comparing individuals cross-

43

sectionally (e.g. with and without an intervention). However, there are important potential

consequences of measuring an individual on the same, or similar, cognitive tests over time.

These factors can complicate the interpretation of scores on repeat neuropsychological

assessment. While there may be some overlap in the variance that each of these factors

contributes to change in test scores over time, for the purpose of clarity, they will be each

addressed independently.

Statistical artefacts such as regression to the mean, measurement error, floor and ceiling

effects are also additional moderating factors when evaluating changes in cognitive

performance. That is, scores may vary in the absence of true change, purely as a consequence

of imperfect test-rest reliability and other random error causing regression to the mean

(Barnett, van der Pols, & Dobson, 2005; Browne et al., 1999; Raymond, Hinton-Bayre, Radel,

Ray, & Marsh, 2005).

Regression to the Mean

The measure of the confidence that a given finding can be consistently reproduced – or

reliability – is directly related to the statistical phenomenon of regression to the mean (RTM).

RTM is direct, and inevitable, statistical effect of unavoidable measurement error where there

is an observed shift in test scores towards the mean. In other words, it is expected even in the

absence of an effect of treatment or intervention.

44

Regression to the mean is particularly problematic for extreme scores, where performance

cannot get any more extreme. Where as low baseline scores may increase, high preoperative

scores are more likely to decline towards the mean at post-operative follow-up. Both cases

have the potential to lead to the erroneous conclusions regarding improvement or cognitive

deterioration. For example, in Newman et al.’s study (Newman et al., 2001), high

preoperative baseline scores significantly predicted cognitive decline at follow-up, while in

Rankin et al.’s (2003) study, upward regression to the mean may account for the reported

improvements in test scores from extremely low or impaired pre-operative cognitive test

performances. Awareness of the influences of regression to the mean, and careful control of

this in study design and analysis is therefore critical.

Practice Effects

Practice effects are another potentially confounding factor in measuring changes in cognitive

performance. It is well known that repeat neuropsychological assessment can result in

improvement in test performance (Beglinger et al., 2005; Benedict & Zgaljardic, 1998;

Chelune, Naugle, Lüders, Sedlak, & awad, 1993; Collie, Maruff, Darby, & Michael, 2003;

McCaffrey, Ortega, Orsillo, Nelles, & Haas, 1992; Rabbitt et al., 2001). Such improvements

have the potential to mask other changes (Lowe & Rabbitt, 1998) resulting in

misinterpretation of post-operative scores. Furthermore, relevant information can be derived

from the absence of improvement, and not only on a deterioration in performance (McCaffrey,

Ortega, & Haas, 1993; McCaffrey et al., 1992). Awareness of the impact of psychometric

45

properties and/or practice effects on serial assessment is therefore fundamental to the

identification of true cognitive change in any longitudinal study.

Many of the studies reviewed in chapter 2 have reported a consistent pattern of early decline

and subsequent recovery within the acute post-operative phase (Bendszus et al., 2002; Browne

et al., 2003; Jacobs et al., 1998; Mahanna et al., 1996; McKhann, Goldsborough, et al., 1997;

Newman et al., 2001; Rasmussen et al., 1999; Selnes et al., 2001; Stygall et al., 2003; Taggart

et al., 1999; Zamvar et al., 2002). Although return to baseline functioning, with the apparent

“recovery” suggests an absence of “impairment” at the late-acute phase, the possibility exists

that practice effects are attenuated and therefore still reflect some degree of impairment. That

is, under many circumstances practice effects should result in better performance at follow-up.

In addition, rates of improvement vary across both tests and individuals (Rabbitt et al., 2004;

Rabbitt et al., 2001; Rabbitt & Lowe, 2000; Rabbitt et al., 2008). This makes it difficult to

determine which cognitive functions, if any, are at risk following CABG.

One major potential limitation to the interpretation of these results is the absence of

appropriate control samples to address the issues associated with repeat assessment (Browne et

al., 1999; Venes & Ore, 2002).

Within the CABG literature, there is growing appreciation of the impact of practice effects on

the assessment of cognitive impairments surgery (Collie, Darby, Falleti, Silbert, & Maruff,

2002; Kneebone et al., 1998; Murkin, Newman, Stump, & Blumenthal, 1995). Furthermore,

the Statement of Consensus on Assessment of Neurobehavioral Outcomes After Cardiac

Surgery (Murkin et al., 1995) recommended that such effects be controlled for in the design

46

and analysis. Despite this, many studies have continued to 1) use methods of assessing change

which fail to account for practice effects at all (Chernov et al., 2005; Diegler et al., 2000;

Jensen et al., 2006; Lee et al., 2003; Lloyd et al., 2000; Lund et al., 2003; Stroobant et al.,

2002; Van Dijk et al., 2002) , or 2) encourage the use of a correction factor in an attempt to

address the issue (Baker et al., 2000; Kneebone et al., 1998; Lewis, Maruff, Silbert, Evered, &

Scott, 2006).

Three approaches have been proposed to lessen the impact of practice effects on measuring

cognitive change in serial assessment. Firstly, the Statement of Consensus advocates the use

of alternate forms (Murkin et al., 1995) to minimise improvement across repeat assessments.

Alternate forms are similarly structured versions of a test, where the items within the task vary

from the original form. Ideally, they should be equivalent in terms of psychometric properties

and tap the same cognitive construct. While alternate forms reduce the influence of item-

specific practice effects (Crawford, Stewart, & Moore, 1989; Geffen, Butterwoth, & Geffen,

1994), the familiarity with test-procedures may enhance performance on repeat testing

(Beglinger et al., 2005; Benedict & Zgaljardic, 1998; Crawford et al., 1989; Shapiro &

Harrison, 1990).

Secondly, single correction factors have been proposed as viable methods for overcoming

practice effects (Kneebone et al., 1998; Lewis et al., 2006). This method involves subtracting

a predetermined amount from post-operative test scores to correct for the likely rate of

improvement on that test that is due to a practice effect. Given that rates of practice vary as a

function of individual differences in ability, age, and across measures (Lowe & Rabbitt, 1998;

47

Rabbitt et al., 2004; Rabbitt et al., 2001; Rabbitt et al., 2008), the use of singe correction

factors is problematic.

Finally, some authors have advocated the use of pre-baseline testing (McCaffrey et al., 1993;

Sacks, Clark, Pols, & Geffen, 1991; Van Dijk et al., 2002), which involves testing individuals

on the same, or similar battery on two occasions prior to surgery, to address the potential

confound of practice effects. This method was derived based on the assumption that the

effects of practice only operate between the first and second administrations of a test

(Beglinger et al., 2005; Collie et al., 2003). This is clearly not the case. As will be discussed

more thoroughly in chapter 3, practice effects can persist across multiple administrations

(Beglinger et al., 2005; Benedict & Zgaljardic, 1998; McCaffrey et al., 1992; Rabbitt et al.,

2001; Wilson, Li, Bienias, & Bennett, 2006; Zimprich, Hofer, & Aartsen, 2004).

The extent of cognitive dysfunction reported is also highly dependent on the timing of post-

operative assessments (Mahanna et al., 1996; Roach et al., 1996; Diederik. van Dijk et al.,

2000). Several researchers have suggested that the incidence of impairment is most

pronounced within the acute stages of recovery from CABG. In accordance with this, Murkin

et al. (1995) recommend that at least one assessment should occur after 3 months.

Of the studies reviewed, only three have examined cognitive changes within the very early

acute post-operative phase (Bendszus et al., 2002; Kneebone et al., 1998; Müllges et al., 2000),

others limited follow-ups to within 3 months (Jacobs et al., 1998; Rasmussen et al., 1999;

Taggart et al., 1999), and several did not explore early post-operative changes (McKhann,

Goldsborough, et al., 1997; McKhann et al., 2005; Selnes, Goldsborough, Borowicz, Enger, et

48

al., 1999; Selnes et al., 2001). Given this variability across studies, it is difficult to draw

conclusions about the true temporal nature of changes.

Those studies that examined only early changes in post-operative cognitive functioning tend to

show a marked decline in cognitive function within this period (Bendszus et al., 2002;

Hammon et al., 1997; Kneebone et al., 1998; Müllges et al., 2000). In contrast, studies that

did not explore early post-operative changes, claim less dysfunction or improved cognition

(McKhann, Goldsborough, et al., 1997; McKhann et al., 2005; Selnes, Goldsborough,

Borowicz, Enger, et al., 1999; Selnes et al., 2001). Many show an initial decline and then

recovery of function (Jacobs et al., 1998; Rasmussen et al., 1999; Taggart et al., 1999),

although these studies limited their assessments to within 3 months, and were therefore not in

a position to determine whether an additional secondary late-decline occurs as some have

proposed (Newman et al., 2001; Selnes et al., 2001; Sotaniemi, 1986) . As such, the timing of

post-operative assessments appears to play an important role in the reported extent of post-

operative cognitive decline.

In essence, the best way to determine the impact of factors such as practice effects, mood, test-

reliability, and regression to the mean is to utilise the data from an adequate control sample

when examining the trajectory of cognitive changes (Browne et al., 1999; Venes & Ore, 2002).

49

Definition of Impairment

The definition or criteria used to determine whether deterioration or dysfunction has occurred

is a critical factor for examining the existence and nature of cognitive deficits (Jensen et al.,

2006; Newman, 1995). Throughout the literature, there is little agreement on how best to

capture decline that is attributable to the CABG procedure and a variety of methods have been

presented. Complicating the issue further is the fact that the prevalence of decline varies

considerably across these definitions (Blumenthal et al., 1995; Kneebone et al., 1998;

Mahanna et al., 1996). However, the less stringent the criteria, the more likely impairment

will be detected Before outlining an alternative, defensible method, three commonly used

methods within the CABG literature will be briefly described.

20 % method

The 20% change method requires a drop in test performance of at least 20% from baseline

levels, on at least 20% of measures. It has been promoted as the most sensitive method of

assessing post-CABG cognitive dysfunction (Mahanna et al., 1996). This approach, however,

has several limitations. Firstly, the 20% method uses an arbitrary cut-off, which is potentially

vulnerable to floor effects in lower scoring individuals (Newman, 1995; Rasmussen et al.,

2001) Secondly, higher scoring individuals would require a relatively larger deterioration in

test performance in order to meet this criterion for dysfunction. Thirdly, this method does not

account for the potential impact of low test reliability and regression to the mean, or the

influence of practice effects on change in test scores (Browne et al., 1999; Collie et al., 2002;

Jensen et al., 2006).

50

Standardized scores

A second approach is to standardise scores against baseline, or using normative data or

performance of a control group as a reference. A standardised score (z score) is simply a score

subtracted from the mean, and divided by the standard deviation of the variable. This process

of standardising scores will produce a distribution with a mean of zero and a standard

deviation of 1. A z score therefore communicates the average deviation units from the mean,

and establishes the probability that a score would be observed by chance alone. Within the

literature, the precise criterion for impairment using standardised scores has varied. Less

stringent approaches require a decline of at least one standard deviation, from baseline, usually

on two or more (or, alternatively 20% or more) measures (Shaw, Bates, Cartlidge, & al., 1986).

Alternatively, scores that fall below a specified cut-off (usually z ≥ -1.96) are considered a

significant deterioration based on the low probability (.025) of a score this low occurring in

the population. In many cases, either a significant deterioration in two or more measures, or in

a composite z score is required to be considered impaired (Abildstrom et al., 2000; Lowe &

Rabbitt, 1998; Moller et al., 1998; Rasmussen et al., 2001).

The criticisms of this approach are twofold. Firstly, when control samples are used, their data

are treated like population parameters, rather than sample statistics (Crawford & Howell,

1998a). Sample statistics relate to observations that have taken place in a given sample,

whereas population parameters refer to theoretical characteristics of the broader general

population. Population parameters are often unknown, and therefore estimated from sample

statistics. This becomes problematic when control samples are small, because the standard

deviation in the sample is usually an underestimate of the population standard deviation.

Underestimating the standard deviation in this way can result in overestimating z, and

therefore the infrequency of the measurement (Crawford & Howell, 1998a). Secondly, this

51

method does not allow for the differential rates of practice, even when correction factors have

been used (Moller et al., 1998), or control for the impact of test reliability.

In addition to these limitations, the general approach has required that deterioration on

multiple tests (≥ 2) or on a composite cognitive index is required before cognitive dysfunction

is inferred. This method of aggregating scores makes little neuropsychological sense, as it

fails to account for the possibility that deficits will be focal and affect only specific aspects of

cognitive performance (Murkin et al., 1995) and disregards the possibility that improvement

on some tests might mask deterioration on others. It is acknowledged, however, that Type I

error (where the null hypothesis is rejected but in fact is true), is increased when multiple tasks

or cognitive domains are examined individually.

Despite the fact that the standardised score approach suffers similar limitations to the 20%

decline method, its use continues (Gottesman et al., 2007; Newman et al., 2001; Vanninen et

al., 1998; Vingerhoets, Van Nooten, Vermassen, et al., 1997; Zamvar et al., 2002). As

Kneebone and colleagues point out, this approach is arbitrary and atheoretical – a fact that is

highlighted by the lack of agreement about exactly how the method should be applied

(Kneebone et al., 1998).

The three methods outlined so far utilise cut-off scores to determine whether post-operative

cognitive performance (or change in cognitive performance from baseline) is impaired. While

deteriorations of required magnitudes, against all other factors (associated with serial

assessment), represent fairly robust effects, these methods are arbitrary and potentially

confounded by statistical artefacts (Kneebone et al., 1998; Newman, 1995). In addition, by

52

considering only those who are declining misses clinically important information (Barry et al.,

2005). The absence of, or reduction in practice effects may reflect neuropsychological

consequences that are specific to the procedure.

Reliable Change Indices (RCI)

A more promising and sensible approach is the use of Reliable Change Indices (RCI) to

evaluate cognitive dysfunction. Jacobson and Truax (1991) described the RCI as a method to

control for test reliability in serial assessment. The RCI is derived by dividing participants’

observed test change score by the standard error of this difference in the sample. This score is

then multiplied by critical values of z to represent the desired confidence around the interval

(i.e. ± 1.96 which corresponds to 95% confidence interval) (Jacobson & Truax, 1991). The

index therefore describes the variance in the distribution that would normally be expected

given inevitable measurement error. Change scores that exceed this index are therefore

considered significant. As such, RCI is useful for determining whether individual changes are

of a magnitude that is meaningful or not, when taking into account the reliability and

measurement error of the test. However, this approach does not accommodate the change over

time that can be attributed to practice (Chelune et al., 1993; Kneebone et al., 1998).

In order to adjust for practice effects in addition to test reliability, Chelune, Naugle, Lüders,

Sedlak, and Awad (1993) propose the use of a correction factor when constructing the RCIs.

This approach has been applied by Kneebone et al. in the CABG literature (Kneebone et al.,

1998), and recently advocated by Lewis and colleagues (Lewis et al., 2006). While this

method is less arbitrary, and more considered than the earlier methods, it assumes that rates of

53

practice do not vary across individuals. This assumption is wrong, and there is mounting

evidence to show that rates of improvement vary with age, and across levels of ability (Rabbitt

et al., 2004; Rabbitt et al., 2001; Rabbitt & Lowe, 2000; Rabbitt et al., 2008). Therefore, the

RCI method lessens the confounding impact of test-retest-reliability but cannot fully alleviate

the complex influence of practice. Thus, there is scope for an even more precise statistical

approach to defining meaningful cognitive decline.

Collectively, the four commonly used criteria for evaluating cognitive decline following

CABG appear to share some limitations. Specifically, none of the methods outlined has

adequately accounted for the complex issues associated with repeat assessment.

An ideal study design should take into consideration all of the methodological limitations, and

criticisms of existing methods for defining dysfunction. The ideal method would

simultaneously deal with measurement error, regression to mean, and differential practice

effects. Study design would also incorporate demographically and medically equivalent

groups, with random allocation to surgical method, and a comprehensive neuropsychological

evaluation that taps a range of cognitive abilities along with current mood state. Figure 3.1.

below shows a model adapted from Barry et al. (2005) which represents the core elements of

this design.

54

Figure 3.1. Schematic representation of a model for assessing cognitive change adapted from

Barry et al. (2005). Note that broken lines represent additional factors to this model.

Predicted Versus Obtained Test Performances: A Novel Approach to Post-CABG

Neuropsychological Dysfunction

One approach that has the potential to do address the limitations outlined is the use of

regression equations as advocated by Chelune and colleagues (McSweeny, Naugle, Chelune,

& Luders, 1993; Sawrie, Chelune, Naugle, & Luders, 199) and also Crawford and colleagues

(Crawford & Garthwaite, 2004, 2006; Crawford & Howell, 1998b). In the case of evaluating

neuropsychological changes over time, regression equations can be built to predict follow-up

scores from their baseline functioning, and any other relevant predictor variables. If this

predicted score is substantially higher than an individuals obtained follow-up score, cognitive

impairment can be inferred (Crawford & Garthwaite, 2004, 2006; Crawford & Howell, 1998b).

Intervention True

cognitive

function

Covariates:

Age, gender,

education,

CESD

Measured

cognitive

performance

Practice

effect

Mood

Psychometric

test properties

55

This thesis uses a method outlined by Crawford and colleagues (Crawford & Garthwaite, 2006;

Crawford & Howell, 1998b) to predict patients’ performances on eleven measures at follow-

up (1, 3, and 12 months). Data from the control sample were used to derive the regression

equations for each test at follow-up with presurgical performance and various demographic

variables as predictors. Each individual’s obtained test scores were then subtracted from their

predicted performance to determine whether post-operative cognition deviated from

expectation. Using an empirically derived standard error with the individual included (not an

estimate based on the sample used to generate the equation), confidence intervals within the t-

distribution can be created against which to compare the predicted difference score (Crawford

& Howell, 1998a). A score was considered significantly impaired at p < .05. This method

simultaneously accounts for differences in presurgical ability, regression to the mean and test

reliability, and practice effects and the effect of individual differences on the trajectory of

change over time (including practice effects). To date the advantages of this approach have not

been fully realised within the CABG literature.

Kneebone and colleagues (Kneebone, Luszcz, & Knight, 2005; Tully et al., 2008) were the

first research group to recognise the benefits of such an approach in the CABG literature.

Tully et al. extended their previous work which used the RCI method (Kneebone et al., 1998),

by employing a standardised regression-based approach to the investigation of post-CABG

neuropsychological impairment. Post-operative scores were predicted from baseline test

performance, age, gender and IQ using regression equations built from a healthy control

sample. Predicted-obtained difference scores were then standardised by dividing by the

standard error of the estimate from the control regressions. This standardisation approach is

suitable when interpreting data from individuals from the same sample as the regression

56

equation, however, it doesn’t account for the additional error that arises from using sample

regression data to estimate population regression coefficients (Crawford & Howell, 1998b).

Therefore, it will likely underestimate the confidence limits and result in a less stringent

criterion for impairment. This is particularly relevant in small sample sizes, such as those

typical in CABG randomised controlled trials such as the study by Tully et al. (2008).

Therefore, whilst the technique used by Tully et al. (2008) is the most considered approach

within the published literature, it would be more correct to adjust the standard error when

evaluating members from a group other than the regression sample.

This has been explored in detail by Howell and Crawford (Crawford & Howell, 1998;

Crawford & Garthwaite, 2006) who have derived an inferential method for use at an individual

case-study level. More precisely, the method is used to examine whether an individual’s

discrepancy score was drawn from the distribution of discrepancy scores within a control

population. This thesis examines whether CABG surgery results in statistically significant

cognitive impairment across a group of individuals, and is concerned with performance of the

sample rather than that of the individual. The basic principle of evaluating predicted-obtained

differences promoted by Crawford and colleagues were extrapolated to evaluate performance

at the group level. To evaluate whether a group’s (i.e. CABG patients) discrepancy score was

drawn from the distribution of discrepancy scores in a control population, the mean predicted-

obtained discrepancy sample is compared with an expected discrepancy of zero under the null

hypothesis. Absence of a statistically significant difference would be expected if the CABG

and control groups were randomly sampled from the same population.

57

In summary, we have seen that quantifying the prevalence of dysfunction following CABG is

difficult, and various factors need to be taken into consideration when determining if

meaningful or true changes have occurred. The following section deals with the nature of the

neuropsychological sequelae following CABG. Whether the proposed dysfunction following

CABG reflects specific deficits, or a global impairment, is of principle interest.

Qualitative Neuropsychological Change Following CABG

Because few studies have examined the nature of the proposed cognitive impairments, it is

uncertain whether all, or specific cognitive functions, are impaired following on-pump CABG,

and whether the pattern of impaired performance differs when CABG is performed off-pump.

Determining which cognitive processes are compromised would potentially guide our

understanding of the likely brain regions affected, giving a better indication of the

neuropathophysiological mechanisms at play. Such information would be valuable in shaping

future treatments to minimise morbidity.

The Statement of Consensus on Assessment of Neurobehavioral Outcomes After Cardiac

Surgery (Murkin et al., 1995) recommends that assessment of cognitive function cover a broad

range of cognitive abilities. Implicit in this suggestion is the idea that different processes may

be differentially affected. Within neuropsychology it is understood that discrete brain regions

and systems subserve specific cognitive processes, and that the location of damage is critical

in determining the effects of cerebral insult more so than the extent of damage. Consequently,

it is possible that not all brain regions are affected in the same manner, and therefore the

58

processes subserved by regions more vulnerable to insult will produce impairment that is more

notable.

This issue was recognised by Stump, Rogers, and Hammon (1996), although appears to have

had minimal impact on reported outcomes within the CABG literature. Instead many authors

within the CABG literature have dichotomised patients as “impaired” or “unimpaired” more

globally (on multiple measures or global scores). As mentioned above, this practice ignores

the possibility that circumscribed deficits might arise as a consequence of CPB.

Tests should be selected on the basis that they are sensitive to subtle cognitive changes, as well

as for practical reasons (timing of assessment, availability of alternate versions). Employing a

limited battery brings with it the risk of missing, or failing to adequately assess all relevant

cognitive domains affected by CABG (Blumenthal et al., 1995). For example, subtle deficits

in executive functioning may only be observed if specifically assessed.

Brief cognitive screening tests have been used by some to examine overall functioning (Baker

et al., 2000; BhaskerRao et al., 1998; Chandarana, Cooper, Goldbach, Coles, & Vesely, 1988;

Diegler et al., 2000; Kilo et al., 2001). Such restricted cognitive testing has limited sensitivity

and fails to cover the range of potential cognitive domains at risk (S. P. Newman, 1995; Stump,

1995). Others have employed multiple measures but then evaluated scores as a unitary

construct (Jensen et al., 2006; Lee et al., 2003; Lloyd et al., 2000; Lund et al., 2003; Mahanna

et al., 1996; Müllges et al., 2002; Newman et al., 2001; Rasmussen et al., 1999; Taggart et al.,

1999; Vanninen et al., 1998; Vingerhoets, Van Nooten, Vermassen, et al., 1997), which also

fails to account for the possibility of differential patterns of change and specific deficits.

59

In addition, mood disturbances may influence the reported prevalence of post-operative

impairment. Elevated depression, anxiety and stress are common in CABG candidates

(Stroobant, & Vingerhoets, G. , 2008) and are likely to exert important influences on pre- and

early post-operative cognitive performance, and therefore the relative change in test scores

over time (Andrew et al., 2000; Brown et al., 1994; Duits et al., 1998; Townes et al., 1989).

Despite this, few of the studies reviewed previously have acknowledged, or accounted for, the

known impact of mood on cognitive performance.

Among CABG patients, cognitive dysfunction has been associated with elevated depression

and anxiety (Andrew et al., 2000; Lloyd et al., 2000; N. Stroobant, & Vingerhoets, G. , 2008;

Townes et al., 1989) although this finding is not universal (McKhann, Borowicz , et al., 1997;

McKhann, Goldsborough, et al., 1997; Tsushima et al., 2005). While it is possible that

differences in age, education, severity of depression and anxiety contributed to this

inconsistency (Tsushima et al., 2005), discrepancies in measures or emotional state, cognitive

tests, methods of analysis, and definition of dysfunction also vary widely, making it difficult to

draw direct comparisons. Given that compared to presurgically, patients show improvements

in anxiety and depressive symptomatology following surgery (McKhann, Borowicz , et al.,

1997) mood would be an appropriate factor to consider when investigating cognitive changes

among these individuals.

Because of the focus on the incidence of neuropsychological dysfunction, and in the shortage

of studies exploring the “nature” and trajectory of cognitive changes following on-pump

CABG, it is necessary to formulate hypotheses based on broader understanding of brain-

behaviour relationships. This can be done by describing the expected deficits given the

60

proposed mechanisms and associated cerebral consequences of potential damage. The

following section will briefly review the proposed pathophysiological mechanisms for cerebral

injury associated with CABG and highlight the candidate cognitive functions at risk.

Pathophysiological Mechanisms and Candidate Cognitive Functions

As outlined in chapter 2, there are two major etiological mechanisms, associated with the use

of CPB in CABG, that are believed to be responsible for cerebral damage and cognitive

dysfunction. These are microemboli and hypoperfusion. Both are responsible for decreased

cerebral metabolism and likely ischemic or hypoxic tissue damage (Takano et al., 2007).

Hypoperfusion is one of the principle mechanisms believed to be involved in the pathogenesis

of neurological injury during on-pump, but not off-pump CABG (Browne et al., 2003;

Chernov et al., 2005; Fearn et al., 2001; Newman et al., 1995; Robson et al., 2000). Reduced

blood flow can limit the availability of metabolites and essential oxygen to neural tissue,

causing ischemic or hypoxic injury to occur.

Brain lesions associated with reduced perfusion, regional cerebral blood flow, and low Mean

arterial pressure, are typical of the types of cerebral changes that occur with hypoxic injury;

including damage to the basal ganglia, parietotemporal, cerebellum, and predominantly mesial

temporal lobes (in particular hippocampal gyri) (Bigler & Alfano, 1988; Caine & Watson,

2000; Cummings et al., 1984; Gale & Hopkins, 2004; Harrison, 1995; Malone, Prior, &

Scholtz, 1981; Moody, Bell, & Challa, 1990; Petito, 1987; Witoszka & Tamura, 1973). While

various regions are affected following global ischemia, damage is believed to be most

61

pronounced within the cortex (Sieber, Palmon, Traystman, & Martin, 1995). Because frontal

and mesial temporal structures are located in the border zones of vascular supply, they are

easily inadequately perfused. In addition, the hippocampus in particular has a

disproportionately high metabolic demand (Ginsberg, Graham., & Busto, 1985; Thal &

Schlote, 1994), rendering it highly vulnerable to fluctuations in metabolic activity.

Pathological changes within the hippocampus have been demonstrated following hypoxia

(Caine & Watson, 2000; Gale & Hopkins, 2004; Kadar, Arbel, Silbermann, & Levy, 1994),

that closely mimic the morphological changes seen in normal age-related decline (Kadar,

Dachir, Shukitt-Hale, & Levy, 1998). When reduced oxygen supply is not sufficient to cause

neuronal death – i.e. incomplete infarction – damage occurs to oligodendrocytes causing white

matter changes and demyelination (Fazekas, Schmidt, & Schretlens, 1998). Thus, given that

hypoperfusion invariably occurs as a consequence of CABG performed on-, but not off-pump

(Chernov et al., 2005; Fearn et al., 2001; Lee et al., 2003), hypoxic and ischemic injury, or

incomplete infarctions are more likely when the pump is used.

In both animal models and humans, memory impairments have been demonstrated following

ischemia associated with mesial temporal damage (Bigler & Alfano, 1988; Gale & Hopkins,

2004; Nunn et al., 1994; Zola-Morgan, Squire, & Amaral, 1986). Diffuse white matter

changes, which are also linked to insufficient cerebral oxygenation, may result in executive

dysfunction and inattentiveness (Filley, 1998) due to disruption of the fronto-striatal networks

believed to underpin executive abilities (Cummings, 1993, 1995; Sultzer et al., 1995; Tekin &

Cummings, 2002). As such, hypoperfusion may predominantly affect memory and executive

abilities.

62

Microemboli are the other principal cause of cerebral injury associated with CABG.

Depending on their size, and composition, emboli lodge in microvessels and temporarily block

the supply of nutrients and metabolites to neural tissue. As with hypoperfusion, if the supply

is restricted for long enough such that the metabolic demands of neurons are not met, tissue

damage will ensue.

Such damage includes neuronal loss, vacuolation, and gliosis around the sites of the occlusion

(Moody et al., 1995). Thus, emboli are likely to result in focal hypoxic damage; dependent on

where in the brain they occur. Although the distribution of emboli is not selective (Moody,

Bell, Challa, et al., 1990), we have already highlighted that certain brain regions are

selectively vulnerability hypoxic events (Bigler & Alfano, 1988; Cummings et al., 1984;

Moody, Bell, & Challa, 1990; Petito, 1987; Sieber et al., 1995; Small & Buchan, 1996).

Therefore, it is plausible that these regions are likely to be more affected by embolic occlusion

than other regions. Certainly there is evidence to support regional differences in the brain's

sensitivity to ischemic changes with areas of high metabolic demand most vulnerable

(Sakamoto, 2000; Tyler, 1988). Given the scattered nature of embolic occlusion, it is difficult

to make firm predictions about the likely brain regions affected. That said, there are important

vascular changes that occur in normal aging that might cause certain areas to be preferentially

affected. In particular, the frontal lobes are considered highly vulnerable to vascular occlusion

as a consequence of their sheer volume, and the fact that much of the cortical tissue within the

frontal regions lies at the boundaries of arterial supply (Pugh & Lipsitz, 2002). Additionally,

focal lesions usually arise from obstruction of small arterioles, and are frequent within the

subcortical white matter, basal ganglia, thalamus, internal capsule, and brain stem (Fisher,

1998).

63

Consistent with this, post-CABG imaging studies have reported infarcts within the deep

subcortical white matter, and other subcortical structures including the basal ganglia and

caudate nucleus (Sylivris et al., 1998; Vanninen et al., 1998). This is not surprising, given the

nature of vascular supply to these regions, and their susceptibility to obstruction from

microemboli.

If damage, caused by showers of microemboli from the use of CPB, affects white matter,

subcortical and or frontal structures, then attention and executive functioning may be

preferentially affected (Filley, 1998; Jokinen et al., 2006; Reed, 2006; Tekin & Cummings,

2002). Some authors have also argued that white matter changes are responsible for reductions

in speed of information processing (de Groot et al., 2000; van den Heuvel et al., 2006;

Ylikoski et al., 1993), although their measures included the interference trial of the Stroop task

(de Groot et al., 2000; van den Heuvel et al., 2006; Ylikoski et al., 1993) and a measure of

verbal fluency (de Groot et al., 2000), which are considered by others measures of executive

function.

In sum, it is clear that CPB is associated with increased embolic rate and decreased cerebral

perfusion, which may potentially cause ischemic neuronal damage. Furthermore, selective

neural regions are highly susceptible to such metabolic disturbances, and post-mortem and

animal studies have shown these regions are affected following use of CPB. Imaging findings

of CPB patients shows damage to white matter and subcortical structures including the basal

ganglia and caudate nucleus that may potentially affect the integrity of fronto-striatal networks

that underpin executive functions.

64

From investigations of ischemic/hypoxic changes arising from reduced blood flow, low

oxygen saturation, or embolic occlusion the hippocampus, white matter, and potentially

fronto-striatal networks appear to be most at risk (Degirmenci et al., 1998; Dijkhuizen et al.,

1998; Hakim, 1987; Symon, 1979).

Neuropsychological Sequelae Following CABG

As mentioned previously, studies within the literature have largely been unable to establish

which cognitive domains are most at risk, and whether the on-pump or off-pump procedures

result in different patterns of cognitive change. It is unclear whether any potential impairment

associated with on-pump CABG reflects dysfunctional processing in specific cognitive

domains or a more global decline in all cognitive functions.

Both of the likely mechanisms for cerebral damage and cognitive decline following CABG

involve either reduced or impeded blood supply to neural tissue. Based on the

neuropathological changes known to occur with these types of vascular events, certain brain

regions would be more vulnerable than others to potential insults from CPB. Specifically, the

hippocampus, white matter, and frontal cortex are likely to be affected. Consequently, it is

anticipated that if deficits are attributable to the use of CPB (and the mechanisms outlined),

then they, too, will be specific. Based on our understanding of brain-behaviour relationships,

deficits should most likely occur within the domains of memory, executive functioning, and

speed of processing. As such, the neuropsychological measures employed in the studies

within this thesis specifically address these domains. Chapter 4 will outline the objective and

hypothesis as well as provide details of the materials and measures used in this thesis.

65

CHAPTER 4 : Objectives, Hypotheses and General Methodology

To recap the research aims covered in chapter 1, the main aim of the current research was to

further our understanding of the neuropsychological sequelae of CABG by employing two

sophisticated and defensible statistical approaches to the measurement of cognitive change.

Whether neuropsychological function is differentially affected following on-, or off-pump

CABG, and therefore whether reported neuropsychological deficits are specific to the use of

cardiopulmonary bypass formed the central question. In addition, this thesis examined

whether all, or specific, cognitive domains are affected, and the trajectory of these changes

over a 12 month period.

As discussed in chapter 3, numerous methodological factors have complicated the research

findings to date. The most salient of these relate to issues of repeat neuropsychological

assessment and the definition of cognitive decline, as well as the potential compounding effect

of psychological distress on poor test performance. As such, it was necessary to examine and

control for these influences in the design and analysis.

Two methods for defining neuropsychological decline following CABG – the Reliable Change

Index (RCI) and the discrepancy between Predicted and Obtained test scores – will be applied

to the data.

66

Thesis objectives

The broad aims of this thesis were to test the idea that on-pump CABG surgery causes

cognitive impairment and that off-pump CABG results in better neuropsychological outcome,

to examine the nature of any deficits, and to determine whether these are transient or persistent.

In order to test whether some aspect of CABG surgery (namely on-pump CABG) causes of

cognitive decline, it was also important to establish the cognitive status of cardiovascular

diseased patients prior to surgery; as well as examine the impact of serial neuropsychological

assessments on cognitive test performance over time.

The specific objectives of the thesis are to:

1) Evaluate the pattern of practice effects and psychometric properties of the selected

neuropsychological test battery.

2) Evaluate the pre-surgical cognitive status among candidates for CABG.

3) Determine whether off-pump and on-pump CABG surgery result in different

neuropsychological sequelae, and specifically whether the off-pump technique

produces better post-operative outcomes compared with on-pump CABG.

4) Determine whether the neurocognitive effects of CABG are acute and resolvable, or

lead to chronic alterations in cognitive function.

5) Determine which cognitive processes/domains, if any, are at risk during CABG

surgery. More specifically, determine whether the performance decline is general, or

is specific to certain cognitive processes.

67

These objectives will be tested in a prospective study of patients who were to undergo elective

CABG surgery for coronary artery disease. Briefly, this thesis examines the

neuropsychological performance among a sample of CABG candidates randomly allocated to

traditional on-pump, or alternative off-pump CABG, prior to, and at 1, 3 and 12 months post-

operatively and compared with a non-surgical control group.

Cognitive outcome, both before and following CABG will be assessed using a battery of nine

neuropsychological measures assessing five cognitive domains. The term cognitive and

neuropsychological “impairment(s)” below referred to deterioration in any of the cognitive

domains assessed. However, as the nature of neuropsychological change following CABG is

not well understood, and in order to examine potential domain-specific findings and so as not

to obscure subtle focal deficits, each measure was examined independently.

Premorbid and potential confounding variables including age, intellectual functioning,

education, gender, as well as current anxiety, stress and depression were also considered in the

study design and analyses. These variables are known to impact on cognition, and potentially

interact with rates of cognitive change associated with repeat assessment. Therefore, these

were important to take into account when examining cognitive outcomes following CABG

surgery.

This longitudinal study had four assessment stages: an initial assessment (baseline)

approximately 1 week before scheduled surgery, a 1 month follow-up, a 3 month follow-up,

and a 12 month follow-up. Figure 4.1. (p. 75) presents a flow chart that outlines the basic

study design and participation.

68

Chapter 5 of the current thesis specifically addresses the nature of the psychometric properties

and practice effects of the neuropsychological assessment battery employed to examine the

longitudinal neuropsychological sequelae among patients undergoing CABG surgery, using

data from a sample of healthy adults aged 45 years and older. Chapter 6 addresses the pre-

surgical cognitive functioning of candidates scheduled for CABG surgery, using data from the

entire surgical sample obtained at the baseline assessment. Chapter 7 examines the acute

neuropsychological outcomes; using data obtained at both 1 and 3 months post-operatively,

while chapter 8 addresses the long-term neuropsychological sequelae, by examining the data

obtained at the 12 month post-surgical follow-up.

Hypotheses

Practice Effects in Healthy Older Adults

H1: Repeated cognitive test administration will improve performance.

Specifically, it is predicted that;

1. There will be improvement in cognitive test performance from baseline to follow-

up.

2. Performance gains will be most pronounced across the first two sessions, followed

by a plateau on subsequent test sessions.

3. There would be differential effects of practice across cognitive domains and tests

with the largest practice effects expected for measures which rely on the novelty of the

task (i.e. those typically falling under the rubric of Executive Functions), followed

closely by memory and working memory tasks which are vulnerable to the

69

development of strategy formation, with the least practice effects expected on

measures of visuospatial skill and speed of processing (Ferrer et al., 2004; Wilson et

al., 2006).

Pre-surgical Neuropsychological Sequelae Among CABG Surgery Patients

H2: CABG candidates will have pre-existing vascular compromise and chronic cerebral

hemodynamic insufficiency that will have affected neuropsychological functioning.

Specifically it is predicted that;

1. CABG candidates will show neuropsychological deficits prior to

surgery, independent of the potential effect of psychological factors. That is,

controlling for potential effects of mood and demographic variables, CABG patients

will demonstrate poorer neuropsychological test performance compared to controls at

initial baseline assessment.

2. Pre-surgical neuropsychological impairments will be most pronounced in domains

tapping areas vulnerable to ischemic damage; speed of information processing, verbal

memory, and executive functioning. That is, CABG patients would show significantly

poorer performance than their healthy counterparts (control group) on such measures.

Post-operative Neuropsychological Sequelae Among CABG Surgery Patients

H3: Any kind of CABG surgery can cause neuropsychological dysfunction.

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Specifically, it is anticipated that;

1. Significant and persisting post-operative deficits will be observed within the overall

CABG group

2. Impairment will be most pronounced on measures of information processing speed,

working memory, and memory.

Differentiation of Neuropsychological Impairments Across On versus Off-pump CABG

H4: In addition to general neuropsychological consequences of CABG surgery, CPB causes

further neuropsychological impairment and avoiding the use of CPB by performing CABG

off-pump is neuroprotective.


1. Patients randomised to off-pump CABG will, on average, show less cognitive decline

compared to traditional on-pump CABG at follow-up

2. There would be a higher incidence of impairment in the on-pump group compared to

the off-pump group.

3. That the above effects would be most pronounced in the acute phase and more subtle

over the long-term.

4. Specific deficits in functions underpinned by areas vulnerable to metabolic

disturbances (e.g. memory, and executive functioning) would be superimposed on

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more diffuse global impairments (speed of information processing) in the on-pump, but

not the off-pump group.

5. Neuropsychological impairments would occur irrespective of, or in addition to, the

influence of elevated anxiety and stress or depressed mood (see H5).

Mood State and its Influence on Neuropsychological Performance in CABG patients

H5: Psychological factors, such as anxiety and depression influence cognitive functioning;


1. elevated depression, anxiety, and stress will be associated with poorer test

performances.

Method

Participants

Surgical Patients

Sixty-two patients who were undergoing first time elective CABG surgery at Sir Charles

Gairdner Hospital, Perth WA, were recruited into the study between February 2003 and May

20051. Surgical eligibility was determined by either one of the two surgeons involved in the

1During recruitment, there was a decrease in the number of CABG procedures performed in Australian Hospitals

that was mirrored by a marked increase in coronary angioplasty procedures over the same period (AIHW).

72

trial before patients were invited to participate. Based on the surgeons’ recommendation,

patients who were deemed eligible were invited to participate in the trial. Ethics approval was

granted by the Sir Charles Gairdner Hospital Human Research Ethics Committee. Patients

were advised that participation in the study was voluntary and that any decision not to

participate would not influence their treatment. Informed, witnessed, written consent was

obtained prior to their first neuropsychological assessment.

Eligibility criteria for Surgical Participants

Consultant cardiothoracic surgeons imposed the study inclusion and exclusion criteria during

their initial consultation with prospective participants. Two of the three cardiothoracic

surgeons at Sir Charles Gairdner Hospital routinely perform both traditional CABG under

CPB (on-pump), and beating heart CABG (off-pump). Therefore, only patients being treated

by these surgeons were considered for trial eligibility.

The study surgical sample was drawn from a population of patients with coronary artery

disease who were presenting for first time elective CABG revascularisation. Patients were

deemed eligible for inclusion if they were aged over 18 years, able to give written informed

consent, able to undertake study procedures (written tests, interviews, completion of

questionnaires in the English language), had angiographically demonstrated coronary artery

disease in more than one vessel, were deemed clinically suitable for either off-pump or on-

pump surgery, defined as those with moderately severe disease being neither: patients with

single Left Anterior Descending/Diagonal coronary artery disease in whom a sequential IMA

graft is to be used, or complex patients with poor ventricular function or severe coronary

73

artery disease characterized by small coronary arteries (≤ 1.0 mm), diffuse disease or non-

superficial coronary arteries.

Patients were to be excluded on the basis of current enrolment in any investigational drug or

device clinical trial, other serious illness at time of enrolment, such that they were unlikely to

survive 12 months (for follow-up studies), prior diagnosis of neurological disorder, prior

diagnosis of psychiatric disorder, planned concomitant cardiac or vascular surgery,

symptomatic carotid artery disease, impaired renal function requiring renal dialysis, history of

stroke with residual deficits, re-operative CABG, or history of cardiogenic shock.

The average age of participants in the combined surgical group at initial assessment was 63.51

(SD = 9.42), with 75.47 % of the sample being male.

On- versus Off-pump CABG

Patients were randomised to one of two CABG procedures (on-pump or off-pump), prior to

baseline assessment. Both participants and the examiner (the author) remained blind to

randomisation throughout the study, and unblinding occurred after collection of the data at 12

months. Thirty-two patients were randomly allocated to on-pump, and 30 were allocated to

off-pump. One person withdrew from the study after baseline and three cases that were

allocated to the off-pump method were placed on the pump during surgery based on the

surgeon’s decision following events during the procedure. These cases were excluded from

any further neuropsychological analyses, and the final surgical sample at baseline was 53.

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In addition, a further five cases could not be entered into the primary data analyses (regression

equations used to predict post-operative cognitive performance) due to missing predictor

variables because of symptoms of angina and breathlessness (1), discontinued performance on

a particular measure (3), and declining to attempt a task (1). These missing data were not

imputed.

Anaesthetic regime was standard and equivalent for both surgical groups, and surgery was

conducted according to existing standardised procedures with the only difference being the use

of the CPB for the on-pump group, and the use of the Octopus system to stabilize the heart

during the off-pump procedure. A description of the demographics of the final sample of on-

and off-pump participants available at each follow-up assessment can be found in the results

sections of chapters 7 and 8.

Healthy Controls

Forty-six healthy community-dwelling heart healthy adults aged over 45 were recruited using

magazine advertising, letters to metropolitan bowling clubs, and a mailbox flyer-drop.

Informed, witnessed consent was obtained prior to commencement of the first session.

Participants were excluded if they reported having previously suffered a stroke, heart attack,

heart disease, head injury, or had undergone surgery under a general anaesthetic within the

previous two years.

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Figure 4.1. Flow chart of study participation.

Participants enrolled into the

study

(N =108)

Randomised to On-pump

(n = 32)

Randomised to Off-pump

(n = 30)

Completed 1 month

assessment

(n = 24)

Completed 1 month

assessment

(n = 22)

Completed 3 month

assessment

(n = 24)

Completed 3 month

assessment

(n = 24)

Completed 1 month

assessment

(n = 34)

Completed 3 month

assessment

(n = 30)

- failed to attend (n = 1)

- uncontactable (n = 4)

- unwell (n = 1)

- developed angina and

breathlessness during assessment

(n = 1)


- distance too great to attend (n = 3)

Controls

(n = 46)

Combined surgical group

n = 62

Excluded from further analyses: - Withdrew from study (n = 1)

- Randomisation not upheld (n = 3)

- Missing data (n = 5)

Combined surgical group at

baseline

(n = 53)

Completed 12 month

assessment

(n = 11)

Completed 12 month

assessment

(n = 20)

Completed 12 month

assessment

(n = 21)




- unwell (n = 1)

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Overall, the average age of control participants at enrolment was 62.26 years (SD = 8.73),

and approximately half (52.2%) the volunteers were male. Table 7.3. (p. 180), Table 7.8. (p.

189) and Table 8.1. (p. 230) outline the demographic characteristics of each sample across

each follow-up. As is common there was some attrition in this study. A number of

participants failed to attend subsequent sessions, which resulted in smaller sample sizes at

each of the three repeat assessments. Figure 4.1. on the previous page is a flow chart of the

recruitment and assessment process in the study described in this thesis.

Recruitment & Sample Size Calculation

As outlined in chapter 1, several studies have demonstrated both pre- and post-operative

deterioration in a number of patients for CABG surgery. Typically, studies have focused

on the change between baseline and post-operative neuropsychological test scores to

examine the extent of neuropsychological impairment. The pattern has varied, although is

suggestive of acute post-operative decline, and return to pre-surgical levels of performance

within 6 to 12 months (Murkin et al., 1995; Taggart et al., 1999; Van Dijk et al., 2002).

As discussed previously, the reported incidence of decline has also varied appreciably

across studies. This variation has been attributed to methodological differences such as a

lack of agreement about the definition for meaningful decline, as well as differences in

assessment times and measurement instruments used to evaluate cognitive changes

(Mahanna et al., 1996). These issues made it difficult to establish a benchmark on which to

determine an appropriate sample size for the current study.

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Recruitment for the trial began February 2003 and due to limitations with study recruitment,

data from the first 17 cases were examined to explore emerging patterns and re-estimate

sample sizes based on our own data. Despite the number of CABG procedures performed

each year, participants who were considered eligible to undergo either on-pump or off-

pump CABG represent a smaller subset of the general CABG population. Whilst this may

make the sample less representative of the overall CABG group, that these patients were

able to be randomly assigned to either surgical procedure remains a significant strength in

the study design. Sample sizes were calculated for six key cognitive outcome domains,

reflecting change from baseline to 1 month. Scores were standardised, by first subtracting

the relevant group mean baseline score, and dividing this by the corresponding standard

deviation. Using a method appropriate for unequal variance, the required samples sizes

(Table 4.1., p. 78) to obtain differences between the on- and off-pump group with 80%

power and alpha set at .008 to account for multiple comparisons, ranged from 19 to over 60

000. It was decided that a final sample size of 60 CABG patients would detect any

meaningful differences in Verbal Learning and Executive Function.

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Table 4.1.

Sample size calculations based on standardised change from baseline to 1 month for on-

and off-pump groups.

Mean SD required n N

Speed of Processing

On Pump -.22 .44 75 137

Off Pump .01 .37 62

Visuospatial skill On Pump -.55 .98 68

Off Pump .02 1.10 76

144

Executive function

Verbal fluency

On Pump -.29 .50 8

Off Pump .68 .68 11

19

Inhibition

On Pump -.05 .37 25

Off Pump .29 .32 22

47

Task switching

On Pump .19 .60 >20000 >60000

Off Pump .20 .38 >40000

Verbal Learning

On Pump -.42 .50 22

Off Pump .16 .84 38

60

Memory

Verbal

On Pump -.38 .96 104

Off Pump .03 .73 80

183

Visuospatial

On Pump -.10 1.00 >20000

Off Pump -.08 .75 >20000

>40000

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Materials

Nine neuropsychological tests were administered pre-operatively, seven of which were

repeated at 1, 3, and 12 months post-operatively. Measures were chosen for a number of

reasons, including:

• To cover a broad range of cognitive domains.

• To tap the cognitive functions known to be most vulnerable to disruption following

hypoxic/ischemic injury.

• To comply with the Statement of Consensus on Assessment of Neurobehavioral

Outcomes After Cardiac Surgery (Murkin et al., 1995).

• To ensure that the assessment took no longer than 1 hour, and

• Where possible, alternative versions were available; which could be used to

minimise the impact of item-specific familiarity and practice effects.

Based on these criteria, the following measures were selected to assess neuropsychological

functioning in this thesis. A brief description and justification for inclusion of each

measure will be provided below.

• Rey Auditory Verbal Learning Test (RAVLT: Rey, 1941; Rey, 1964).

• Medical College of Georgia Complex Figure Test (MCG: Meador et al., 1991).

• Experimental Stroop task.

• Symbol Digit Modalities Test (SDMT: Smith, 1982). Written version.

• Kaufman Hand Movement Test (KHMT: Kaufman & Kaufman, 1983).

• Trail Making Test (TMT: Reitan, M, 1958).

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• Controlled Oral Word Association Test (COWAT: Benton, Hamsher, & Sivan, 1994).

• The National Adult Reading Test - Second Edition (NART: Nelson & Willison, 1991).

• Ravens Standard Progressive Matrices (RSPM: Raven, 1958).

Neuropsychological Variables

The specific data used for the current thesis was selected from this range of collected

information. Table 4.2. (p. 99) outlines the cognitive domains, neuropsychological

measures, alternate forms, and final variables included in the studies that form this thesis.

A discussion of the cognitive domains examined in this thesis, and justification for the

inclusion of particular measures of these processes occurs below.

Speed of information processing

Speed of processing refers to how quickly one can process and respond to information.

Measures of speed are timed; with faster, accurate performance reflecting more efficient

processing. It is a domain that is highly vulnerable to dysfunction and neurological

compromise. Collectively, measures of processing speed have been shown to predict

severity of brain damage (Suchy, Leahy, Sweet, & Lam, 2003). Two commonly employed

measures of processing speed are Part A of the Trail Making Test (TMT) and the Symbol

Digit Modalities Test (SDMT). Both the TMT and SDMT have been shown to be sensitive

to even subtle brain damage and dysfunction (Demakis, 2004; Lezak, Howieson, & Loring,

2004), as well as the effects of advancing age (Corrigan & Hinkeldey, 1987).

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The TMT is a widely used measure of sustained attention and task alternation (Arbuthnott

& Frank, 2000). It originally formed part of the Army Individual Test Battery, although

has been included in other neuropsychological test batteries (Reitan & Wolfson, 1985).

The test is composed of two parts (A and B), which involve connecting sequences (of

numbers in Part A, or alternating between numbers and letters in Part B). Part A of the

TMT requires participants to draw a line connecting the numbers 1-25 (in numerical order)

that are distributed across an A4 page. Accurate performance requires the participant to

scan and process visual material, as well as sequencing and an efficient motor response.

The published version was used and administered according to standardised instructions.

Responses were timed with a stopwatch, and time to complete Part A (TMTa) and Part B

(TMTb) were recorded separately. Time to complete Part A was used to measure speed of

processing, and a derived ratio score (TMTb÷TMTa: Arbuthnott & Frank, 2000) was used

as a measure of cognitive flexibility under the domain of executive function.

TMTa has moderate test-retest reliability (r = 0.49-.50: Bardi, Hamby, & Wilkins, 1995),

and has been shown to correlate strongly with timed motor tasks (Grooved Peg Board)

(Suchy, Leahy, Sweet, & Lam, 2003), and performance based measures within the

Wechsler Adult Intelligence Scale – Revised (WAIS-R) and the Wechsler Memory Scale

(WMS) (Corrigan & Hinkeldey, 1987). Moderate correlations have also been reported

between Part A of the TMT and verbal measures from the WAIS-R and WMS, with

coefficients ranging from r = -.15 (Vocabulary) to r = 0.33 (Similarities). Other than with

Part B, Part A of the TMT does not correlate with timed measures of executive function

such as the Stroop and verbal fluency, suggesting minimal executive processing is involved

(Suchy et al., 2003).

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Similarly, the Symbol Digit Modalities Test (SDMT) is another commonly used measure of

motor response and response speed (Smith, 1982). The task requires participants to record

the digits (0-9) that correspond to a series of symbols as quickly as possible within a 90-

second interval. The original and alternate forms (Hinton-Bayre, Geffen, & McFarland,

1997) were used across repeat assessments according to published standardised instructions.

The examiner (the author) recorded the number of items correct in a timed 90-second

interval.

As with the TMT, the SDMT possesses good test-retest reliability with estimates ranging

from r = 0.72 (Hinton-Bayre et al., 1997) to r = 0.80 for the written form (Smith, 1982),

although significant practice effects occur with repeat administration (Hinton-Bayre et al.,

1997; Smith, 1982). To overcome this, Hinton-Bayre et al. designed three new alternate

forms of this measure. Their analysis revealed equivalence of the forms, although

significant improvements across repeat assessments continued to be observed.

The SDMT correlates highly with its inverse, the Digit Symbol Coding subtest within the

Wechsler Scales (Lezak et al., 2004, 1995; Morgan & Wheelock, 1992; Spreen & Strauss,

1998). Using hierarchical regression, Crowe, Benedict, Enrico, Mancuso, Matthews and

Wallace (1999) showed that performance on the SDMT was underpinned by education,

verbal IQ, and motor execution (Symbol Copy, TMTa), whilst executive functioning

(indexed by performance on TMTb) only contributed to performance on the Digit Symbol

Coding subtest. Sheridan and colleagues (2006), however, found no education effect on

performance of the SDMT and argue that it is a robust measure of cerebral integrity, that is

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uninfluenced by demographic factors. The absence of effect in this study may have been an

effect of small sample size and restricted range.

Working memory

The construct of working memory refers to the short-term storage and manipulation of

information. Tasks tapping working memory therefore involve maintenance and retrieval

of information from recent experience (Baddeley & Logie, 1999). Participants were

administered the Kaufman Hand Movement Test (KHMT) as a measure of verbal working

memory.

The KHMT is a measure of immediate memory for sequences of hand movements. It is a

serial recall task, analogous to traditional working memory span tasks such as digit or

spatial span that requires participants to repeat sequences of hand movement positions

immediately after presentation (Kaufman & Kaufman, 1983). The examiner (author)

recorded the total number of correct sequences out of a possible 21.

Greater disruption of task performance from articulatory suppression than concurrent finger

movements or spatial tapping (Frencham, Fox, & Mayberry, 2003) suggests engagement of

verbal (phonological loop), rather than non-verbal (visuospatial) working memory.

Additionally, that verbal labelling of hand movements enhanced task performance and

incongruent labels impeded performance, provided further support that the KHMT

measures verbal working memory (Frencham, Fox, & Mayberry, 2004). Initially developed

as part of a paediatric battery, the KHMT has been used in adult populations (see Barry &

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Riley, 1987; or Spreen & Strauss, 1998), and is shown to be sensitive to mild traumatic

brain injury (Fox & Fox, 2001).

Visuospatial skill

Visuospatial construction refers to the ability to perceive an object and then reproduce it.

Numerous measures of visuospatial construction have been described (Lezak, 1995), with

Complex Figure tasks popular (particularly the Rey-Osterrieth Complex Figure)

(Deckersbach et al., 2000). Participants completed the MCG complex figure task (copy

and incidental recall). The MCG figures are a series of complex geometric designs

measuring visuospatial skill and visual memory (Meador et al., 1991). Four published

versions of this task were administered and scored according to standardisation criteria at

each occasion (MCG: seeLezak et al., 2004). As a measure of visuospatial skill, an

accuracy score (out of a possible 36) was calculated using standard scoring criteria of the

depiction and correct placement of the 18 elements in the design. Discussion of the recall

trial of this task will occur under the domain of memory (below).

Visuoconstructional tasks, such as figural reproduction, are known to be sensitive to brain

dysfunction (Trojano et al., 2004), including vascular and Alzheimer’s dementia (Cherrier,

Mendez, Dave, & Perryman, 1999), and Obsessive Compulsive Disorder (Deckersbach et

al., 2000).

There is limited published information regarding the psychometric properties of the MCG

figures, though inter-rater reliability for the accuracy of the copy trial for the analogous

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Rey-Osterrieth Complex figure is usually high (r = .90; Meyers & Meyers, 1995)

Correlations between alternate forms of complex figure tasks are considered untenable,

because of restricted range (Delaney, Prevey, Cramer, Mattson, & group., 1992).

In terms of construct validity, performance on the copy trial of a complex figure task

correlates with other visuospatial skills including judging angle width, mental assembly of

abstract geometric shapes, and line orientation (Trojano et al., 2004). This suggests that

basic visual-perceptual and representational skills contribute to visuoconstructional abilities.

On this basis, the accuracy of the copy trial for the MCG figures will be used as a measure

of visuospatial ability in this thesis.

Memory

Memory is the process of encoding, retaining, and retrieving information. It is a complex

phenomenon that can be conceptualized a number of ways. Memory theories describe

processes, systems or stages (see Foster & Jelicic, 1999). Process-based models fortunately

share a common framework, which divide memory into three fundamental components

(Ellis & Young, 1996; Skeel & Edwards, 2001). Although different theorists employ

different terminology, for simplicity they will be referred to here as: encoding, storage and

retrieval. Encoding can be described as the process by which skills and information are

originally processed for either storage or use (Skeel & Edwards, 2001). Storage is the

process of consolidating information for storage, and retrieval is the process of recalling or

remembering information that has been stored. That is, for information to be recalled or

used later, it must first be entered into memory (encoding), then it must be put somewhere

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(storage), and finally returned to awareness for use (retrieval). In addition, memory can also

be classified according to the nature of the material that is to be remembered (i.e. verbal,

visuospatial).

So that these facets of memory are addressed, memory testing should include evaluation of

acquisition of new material (learning), encoding, forgetting, and retrieval, for both verbal

and visuospatial material (Spreen & Strauss, 1998).

This thesis employed the RAVLT (Rey, 1964) as a measure of verbal learning and memory,

and delayed incidental recall of the MCG Complex Figures (Meador et al.) as a measure of

visuospatial memory. These tests were selected based on their adequate psychometric

properties, brevity, ease of administration, and the availability of four equivalent alternate

forms.

Verbal Learning and Memory

The RAVLT is a commonly used (Geffen et al., 1994) short and versatile measure of

immediate memory, learning, interference, delayed recall and recognition. It consists of a

15-item word-list, which is repeated across five consecutive trials (learning phase). After

each repetition the examinee is required to recall as much of the list as possible. Following

the fifth trial, a distracter list (List B) is administered and recalled. The examinee is then

asked to recall the initial list once again. A twenty-minute delay follows, before the final

free recall trial, and a subsequent recognition trial, which includes old words from both of

the lists, as well as new words.

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The RAVLT is sensitive to subtle memory disturbances, such as those observed in pre-

clinical Alzheimer’s (Estaves-Gonzalez, Kulisevski, Boltes, Otermin, & Garcia-Sanchez,

2003), and can differentiate mild brain injured patients from demographically matched

controls (Guilmette & Rasile, 1995). Different patterns of performance on verbal learning

and memory tasks, including the RAVLT have also been shown to differentiate between

cortical and subcortical dysfunction. For example, Tierney, Nores, Snow, Fisher, Zorzitto,

and Reid, (1994) found that Alzheimer’s patients showed different patterns of primacy and

recency effect, poorer immediate recall, as well as significantly weaker recognition

performance compared to patients with Parkinson’s dementia.

Test-retest reliability for the RAVLT is modest to strong, with correlation coefficients

ranging from .29 (trial 1 over 12 months) to .78 (delayed recognition trial over three years)

(Uchiyama et al., 1995).

In terms of validity, the RAVLT total, and RAVLT delayed recall scores correlate strongly

with other measures of verbal memory including the Wechsler Memory Scales (Callahan &

Johnston, 1994; Stamp Macartney-Filgate & Vriezen, 1988), the Buschke Selective

Reminding Test (Stamp Macartney-Filgate & Vriezen, 1988), and the California Verbal

Learning Test (Stallings, Boake, & Sherer, 1995). Performance on trial five of the RAVLT

does not correlate with measures of attention, although it has been shown to correlate with

performance on executive function tasks (Callahan & Johnston, 1994), suggesting that

other cognitive processes are also involved.

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There are a number of different scores that can be obtained from the RAVLT to reflect

different aspects of memory performance. For example, number of correct words for each

trial, number of intrusions (non-list words that are recalled), perseverations, total number of

words recalled during learning (trials 1-5), number of words lost from trial five to short- or

long-delay recall.

The original list, and three alternate versions (Geffen et al., 1994; Spreen & Strauss, 1998),

were administered using instructions given by Spreen and Strauss (Spreen & Strauss, 1998).

The total score and number of words recalled at the 20-minute delayed recall (trial 7),

measuring verbal learning and verbal memory respectively, were the variables extracted for

analyses.

Visuospatial Memory

Visuospatial Memory can be assessed a number of ways (Lezak, 1995). One approach is to

have participants copy a complex geometric design, and then ask them to recall it

(incidentally) either immediately, or following a delay. The most well known, widely used

of these measures is the Rey-Osterrieth Complex Figure (RCFT; Osterrieth, 1944; Rey,

1941). Alternate versions to the RCFT have been devised for situations were a follow-up

assessment is required. The favoured of these has been the Taylor figure, which is often

used interchangeably with the RCFT. The Taylor figure, however, has been clearly shown

to be less difficult to remember (Delaney et al., 1992; Tombaugh, Faulkner, & Hubley,

1992).

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The Medical College of Georgia complex figures (MCG) were developed to provide a set

of alternate forms, which were more equivalent for use on repeat neuropsychological

assessments. Alternative forms are commonly used to reduce the effects of practice on

subsequent occasions, and are particularly important for items thought to measure memory.

The four alternate forms of the MCG figure are considered equivalent (Lezak, 1995) and

were therefore ideally suited to the four testing occasions in the current study.

To date, there is very limited information about the psychometric properties, and the

construct validity of complex figures in general (Hubley & Jassal, 2006), with only one

study examining the reliability of two, out of the four, MCG figures (Ingram, Soukup, &

Ingram, 1997). In general, correlation between the RCFT and the Taylor figure are

moderate (r = 0.60: Delaney et al., 1992).

Complex figure recall is believed to engage episodic, non-verbal memory (Deckersbach et

al., 2000). Recall performance is enhanced when the figure has been organised into

meaningful components during encoding (Deckersbach et al., 2000; Schorr, Delis, &

Massman, 1992). Memory for complex figures, in general, show good convergent and

discriminant validity through strong correlations with measures of visuospatial ability and

verbal learning and memory, and negligible correlations with measures of verbal

knowledge and verbal fluency (Hubley & Jassal, 2006).

Presumably because of the reliance on organisation at encoding and retrieval, patients who

have damage within fronto-striatal pathways demonstrate weak complex figural memory

(Bondi, Kazniak, Bayles, & Vance, 1993). Deficient performance is also likely following

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damage to mesial temporal structures (hippocampus), because of difficulty consolidating

the to-be-remembered material. As such, incidental recall is a sensitive measure of cerebral

dysfunction (Deckersbach et al., 2000).

Executive functioning

Within neuropsychology, the term executive function is used to describe a selection of

“loosely related” (Spreen & Strauss, 1998 p 171) cognitive abilities which enable

individuals to engage in higher-order, goal directed, and purposeful behaviours (Lezak et

al., 2004). That is they are supervisory functions (Beaumont, Kenealy, & Rogers, 1999),

and assist in the organization and direction of lower order functions (Stuss & Levine, 2002).

The term is often used interchangeably with “frontal lobe functions” (Phillips, 1997).

While the integrity of the frontal lobes is relevant for executive control, that other non-

frontal regions can also result in severe executive deficits (Anderson, Damasio, Jones, &

Tranel, 1991 Tranel, 1991), and some frontal patients perform well on executive tasks

(Shallice & Burgess, 1991) suggests “frontal” and “executive” are not synonymous

(Baddeley, Della Sala, Gray, Papagno, & Spinnler, 1997; Miyake et al., 2000).

Such processes as planning, problem solving, initiation, cognitive estimation, hypothesis

generation, cognitive flexibility, shifting, judgement, and decision making have all fallen

under the rubric of executive functioning (Burgess, 1997; Spreen & Strauss, 1998). Others

have also included working memory, inhibition, and performance monitoring in the types

of processes that are considered executive (Greenwood, 2000). According to Burgess

(1997), the consensus regarding the executive functions considers them as a “process, or set

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of processes whose primary purpose is to facilitate adaptation to novel situations” (p. 83), a

goal which is achieved by mediating or directing other more rudimentary cognitive skills

(such as language).

Within psychological research, there is ongoing debate as to whether executive functions

are best conceptualised as a collection of separate abilities, or a single entity (Miyake et al.,

2000; Rabbitt, 1997). Delineating such functions as ‘inhibition’, ‘set-shifting’, ‘planning’

and ‘monitoring’ as separate processes remains controversial (Rabbitt, 1997), though is

common in clinical practice. According to Rabbitt, these entities are purely descriptions of

task demands and may be met by similar functional processes. Indeed, Rabbitt’s research

into executive function in the elderly (see Rabbitt, 1997; Rabbitt & Lowe, 2000) clearly has

shown no evidence for clustering of such separable executive processes, and typically,

variance in executive performance is almost entirely accounted for by general intelligence.

Similar findings are reported by Foster, Black, Buck, & Bronskill (1997), while others have

shown clear dissociations between executive tasks, and used factor analytic evidence to

support the idea of independent, and separable executive abilities (Miyake et al., 2000).

Converging evidence from lesion and imaging studies suggest that anatomically discrete

networks underpin separable cognitive ‘executive’ processes (Cummings, 1993, 1995;

Tekin & Cummings, 2002; Ullsperger, 2006). In their review of the literature, Tekin and

Cummings (2002) highlight the different clinical patterns associated with damage within

the dorsolateral prefrontal circuit, the orbitofrontal circuit, and the anterior cingulate circuit.

For example, planning, reasoning, and cognitive flexibility are typically affected following

disruption to the dorsolateral prefrontal circuit; while personality change, behavioural

92

disinhibition and emotional dysregulation are common features of orbitofrontal damage;

and apathy, aboulia and response disinhibition are hallmark features of damage within the

anterior cingulate circuit.

The abilities which neuropsychologists refer to as executive function have historically been

ascribed to the functioning of the frontal lobes, and patients with damage to frontal regions

are often described as presenting with a ‘frontal lobe syndrome’ or as ‘dysexecutive’,

although damage to other brain regions – particularly subcortical regions- may also produce

executive deficits (Anderson et al., 1991 Tranel, 1991; Filley, 1998; Jokinen et al., 2006;

Reed, 2006; Tekin & Cummings, 2002).

Alexander, DeLong, and Strick (1986) defined a series of anatomically discrete pathways

between subcortical and frontal structures. While they pass through the same anatomical

structures (prefrontal cortex, striatum, globus pallidus, substantia nigra, and thalamus), the

circuits remain segregated through the entire pathway. Furthermore, these circuits remain

not only anatomically, but functionally distinct (Cummings, 1995) and different syndromes

have been described for each of the fronto-subcortical circuits (see Tekin and Cummings,

2002 for a review).

Given the nature of executive functions, characterisation and measurement of these abilities

remains controversial. Furthermore, the validity and reliability of executive function tests

often falls well below that of measures within other cognitive domains (Spreen & Strauss,

1998), leading to the perception that measurement of executive functioning is imprecise

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and inadequate. Keeping in mind that by their nature executive function tests are reliant on

novelty and, because of this, test-retest values are essentially uninformative.

A range of tests have been developed to assess the various aspects of executive functioning

(Lezak et al., 2004). Three such tasks will be used in this thesis to index each of these

processes. These are the Controlled Oral Word Association Test (COWAT), a Stroop task,

and Part B of the Trail Making Test to measure executive processes of fluency

(generativity), inhibition, and mental flexibility (switching).

Verbal fluency

The COWAT (Benton et al., 1994) is a measure of verbal fluency or generativity, which

requires the participant to generate as many words as possible that begin with a specific

letter of the alphabet within a given time limit (Ruff, Light, & Parker, 1997). Rather than

continuous speech fluency per se, verbal fluency measures evaluate single word production

under restricted conditions (Spreen & Strauss, 1998). It is considered an executive task, on

the basis that it is novel, and requires the participant to develop strategies based on rules

and prior knowledge (Perret, 1974). Divided attention studies provide support for the

executive nature of phonemic fluency measures (Troyer, Moscovitch, & Winocur, 1997). In

the current study, two alternate versions of this task (COWAT: Benton et al., 1994) were

administered successively across testing occasions. These two forms (CFL and PRW) have

been deemed equivalent (Benton et al., 1994; Ruff, Light, Parker, & Levin, 1996). The

score was the total number of correct words generated across the three one-minute trials.

94

Fluency measures such as the COWAT involve a number of cognitive processes including

immediate attention, lexical and semantic access, verbal memory, and aspects of executive

function such as initiation, sequencing, and working memory to organise and monitor

performance (DesRosiers & Kavanagh, 1987; Malloy & Richardson, 1994; Perret, 1974;

Ruff et al., 1997; Troyer et al., 1997). Shifting cognitive sets may also be involved (Ruff et

al., 1997; Troyer et al., 1997). The COWAT is considered executive, on the basis that it is

novel, and requires the participant to develop strategies based on rules and prior knowledge

(Perret, 1974). Divided attention studies provide support for the executive nature of

phonemic fluency measures (Troyer et al., 1997).

The clinical utility of verbal or word fluency measures has been well established, with clear

sensitivity to cerebral dysfunction from a range of aetiologies (Henry & Crawford, 2004;

Ruff et al., 1997). In particular, letter fluency deficits are highly sensitive to those with

frontal-damage (Henry & Crawford, 2004). In addition, in a meta-analytic study, Henry

and Crawford (2004) demonstrated that phonemic fluency had a higher specificity for

frontal-lobe damage than the widely accepted gold standard of executive function, the

Wisconsin Card Sort Test. Consistent with the lesion study data, imaging studies have

shown activation within the supplementary motor cortex, anterior cingulate cortex,

cerebellum, left dorsolateral prefrontal cortex, and left inferior frontal cortex (Ravnkilde,

Videbech, Rosenberg, Gjedde, & Gade, 2002; Schlösser et al., 1998).

The letters “F” “A” and “S” are favoured (Spreen & Strauss, 1998), although other have

also been used (J. E. Harrison, Buxton, Husain, & Wise, 2000; Ruff et al., 1997; Ruff et al.,

1996). Benton, Hamisher and Sivam (1994) selected the CFL and PRW sets on the basis

95

that these letters have relatively equivalent frequency in the English language, and therefore

are of equivalent difficulty.

With Benton et al.’s (1994) measure, each set was constructed so that level of difficulty

progressively increased across the letters in the set. That is, the frequency of dictionary

words was highest for the initial letter, and least for the final letter. According to Spreen

and Strauss (1998), the FAS allows for more choices than the CFL or PRW sets, although

the former were selected arbitrarily, and the latter are more equivalent (Ruff et al., 1996).

As such, the CFL and PRW are the most sensible choice for alternate forms.

Both inter-rater and test-retest reliability for verbal fluency measures are strong (Bardi et al.,

1995; DesRosiers & Kavanagh, 1987; Harrison et al., 2000; Spreen & Strauss, 1998). For

the CFL and PRW forms specifically, internal consistency is high (r = .83), as is the

average intercorrelation (i.e. equivalence; r = 0.61) between the number of items generated

for each letter (Ruff et al., 1996). Additionally, test-retest reliability for alternate forms

(with CFL always preceding PRW) over 6 months is high (r = .74), although a significant

practice effect, equivalent to three words, occurs (Ruff et al., 1996).

Overall, the COWAT appears to be a reliable and stable measure of verbal fluency, which

engages aspects of language, executive function, memory and attention. Fluency measures

are highly sensitive to cerebral damage, and have excellent specificity for damage within

the frontal lobes. As such, the COWAT will form part of the core battery within this thesis,

falling under the domain of executive functioning.

96

Inhibition

Another commonly used measure of executive function is the Stroop. There are numerous

versions of this task, although the basic phenomenon requires participants to inhibit a

strong, over-learned response in order to engage in a novel behaviour. The Stroop task was

initially designed to assess selective attention and cognitive flexibility (Stroop, 1935), and

more recent evidence shows that it also involves inhibition and interference control

(Demetriou, Spanoudis, Christou, & Platsidou, 2002). Using different forms of Stroop

tasks (verbal, numerical, figural) Demetriou et al. (2002) showed that a linear combination

of dimension selection, encoding and interference control accurately predicted the Stroop

effect, irrespective of the modality.

Performance on Stroop tasks has been shown to successfully discriminate between

neurologically normal individuals from those with known executive function deficits

(Hanes, Andrewes, Smith, & Pantelis, 1996). Additionally, it shows good construct

validity, with strong correlations with other executive tasks, and smaller correlations with

non-executive tasks (Hanes et al., 1996; Suchy et al., 2003).

The Stroop task has been shown to be selectively sensitive to frontal damage, although

there is some disagreement about precisely which regions underpin the processes necessary

for this task (Demakis, 2004; Perret, 1974; Stuss, Floden, Alexander, Levine, & Katz,

2001). Demakis’ meta-analysis of lesion data showed the Stroop to be selectively sensitive

to left-, rather than right frontal damage. Imaging findings have also produced an array of

anatomic sites that are activated during Stroop tasks, including the thalamus, cerebellum

and supplementary motor cortex and left anterior cingulate cortex (Bench et al., 1993;

Ravnkilde et al., 2002).

97

The test-retest reliability of various forms of the Stroop have been shown to be adequate,

with coefficients ranging from 0.67 to 0.91 (Franzen, Tishelman, Sharp, & Friedman, 1987;

Siegrist, 1997). Siegrist has shown that one component explains majority of the variance

on a range of very different Stroop tasks (ranging from colour words to taboo words). This

was interpreted as a single core ability underpinning the phenomenon – that is the ability to

ignore, or inhibit, irrelevant stimuli. As such, the Stroop phenomenon is a valid and

reliable measure of a key aspect of executive functioning- inhibition- and appears sensitive

to disrupted frontal lobe processing.

The Stroop task employed in this thesis comprised two forms, word reading (Stroop word)

and colour naming (Interference). Each stimulus form was printed on A4 white paper, with

colour-names (“Red”, “Blue”, “Tan”, “Green”) written in incongruent ink colours. Colour

names were printed in each of the three incongruent ink colours 12 times, and randomly

distributed across nine columns. For the baseline condition (Stroop word), participants

were provided a laminated stimulus card and read standardised instructions asking them to

read the words as quickly and as accurately as possible. For the Interference task, a second

laminated stimulus card was placed in front of the participant who was then asked to name

the colour of the ink the letters were printed in (and not read the word); again as quickly

and as accurately as possible. The time taken to complete the Stroop Interference task was

recorded by the examiner and used as a measure of inhibition in the analyses.

98

Task switching

As mentioned previously, the TMT requires a number of important cognitive processes

including number and letter recognition, visual scanning, rapid motor response, and mental

flexibility. Part A has already been discussed above in the context of processing speed.

Part B takes longer to complete than Part A, and is assumed to engage additional cognitive

processes, in order to effectively switch between sequences of numbers and letters

(Arbuthnott & Frank, 2000).

Part B places different demands on the participant and the relationship between the Part A

and B has been shown to be sensitive to brain dysfunction (Demakis, 2004; Lezak et al.,

2004); particularly to damage within the frontal lobe (Ameiva et al., 1998; Stuss, Bisschop,

et al., 2001). Although a meta-analysis of lesion studies, failed to confirm this frontal

specificity (Demakis, 2004), recent imaging evidence has highlighted the involvement of

dorsolateral prefrontal cortex, anterior cingulate, and medial frontal gyrus specifically with

Part B versus Part A of the TMT (Zakzanis, Mraz, & Graham, 2005). Given the nature of

the task, it is hardly surprising that the area of the brain linked to shifting cognitive set, and

regions responsible for coordination of motor responses are activated during this task.

Suchy et al. (2003) found that Part B of the TMT loaded highly on a general fluid

intelligence factor as well as motor programming factor. In addition, strong correlations

with other measures of executive ability such as the Stroop are cited (r= -.560: Suchy et al.,

2003), COWAT (r = -3.59: Suchy et al., 2003), and set-shifting (Arbuthnott & Frank,

2000). Moderate to strong correlations with measures of attention, working memory, and

verbal IQ have also been reported (S. Crowe, 1998).

99

Table 4.2.

Neuropsychological domains, tests, principal measures, and use of alternate forms.

Cognitive domain Test Measure Alternate forms

Speed of Processing SDMTa Total score

4 alternate forms

TMTb Part A (time)

Working Memory KHMTc Total correct

Visuospatial Skill

MCG

d

Copy (out of 36)

4 alternate forms

Memory

Visuospatial

MCG d

30-minute delayed

recall

4 alternate forms

Verbal Learning

Verbal Delayed Recall RAVLT

e

Total score

delayed recall 4 alternate forms

Executive Function

Fluency

COWATf Total score

Inhibition Stroop Task Stroop Interference

(time)

Cognitive Flexibility (Task

switching) TMT b Ratio B/A

2 alternate forms

(CFL, PRW)

Mood state DASS g

Depression score

Anxiety score

Stress score

Fluid Reasoning RSPM h – 10 minute

timed version Total correct

Premorbid intellectual

function NART

i Error score

Key: a

SDMT, Symbol Digit Modalities Test (Smith, 1982); bTMT, Trail Making Test

(Reitan, 1958);

cKHMT,

Kaufman Hand Movement Test (Kaufman & Kaufman, 1983); dMCG, Medical College of Georgia Complex Figure

(Meador et al.); eRAVLT, Rey Auditory Verbal Learning Test (Rey, 1964);

fCOWAT, Controlled Oral Word

Association Test (Benton et al., 1994); gDASS, Depression Anxiety and Stress Scale (Lovibond & Lovibond, 1995);

hRSPM, Ravens Standard Progressive Matrices (Raven, 1976);

i NART, National Adult Reading Test- Revised

(Nelson, 1991).

100

Supporting its use as a measure of executive ability, the TMT Part B has been shown to

involve cognitive flexibility or alternation, in addition to visual search (Arbuthnott & Frank,

2000; S. Crowe, 1998).

Overall, Part B of the Trail Making Test appears to be a valid, reliable and stable measure

of one aspect of executive function. The ratio between Parts A and B is considered a more

pure, sensitive measure of cognitive flexibility, which is independent of processing speed,

than raw scores or A – B difference scores (Arbuthnott & Frank, 2000; Lezak et al., 2004),

and will therefore be used for the purpose of examining cognitive flexibility in this thesis.

Control Variables

A number of control variables were used as predictors in the regression-based approach.

These include;

1. Age: Information about patients’ age was obtained by self-report at baseline.

2. Gender: Information about patients’ gender was obtained by self-report at baseline.

3. Years of education: Participants were interviewed as to the number of years of

formal education they had completed.

4. Premorbid intellectual functioning: Participants were administered the National

Adult Reading Test - Second Edition (NART: Nelson & Willison, 1991) at the

initial baseline assessment as a measure of premorbid intelligence. The NART

comprises a list of 50 words with irregular spelling that examinees are required to

read aloud. Accuracy of correct pronunciation is then used to estimate premorbid

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Full Scale IQ using a simple equation and normative data. Word reading correlates

strongly with IQ in the normal population and, unlike many intellectual abilities,

remains relatively stable in the presence of cognitive deterioration (Crawford, Deary,

Starr, & Whalley, 2001). The NART is considered uninfluenced by reasoning skill,

as correct pronunciation cannot be achieved through deduction or guessing, or

employment of grapheme-to-phoneme translation rules. Rather than placing

demands on current cognitive abilities the NART relies on prior knowledge of

correct pronunciation (Crawford et al., 2001). As such, with the exception of use in

severely demented, dyslexic or illiterate individuals (Bright, Jaldow, & Kopelman,

2002; Taylor, 2000), it is used as a reliable measure of premorbid intellectual

function.

5. Fluid Reasoning Ability: Raven’s Standard Progressive Matrices (RSPM) was

administered to participants at baseline as a measure of general fluid reasoning

ability. The RSPM is a 60-item test designed to assess inductive and abstract

analogical reasoning. It is often described as a non-verbal test of current intellectual

functioning that does not rely on crystallized knowledge. It is a valid and reliable

measure of the processes involved in fluid reasoning (Llabre, 1984; Snow, Kyllonen,

& Marshalek, 1984) and is the gold-standard test of “g” (Jensen, 1980). It consists

of five sets of 12 items each made up of a series of diagrammatic patterns with one

component/element missing. These items vary progressively in difficulty. Each

item requires the examinee to inductively infer a rule relating to a sequence of

components. Using this rule, the examinee then selects an element to complete the

pattern from a choice of six or eight. A timed version of the RSPM test was

administered to participants at baseline as a brief measure of fluid ability.

102

Standardized instructions were used, although participants were told that they would

be given 10-minutes to complete as many items as possible. Timed formats of the

RSPM have been previously described (Jensen, Saccuzzo, & Larson, 1988), and this

approach was chosen to keep assessment times no longer than one hour in order to

minimise fatigue and maximise participation. The RSPM score reflected the total

number of correct responses completed in 10-minutes.

6. Mood: Participant’s emotional status was also measured at each assessment in order

to take into account the effect of emotional state at the time of assessment and

enable independent evaluation of the effect of surgery on neuropsychological

functioning. As discussed earlier, psychological effects - distinct from

neuropsychological effects - can adversely impact cognitive test performances.

Understanding, and measuring, the contribution of such psychological factors is

essential when attempting to explain neuropsychological impairment in patients

following CABG surgery.

Elevated anxiety, stress, and low mood may place additional demands and detract from the

cognitive resources available to patients; consequently, reducing efficiency and

performance on neuropsychological tasks. In addition, according to the vascular depression

hypothesis (Alexopoulos et al., 1997), vascular disease might contribute to depressive and

cognitive symptomatology, although the evidence for a physiological underpinning to this

hypothesis remains controversial(Habra, 2010; Kumar, 2002). Current mood state was

assessed using the Depression Anxiety and Stress Scale (DASS: Lovibond & Lovibond,

1995). The DASS is a 42 item self-report inventory on which participants’ rate

symptomatology over the past week.

103

Procedure

The tests outlined above were administered, by the author, at four different occasions with

repeat assessments taking place 1, 3 and 12 months after baseline. Both patients and

healthy controls were assessed at similar intervals using the same neuropsychological test

battery. Assessment times were selected to replicate existing on- and off-pump trials, and

to examine whether changes in neuropsychological functioning are transient or persisting.

Patients were assessed after randomization at baseline approximately 7 days before

scheduled surgery, and post-operatively at 1, 3, and 12 months. The control participants

were assessed at similar intervals, with follow-up times adjusted by one week to account

for the time-to-surgery in the patient group. Informed, witnessed, written consent was

obtained at baseline, along with demographic information such as date of birth, handedness,

gender, years of formal education, and occupation (or former) via interview. The

neuropsychological battery was administered in a quiet office, or at the participant’s home,

by the same examiner (the author). The tests were administered, using standardised

instructions, in the following predetermined order; MCG Copy trial, RAVLT trials 1-6,

DASS, TMT, Stroop Task, RAVLT delayed recall, MCG complex figure delayed recall,

COWAT, SDMT, and KHMT. In addition, the NART, and a ten-minute timed version of

RSPM were administered at baseline to estimate premorbid and current level of intellectual

function respectively. The order of test administration was selected to allow for

appropriate delays for the memory tasks while minimising the potential for domain-specific

interference. While set order potentially introduces systematic bias from factors such as

test anxiety (particularly for earlier tasks) and fatigue (particularly for later tasks), the

influence of these effects are either benign, or absent in neuropsychologically intact adults

(Kizilbash, 2002; Neuger et al., 1981; Uttl, 2000; Waldstein, 1997; Wills, 2004).

104

In total, each assessment required approximately one hour. Published, alternate versions

were used, where available, for tasks considered likely to be vulnerable to item-specific

practice. As such, four alternate batteries were constructed (A, B, C, D). The order of tests

within each battery was identical for each participant and re-administration. Alternate

versions of the battery were always presented in a forward sequence (A, B, C, D), although

the version administered at baseline varied across participants. This meant that no

participant repeated the identical battery at any follow-up.

Data Analyses

The following outlines the main analyses used to address each of the hypotheses presented

in chapter 4. Statistical analyses were performed using the SPSS statistical software

package (SPSS, Chicago, IL). Outliers were defined as standardised scores for each

variable that exceeded ± 3.29 (Tabachnick & Fidell, 2007). Unless otherwise specified

alpha was set at p < .05.

Practice Effects in Healthy Older Adults

Figure 4.2. (p. 107) outlines the approach to the analyses for practice effects and evaluation

of the psychometric properties of the neuropsychological battery used throughout this thesis.

To address hypothesis 1 (p. 68) repeated measures Analysis of Variance (ANOVA) across

three assessment times (baseline, 1 month, and 3 month) were performed for each measure.

105

The 12 month data were omitted from this analysis due to the very small number of

participants who had completed this follow-up (see Figure 4.1. p. 75).

Given that specific, directional predictions were made, planned comparisons were used to

explore the locus of the learning effects for each measure that reached significance on the

repeated measures ANOVAs (H1, prediction 2). A reverse Helmert method was used such

that each measure was compared with the equivalent measure at the previous assessment

time. That is, performance on test X at 3 months was compared with performance on Test

X at 1 month, which was compared with Test X at baseline.

As presented in Figure 4.2. (p. 107), Pearson correlations were obtained for adjacent

measures (i.e. baseline & 1 month, 1 month & 3 months, 3 months & 12 months) to

examine the test-retest reliability of the battery. For this analysis, data were collapsed

across alternate forms. Test-retest reliability was considered adequate when Pearson

correlations exceeded 0.6.

Inter-form reliability was examined using the entire group data at Baseline. Pearson

correlations were obtained for the four alternate forms of the Medical College of Georgia

Complex Figures (MCG), Rey Auditory Verbal Learning Test (RAVLT), Symbol Digit

Modalities Test (SDMT), and the two alternate forms of the Controlled Oral Word

Association Test (COWAT). Inter-form reliability was considered adequate when Pearson

correlations among alternate forms exceeded 0.6.

106

Pre-surgical Neuropsychological Sequelae Among CABG Surgery Patients

To examine hypotheses 2 (p. 69), baseline neuropsychological test performance of the

combined surgical group (on-pump, off-pump) was compared to that of the healthy controls,

using ANCOVA. Demographic and psychological variables were used as covariates in the

analyses. Statistically significant poorer performance in the surgical samples, compared to

the control sample, reflected cognitive “impairment” at p < .05.

Neuropsychological sequelae of on- vs. off-pump CABG

The primary data analyses examined the neuropsychological test performance of patients

allocated to on pump or off-pump CABG at 1-, 3-, and 12 months post-operatively. Two

statistical approaches to define impairment were employed; The RCI and the discrepancy

between predicted and obtained neuropsychological test performance. Figure 4.3 overleaf

represents the primary approach to data analyses at each post-operative follow-up.

In the “predicted-obtained” approach, regression equations were developed using data from

the healthy control group and used to predict each individuals performance from their

baseline test performance in combination with selected demographic variables. The

predictor variables for each regression equation were selected apriori, and entered

simultaneously into each regression. For each measure, the predictors included the baseline

performance on that measure, gender, age, education, estimated premorbid functioning

(NART error score), and total score on Ravens Standard Progressive Matrices (RSPM, to

reflect current intellectual functioning).

107

Figure 4.2. Schematic representation of the data analyses for practice effects and the

psychometric properties of the test battery.

Using the regression approach advocated by Crawford and colleagues (Crawford &

Garthwaite, 2006; Crawford & Howell, 1998b), patients’ predicted performances on eleven

measures at each follow-up assessment were calculated. On two measures in the battery,

the possibility existed that predicted scores might exceed the maximum for the test. Given

that this could potentially result in a misleading significant difference between obtained and

predicted scores, predicted scores above the maximum score for the test were replaced with

the maximum score, and the difference scores recalculated.

Obtained scores were subtracted from the predicted scores for all variables (i.e. predicted-

obtained difference scores). All difference scores were converted such that a positive

difference represented poorer obtained relative to predicted performance. At each follow-

Control Data

Psychometric properties Practice Effects

Baseline

Test-retest Reliability Inter-form reliability

1 month

3 months

12 months

Repeated

Measures

ANOVA

Test

version

1 Test

version

2 Test

version

3 Test

version

4

Correlations

Correlations

Correlations

Correlations

108

up, the relative performance of on- and off-pump groups on these difference scores was

compared with univariate ANOVAs for each variable (under hypotheses 4). Cognitive

“impairment” was considered to have occurred when the predicted-obtained difference

score was significantly different from zero. To examine the overall performance of the

CABG patients (hypothesis 3), independent of procedure, predicted-obtained difference

scores were compared to zero (no difference) using t-tests.

For comparison with the new regression-based approach Reliable Change Indices (RCI)

were also calculated by dividing participants’ observed test change score by the standard

error of this difference in the whole sample and then multiplying by ± 1.96. The resulting

index accounts for the variance that would normally be expected given inevitable

measurement error. Therefore, change scores that fall outside of this index are considered

significant. Mean scores from the control group were used as correction factors which

were applied to the RCI for each measure at each interval, in order to account for practice

effects (Kneebone et al., 1998; Lewis et al., 2006).

The incidence of impairment for each measure was calculated using both the predicted-

obtained method and the adjusted RCI approach at each follow-up visit. Chi-squared

statistics were used to examine whether the rate of impairment differed across these

methods both for the overall CABG group as a whole, and comparing on- versus off-pump

groups (hypothesis 6). Yates correction was applied when expected cell frequencies fell

below five, and Fisher’s exact tests were employed for cell counts below one.

109

Mood state and its influence on neuropsychological performance

The severity of each individual’s ratings across the three subscales within the DASS

(Depression, Anxiety, Stress) was classified according to the manual as normal, mild,

moderate, severe, or extremely severe. The frequencies across these classifications were

compared across groups using chi-squared analyses at each assessment. In addition, partial

correlations were used to examine the magnitude of relationships between cognitive

variables and current psychological symptoms of depression, anxiety and stress; with

demographic and individual difference variables held constant (hypothesis 5).

Figure 4.3. Schematic representation of the approach to the analysis of post-operative

neuropsychological performance.

Predicted-Obtained Method

Predicted-obtained scores

(surgical group)

Control Regressions

Mean discrepancy Incidence

Whole

surgical group

Whole

surgical group

On-pump Off-pump On-pump Off-pump

Reliable Change Index Method

Incidence

Whole surgical

group

On-pump Off-pump

χ2

χ2

T-

test

χ2 ANOVA/ANCOVA

Test-retest reliability

coefficients (control data)

110

CHAPTER 5 : Practice Effects in Healthy Older Adults

Overview

The aim of the study reported in this chapter is to examine and quantify the influence of

repeated neuropsychological assessment across a range of standardized neuropsychological

measures. As outlined in chapter 3, there are a number of factors that have the potential to

influence cognitive test scores that are acquired longitudinally. Among these influences are;

(1) the effects of interest (i.e. pathology, intervention, recovery); (2) measurement error and

reliability; and (3) improvements due to familiarity with test materials or procedures

(practice effects). This chapter will describe a study of repeat neuropsychological

assessment among a sample of healthy older adults to identify the temporal changes on

standardized neuropsychological measures across a number of cognitive domains. These

data will inform the approach used in the experimental randomised trial, which forms the

core of this thesis; and participants were therefore selected to be of a similar age and

educational background to the sample in the study of neuropsychological outcomes before

and after CABG surgery.

Existence of practice effects and their potential to disguise other changes in cognition is

widely acknowledged (Basso, Bornstein, & Lang, 1999; Beglinger et al., 2005; Benedict &

Zgaljardic, 1998; Bruggemans, Van de Vijver, & Huysmans, 1997; Collie et al., 2003;

McCaffrey et al., 1992). However, practice effects remain poorly characterised, and are

rarely accounted for in investigations of cognitive changes over time (Rabbitt, Diggle,

Holland, & Mc Innes, 2004; Rabbitt, Diggle, Smith, Holland, & Mc Innes, 2001; Watson,

Pasteur, Healy, & Hughes, 1994). Characterising the temporal nature of practice effects,

111

and understanding whether they affect cognition universally or whether some domains or

tasks are more susceptible than others has important implications for any assessment of

cognitive change.

It is also important that the nature of re-test effects, and the factors exerting influence on

rates of change, be better understood so they can be more effectively dealt with in clinical

practice, as well as study design and analyses. Failure to do so may mislead our

interpretation of longitudinal data. The current chapter examines practice effects, and

psychometric properties of a number of standardised neuropsychological tasks tapping

attention, working memory, memory, visuospatial skill, speed of processing, and executive

function.

A sample of healthy, community dwelling adults aged over 45 were administered a battery

of tests repeated four times over a period of 12 months. Intervals of 1, 3, and 12 months

were selected to correspond with acute and long-term follow-up assessments in a

randomised clinical trial of cognitive changes following coronary artery bypass surgery to

provide a normative comparison. Such intervals would not be uncommon in clinical

settings where the purpose is to evaluate cognitive changes (impairment, progression, or

recovery) following potential neurological insult, recovery, or the efficacy of an

intervention.

The following will extend the information presented in chapter 3 regarding the

methodological considerations for assessing changes in cognitive function over time,

outlining the potential test- and person-specific factors that may mediate re-test effects.

112

Methodological Considerations for Assessing Cognitive Change

As discussed in chapter 3, longitudinal research is regarded as a powerful tool for

examining change because it allows researchers to partition out the variance in a measure

for one individual over time from the variation between individuals (Diggle, Heagerty,

Liang, & Zeger, 2002). Thus, within a longitudinal design we can simultaneously explore

both cross-sectional and longitudinal patterns.

Neuropsychologists, both in clinical practice and research, frequently rely on longitudinal

assessments to draw conclusions about the temporal changes associated with injury or

intervention (Beglinger et al., 2005; McCaffrey et al., 1993). While repeat testing is

necessary to examine such cognitive change over time, there are several key factors that

limit the interpretation of such findings (McCaffrey et al., 1993). Neuropsychological

research, particularly employing a longitudinal design, should consider the effects of these,

as well as additional methodological biases stemming from sample biases such as

recruitment (Rabbitt et al., 2001), cohort effects, and subject attrition (Ferrer et al., 2004;

Rabbitt et al., 1994).

Essentially, explanations for change in neuropsychological performance can be partitioned

into four categories. The first is change (either decline or improvement) that is related to

the variable of interest. The second is change as a function of psychometric properties of

the test: Specifically, change that can be ascribed to imperfect test-retest reliability. The

third is change that might be due to some confounding variable that is influencing test

scores. The fourth is change that is attributed to practice effects. In reality, it is highly

likely that change measured by repeat neuropsychological assessment reflects a

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combination of each of the above. Detailed exploration of data from neurologically healthy

individuals will further our understanding of the contribution of such factors to any changes

in neuropsychological test scores in our sample of interest over time. In doing so, our

capacity to delineate these from other effects of interest will be enhanced.

Psychometric properties: reliability and regression to the mean

All measurement instruments have imperfect reliability, and it is rare to collect data without

any measurement error (Barnett et al., 2005). Test scores may vary considerably due to

error or chance alone (Raymond et al., 2005). Non-specific variation around a true mean,

or random measurement error, is problematic in repeat assessment because it can give rise

to the statistical phenomena of regression to the mean. With regression to the mean, repeat

observations on a measure tend to shift towards the mean value, regardless of whether true

change has actually occurred. When there is considerable variability in a measure, such

changes in test scores can be large, and may be misinterpreted as either an improvement or

deterioration in performance over time. This could result in wrongly concluding that

recovery, disease progression or cognitive impairment has occurred.

Practice effects

It is also likely, that repeated administration will result in improvements in performance

that are due to practice effects. Such gains associated with repeated administration can

“mask” other changes and therefore lead to underestimation of impairment (Cooper, Lacritz,

Weiner, Rosenberg, & Cullum, 2004; Rabbitt et al., 2001).

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Studies of both age-related cognitive decline (Ferrer et al., 2004; Rabbitt et al., 2004;

Rabbitt et al., 2001; Salthouse, Schroeder, & Ferrer, 2004) and recovery from neurological

insult (Spikman, Timmerman, van Zomeren, & Deelman, 1999) have utilised sophisticated

modelling techniques to emphasise this point. Remarkably, practice effects are estimated

to be 9 to 20 times larger than annual age-related decline (Salthouse et al., 2004), or

equivalent to the extent of the age-related neuropsychological deterioration that occurs

from 49 to 70 years, and across the seventh decade of life (Rabbitt et al., 2001). Thus,

practice effects are substantial and should not be ignored. These effects must be accounted

for in any assessment that requires serial assessment.

A corollary of this is that clinically important information can sometimes be derived from

the absence of improvement on some tasks (i.e. those vulnerable to practice effects), and

not necessarily only from an observed decline in performance. Awareness of the impact of

psychometric properties and/or practice effects on serial assessment is therefore

fundamental to the identification of true cognitive change in any longitudinal

neuropsychological study (McCaffrey et al., 1993). Failure to acknowledge and correct for

these will result in a less than accurate representation of cognitive change. For example,

failure to correct for measurement error can result in either an over- or underestimation of

cognitive impairment (Bruggemans et al., 1997), while failure to account for practice

effects can result in an underestimation of cognitive impairment (Rabbitt et al., 2001). As

Rabbitt et al. point out; these issues are very seldom recognized in the literature and

consequently rarely adequately dealt with.

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In terms of practice effects, a number of potential mediating factors have been proposed.

These can be partitioned into those that relate to the nature of the task (task-related) and

those that are associated with characteristics of the individual being assessed (person-

related). These task-related and person-related factors will now be briefly reviewed.

Task-related Factors Influencing Rates of practice Effect.

While practice effects are consistently reported (Basso et al., 1999; Beglinger et al., 2005;

Benedict & Zgaljardic, 1998; Collie et al., 2003; Ferrer et al., 2004; McCaffrey et al., 1992;

McEvoy, Smith, & Gevins, 1998; Rabbitt et al., 2004; Rabbitt et al., 2001; Watson, Pasteur,

Healy, & Hughes, 1994; Zgaljardic & Benedict, 2001), the magnitude and nature of these

are still a matter of controversy. Whether practice effects occur universally, in parallel, or

differentially among different tests and cognitive domains is of particular importance when

attempting to make inferences about the vulnerability of certain cognitive processes and

their underlying brain regions to pathology, or characterize disease progression or recovery.

Benedict and Zgaljardic (1998) suggest that task-related practice effects can be further

classed as either test-specific, or item-specific. Test-specific practice refers to the

improvement that comes about from development of more efficient test-taking strategies

after repeated exposure to the test. On the other hand, item-specific practice occurs when

participants remember the items from the previous assessment, thereby enhancing their

performance. The former is unavoidable in serial assessment, although the latter may be

effectively attenuated through use of alternate forms. It is likely, however, that the relative

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contribution of both test- and item-specific practice will vary across different cognitive

domains.

The following section will briefly summarise the general literature on practice effects

across the broad cognitive categories used within this thesis; information processing speed,

attention and working memory, visuospatial skill, memory, and executive functioning.

Practice effects across cognitive domains

Consistent practice effects have been reported across a range of measures tapping attention

and working memory (Beglinger et al., 2005; Collie et al., 2003; Lowe & Rabbitt, 1998;

McEvoy et al., 1998; Wilson et al., 2006). In general, both verbal and visuospatial memory

appear vulnerable to practice effects (Benedict & Zgaljardic, 1998; Collie et al., 2003;

Ferrer et al., 2004; McCaffrey et al., 1992; Rabbitt et al., 2004; Watson et al., 1994),

although reverse practice effects have been observed and require further investigation

(Kneebone et al., 1998; Lowe & Rabbitt, 1998; Rabbitt et al., 2004). Data on practice

effects in visuospatial skills is inconsistent, and findings have varied considerably (Ferrer et

al., 2004; Salthouse et al., 2004; Wilson et al., 2006; Zgaljardic & Benedict, 2001). The

larger studies reported significant and persisting gains on composite measures of

visuospatial ability across repeated administrations (Wilson et al., 2006); suggesting that

visuospatial ability is likely to be sensitive to practice-related improvements. For measures

of psychomotor and information processing speed, the findings have also been inconsistent

(Basso et al., 1999; Bird, Papadopoulou, Ricciardelli, Rossor, & Cipolotti, 2004; Ferrer et

al., 2004; McCaffrey et al., 1992; Wilson et al., 2006; Zimprich et al., 2004). Further,

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markedly different results have been observed even when the same tasks have been used

across studies (Basso et al., 1999; Beglinger et al., 2005; McCaffrey et al., 1992). This

suggests that practice effects are not necessarily reliably observed in speed of processing, or

they are potentially moderated by other factors (such as sample characteristics, retest

intervals, and number of reassessments).

Some have argued that repeat assessment of executive skills is unrealistic given the poor

retest reliability and cognitive specificity of executive tasks and that novelty, and therefore

the need for executive processes, is reduced with familiarity (Burgess, 1997; Lowe &

Rabbitt, 1998; Phillips, 1997; Rabbitt, 1997). However, latent variable analyses have

recently shown that the executive contributions to performance on standard executive

function tasks do not change when tasks are repeated (Ettenhofer, Hambrick, & Abeles,

2006). That is, the same processes appear to continue to play a role even on subsequent

administrations of executive function tasks. On specific executive function tasks, the

evidence for the existence of practice effects is not overwhelming. Although there have

been a number of studies which have demonstrated improvements across an array of

executive tasks (Basso et al., 1999; Lowe & Rabbitt, 1998; Salthouse et al., 2004; Spikman

et al., 1999), there have been conflicting results for Part B of the Trail Making Test and for

verbal fluency (Basso et al., 1999; Beglinger et al., 2005; DesRosiers & Kavanagh, 1987;

Frank, Wiederholt, Kritz-Silverstein, Salmon, & Barrett-Connor, 1996; McCaffrey et al.,

1992). Even within individual studies, there are different practice effects for similar

measures purportedly assessing the same cognitive construct (Ettenhofer et al., 2006;

Rabbitt et al., 2004).

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In accounting for the inconsistency across studies, it seems likely that differences in sample

characteristics moderated practice effects in many reported results. Specifically, lack of

practice effects were apparent in the slightly younger, more able samples (Basso et al.,

1999; Beglinger et al., 2005) over the older, and compromised groups (DesRosiers &

Kavanagh, 1987; Frank et al., 1996; McCaffrey et al., 1992; Spikman et al., 1999).

Intertest intervals and number of assessments are also likely contributing factors to the

variability in results with repeat assessments conducted at intervals ranging from hours

(Collie et al., 2003), days (McCaffrey et al., 1992), weeks (Beglinger et al., 2005; Lowe &

Rabbitt, 1998), months (Bird et al., 2004; Spikman et al., 1999), to years (Basso et al.,

1999; Ferrer et al., 2004; Wilson et al., 2006; Zimprich et al., 2004).

Variability in the magnitude, and temporal nature of practice effects across tasks or

domains could seriously mislead interpretation of longitudinal neuropsychological data.

However, investigations which characterise these changes are lacking (Wilson et al., 2006).

In summary, although practice effects are reliably observed, the domains most susceptible

to improvement with practice appear to vary across studies. This is largely due to

differences in sample characteristics, number of assessments, use of composite measures

versus individual tasks, and classification of tests into cognitive domains. However, fairly

consistent findings have been reported within the domains of attention and working

memory.

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Test-retest intervals and repetitions

Another factor that may potentially influence the presence and magnitude of practice

effects is the interval between follow-up and the number of times tasks have been repeated.

The temporal nature of practice effects for different measures and cognitive domains varies

both within, and across studies.

Arguing that performance gains occur primarily at the second administration and then

subsequently plateau (Beglinger et al., 2005; Collie et al., 2003) has led some to advocate

for a “pre-baseline” assessment (McCaffrey et al., 1993; Sacks et al., 1991). While rates of

practice do typically decelerate across sessions, this trajectory is not universal across tasks

(Beglinger et al., 2005; Benedict & Zgaljardic, 1998; Ferrer et al., 2004; Lowe & Rabbitt,

1998; Rabbitt et al., 2004; Salthouse et al., 2004; Spikman et al., 1999; Watson et al., 1994;

Wilson et al., 2006; Zgaljardic & Benedict, 2001). Improvements have been reported to

primarily occur at later test sessions (Ferrer et al., 2004; Shapiro & Harrison, 1990), and

considerable gains continue to be observed even after multiple repetitions (Beglinger et al.,

2005; Wilson et al., 2006; Zimprich et al., 2004).

Furthermore, improvements have been observed in retest intervals ranging from minutes

(Collie et al., 2003), hours, days and weeks (Beglinger et al., 2005; Bird et al., 2004; Collie

et al.; Cooper et al., 2004; Ettenhofer et al., 2006; McEvoy et al., 1998; Salthouse et al.,

2004; Watson et al., 1994; Zgaljardic & Benedict, 2001), to months (Spikman et al.) and

years (Basso et al., 1999; Ferrer et al., 2004; Rabbitt et al., 2004; Rabbitt et al., 2001;

Rabbitt et al., 2008; Wilson et al., 2006). While it may be that the magnitude of practice

effects alters as a function of time between assessments, it is difficult to compare the extent

of practice effects across studies because of considerable methodological differences.

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Mixed effects modelling techniques, applied to individuals retested at varying intervals

(from 1 week to 35-years) have shown that the average magnitude of improvement remains

stable across intervals of up to seven years (Rabbitt et al., 2004; Salthouse et al., 2004;

Zimprich et al., 2004). Therefore, practice effects persist even with protracted and variable

re-test intervals.

Alternate forms

The use of alternate versions of a test is another factor that has been proposed to modulate

rates of practice. Alternate forms are believed to reduce item-specific practice effects, or

familiarity with test items (Benedict & Zgaljardic, 1998; Crawford et al., 1989).

Alternate forms have been investigated in a number of populations, cognitive domains, and

standardised measures. In general, alternate forms typically attenuate the practice effects

ordinarily observed when an identical version of a task is repeated (Beglinger et al., 2005;

Benedict & Zgaljardic, 1998; Crawford et al., 1989; Geffen et al., 1994; Shapiro &

Harrison, 1990). However, it would also appear that the degree of benefit from the use of

alternate forms is dependent on the nature of the task demands. That is, direct or item-

specific practice will be attenuated through employment of alternate forms, although test-

specific or general practice effects will not. Indeed, alternate forms are least effective at

eliminating practice effects for tasks vulnerable to test-specific practice effects (Benedict &

Zgaljardic, 1998). That is, those tasks dependent on novelty, or vulnerable to strategy

development (Phillips, 1997). In contrast, those that are vulnerable to item-specific

practice are more likely to benefit from alternate forms.

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The central problems with the use of alternate forms to compensate for practice effects

include; availability of valid alternate forms (McCaffrey et al., 1992), equivalence of

alternate forms, and the development of strategies to maximise performance. Indeed

practice effects still occur with the use of alternate forms. Thus, while they potentially

reduce item-specific practice effects, they fail to address test-specific practice effects, or

familiarity (Benedict & Zgaljardic, 1998).

Person-related Factors Influencing rates of practice effect

A number of person-specific factors have also been identified which may influence the

extent of practice observed in serial neuropsychological assessment.

Age and individual differences.

Work by Rabbitt and colleagues have highlighted differential impacts of individual

differences on the magnitude of practice effects across a range of tasks. Somewhat

paradoxically their findings show that, at least on simple tasks, more able individuals show

less benefit from repeat administrations than do their less able counterparts. The reverse

pattern appears to be true for tasks considered more cognitively demanding (Lowe &

Rabbitt, 1998; Rabbitt et al., 2004); though moderately intelligent individuals show more

improvement than higher functioning individuals on measures of overall ability raising the

possibility that ceiling effects can account for the absence of improvement in the high

scoring group (Rabbitt et al., 2008). Others (Basso et al., 1999; Spikman et al., 1999) have

not replicated these findings in younger samples on measures of executive functioning and

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attention across intervals of up-to one year. The association between ability and practice

may therefore be highly test, or domain, specific or dependent on other factors such as age.

If there are different patterns of improvement across levels of overall ability and cognitive

measures they may relate to task requirements. In particular, it may be that the level of

executive control required on each task is the critical feature in determining whether an

optimal strategy can be developed to enhance performance (Lowe & Rabbitt, 1998). It is

also more likely that individuals of higher intelligence learn and retain material more

efficiently than those with lower intelligence. This may suggest that those with higher

intelligence scores should show relatively greater improvement on measures vulnerable to

test-specific practice effects. Unfortunately, cognitive tasks are not “process pure”

(Weiskrantz, 1992), and the relative contribution of different cognitive processes to

performance on a given task is likely to vary across individuals, and over time. Further

investigation into the relationship between ability and rates of change across different

cognitive domains is necessary.

In addition to different trajectories of change observed between individuals of high or low

intellectual ability, Rabbitt and colleagues (Rabbitt et al., 2004; Rabbitt et al., 2008), have

also found independent interactions between age and practice effects. Both studies

examined the pattern of performance change on measures of general intelligence (AH4

Group Test of General Intelligence [AH4-1 and AH4-2]) across four-year retest intervals in

a very large sample of individuals’ aged 49 and over. Significant interactions between age

and practice effects (or change over time) were observed. Specifically, the older adults in

their sample appeared to gain less from repeat testing than their younger counterparts

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(Rabbitt et al., 2008). Previously, Shapiro and Harrison (1990) reported attenuated general

practice effects in older, frailer samples.

Unlike the differential practice effects observed by Rabbitt and colleagues (Rabbitt et al.,

2004; Rabbitt et al., 2008), Wilson et al. (2006) reported no differences in practice across

age, sex or level of education across composite cognitive domains reflecting speed of

processing, episodic memory, semantic memory, working memory and visuospatial

processing. They did, however, find that individual variability, presumably not captured by

these other variables, were an important feature in retest effects, and that these individual

differences were not consistent across cognitive domains. This suggests that there are

important person-related factors that contribute to the variability in practice effects.

Practice Effects and Cognitive Decline

The evidence reviewed indicates that practice effects are an important consequence of serial

neuropsychological assessments. Such improvements may also moderate other changes in

complicated ways that will mislead our interpretation of longitudinal neuropsychological

data. That is, practice effects may obscure other effects. Of particular concern is the

likelihood that practice effects are not universal either across cognitive domains, tasks, over

time, or even across individuals. Because of the differential trajectories of practice across

individuals, tasks, and re-test intervals, longitudinal neuropsychological data are at risk of

being misinterpreted as evidence that different processes are less, or more, vulnerable than

others to pathology, intervention, or recovery.

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Detailed investigation into the effects of repeat neuropsychological testing on a range of

standardised instruments is fundamental when attempting to tease apart the effects of

practice from the effects of an intervention or potential neurological insult. Such

information would reduce “noise” in longitudinal data and more clearly elucidate the

effects of interest (Beglinger et al., 2005). Despite this, empirical investigation of repeat

neuropsychological assessment is scarce. In particular, there is a lack of data from such

effects in the absence of therapeutic interventions or suspected brain injury. Furthermore,

such investigations are often limited to experimental measures, studies which assess

specific cognitive domains, and typically only across two sessions. In order to understand

what drives change over time, further research of repeat testing in healthy adults is essential.

Rationale and Aims

The nature of change over time seems to be dependent on a number of factors. The aim of

the study presented in this chapter is to examine the learning effects in healthy community

volunteers on the neuropsychological test battery and assessment times used in this thesis to

examine post-CABG neuropsychological sequelae. These are crucial for an examination of

the cognitive changes associated with two forms of CABG surgery in the subsequent

chapters. Cognitive tasks and re-test intervals were therefore selected to provide re-test

data that could be used in the clinical investigation of the neuropsychological sequelae of

CABG surgery.

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Hypothesis

To recap the hypothesis and predictions presented in chapter 4 (p. 68), given the consensus

regarding the reduced improvements on later administrations, it was predicted that there

would be improvements in cognitive test performance over time, and that these practice

effects would be most pronounced across the first two sessions, followed by a plateau on

subsequent test sessions. Additionally, it was also predicted that there would be differential

effects of practice across cognitive domains and tests with the largest practice effects

occurring on measures relying on task novelty (i.e. Executive Functions), followed closely

by memory and working memory tasks, with the least practice effects expected on

measures of visuospatial skill, and processing speed.

Method

The methodology for this study has been presented in detail in chapter 4 (from p. 71).

Briefly, a sample of healthy adults aged 45 years and older (n = 46) were recruited into this

study and evaluated on four occasions over 12 months using a battery of

neuropsychological measures (see Table 4.2, p. 99). Data for control variables (age, years

of education, gender, premorbid intellectual functioning, and current fluid reasoning ability)

were also collected.

The analyses reported in this chapter pertain to hypothesis 1 (see p. 68). Specifically, the

average practice effects were examined using repeated measures ANOVAs for each of the

core neuropsychological outcome measures over time. Due to insufficient sample size,

data from the 12 month follow-up were omitted from these analyses. Planned directional

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comparisons further explored the learning effects on adjacent follow-up visits (e.g. baseline

to 1 month, 1 month to 3 months).

Although not central to the current study, correlation analyses were also performed on the

neuropsychological measures both over time (test-retest) and across alternate versions

(inter-form reliability).

Sample Characteristics

As presented in chapter 4, a sample of 46 healthy adults was recruited as an age-matched

control group for the surgical participants. A number of participants failed to attend

subsequent sessions, which resulted in slightly smaller sample sizes at each of the three

repeat assessments. From the original sample of 46 age-matched, healthy controls, 34

participants were tested at 1 month, 30 at 3 months, and 11 at 1 year. Table 5.1. (p. 127)

outlines the demographic characteristics of those who attended versus those who did not

attend at each assessment (baseline, 1 month, 3 months, and 12 months). One significant

difference emerged, with a higher mean age of participants who attended at 12 months

compared to those who failed to attend this follow-up, t (44) = 2.32, p < .05.

127

Table 5.1.

Demographic characteristics of healthy controls at each assessment.

N Age

Mean (SD)

Education

Mean (SD)

Gender

% male

NART Errora

Mean (SD)

Baseline

Entire Sample

46

62.26 (8.73)

12.9 (3.4)

52.2%

16.22 (7.63)

1 month

Did not attend

12

60.92 (7.68)

12.0 (3.2)

58.3%

16.50 (8.33)

attended 34 62.74 (9.13) 13.2 (3.5) 50.0% 16.12 (7.50)

3 months

Did not attend

16

59.75 (8.54)

12.4 (3.1)

50.0%

18.38 (7.22)

attended 30 63.60 (8.67) 13.1 (3.6) 53.3% 15.07 (7.71)

12m

Did not attend

35

60.53 (8.19)

13.3 (3.4)

45.7%

16.47 (7.15)

attended 11 67.17 (8.66)* 11.6 (3.3) 72.7% 15.50 (9.17)

Key: * p < .05. a Number of errors on the National Adult Reading Test – Second Edition

(Nelson,1991). FSIQ, Estimated Full Scale Intelligence Quotient. With the exception of age

at 12 months, differences were not significant.

Results

Practice Effects

In total, four outliers (standard scores exceeding ± 3.29; Tabachnick and Fidell, 2007) were

identified across the cognitive measures at baseline, 1 month, and 3 months. These were

replaced with respective means from each variable. Assumptions of normality were

violated for a measure of visuospatial skill at 1 month (Medical College of Georgia (MCG)

Complex Figure copy), all measures of processing speed at baseline and 3 months

((Symbol Digit Modalities Test (SDMT), Trail Making Test Part A (TMTa)), and two

128

executive measures at baseline (Trail Making Test ratio score (TMT ratio) and 1 month

(Stroop Interference) respectively. For these variables, data were transformed prior to

analyses. The SDMT and the Stroop Interference task were effectively normalised using

Square root transformation, where as the TMT ratio required a Log transformation, and the

heavily skewed TMTa was transformed by taking the reciprocal of participants’ scores. As

the assumption of sphericity was violated for one measure (Stroop Interference) measures,

the degrees of freedom used to evaluate the significance of the obtained F ratio for this

measure were adjusted using Huynh-Feldt epsilon.

Significant practice effects were found for four of the nine key cognitive measures in the

test battery (Table 5.2., p 130). Specifically, improvements were noted in one speed of

processing task; (TMTa) F (2, 54) = 4.72, p = .01, and two timed executive function

measures tapping inhibition (Stroop Interference), F (1.55, 41.95) = 4.36, p = .02, and

verbal fluency (COWAT), F (2, 54) = 9.118, p < .001, Significant improvements over time

were also seen for verbal working memory (KHMT), F (2, 54) = 9.81, p < .001. No

significant gains were noted in visuospatial skill (MCG figure) or a second measure of

processing speed (SDMT).

Planned comparisons for each measure revealed that practice effects consistently occurred

on these measures from baseline to 1 month. In addition, significant practice effects were

also observed from 1 month to 3 months for verbal working memory (KHMT), F (1, 27) =

11.16, p < .01, and inhibition (Stroop Interference), F (1, 27) = 14.83, p < .01. Effect sizes

were calculated to examine the magnitude of practice across different measures (Table 5.2.,

p. 130).

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Effect sizes were typically modest, ranging from small (d = .01) to medium (d = 0.62), and

varied across cognitive domains and assessment times. The largest practice effects were

seen from baseline to 1 month for verbal fluency (COWAT) and one processing speed

(TMTa). A moderate gain was also observed from baseline to 1 month, followed by a

small-moderate gain from 1 to 3 months for a measure of verbal working memory (KHMT).

The magnitude of practice effect remained relatively stable from baseline to 3 months for a

measure of inhibition (Stroop Interference).

Test-retest Reliability

Test-retest reliability was examined by correlations for each measure at adjacent follow-ups

(see Table 5.3., p. 132). In total, eight outliers were identified for across the four sessions,

and the assumption of normality was violated for the repeat assessments for the visuospatial

skill (MCG figure), two measures of executive functioning (TMT ratio score, and Stroop

Interference), and both measures of processing speed (TMT and SDMT). Spearman’s Rho

was used for these variables, while Pearson correlations were used for normally distributed

variables.

130

Table 5.2.

Mean neuropsychological test performance at baseline, 1 month and 3 months.

Cohen’s d

Cognitive domain Variable Baseline 1 month 3 months p baseline-

1 month

1-3

months

SDMTb

(total written score) Median (Interquartile

range)

49.50

(11.00)

49.50

(11.50)

50.00

(12.25) .30

a .16 .02

Speed of processing

TMTc Part A (seconds)

Median (Interquartile

range)

32.00

(9.00)

28.00

(10.00)

27.00

(8.00)

.01 a

.62

.06

Working Memory KHMTd (total correct) Mean (SD)

13.32

(3.20)

14.50

(3.42)

15.21

(3.19) <.001 .36 .22

Visuospatial Skill MCG e

(copy total) Mean (SD) 34.15

(1.69)

33.99

(1.28)

34.02

(1.34) .83

.11 .09

Visuospatial Memory MCG e

(delayed recall) Mean (SD) 19.82

(5.86)

19.89

(6.03)

20.57

(5.10) .71 .01 .12

Verbal Learning RAVLT

f (total words, trials

1-5)

Total

Mean (SD)

47.00

(9.59)

48.64

(9.23)

49.79

(10.25)

.21

.17

.12

Verbal Delayed

Recall

RAVLT f

(total number of

words: delayed recall) Mean (SD)

9.00

(2.96)

9.36

(3.07)

9.71

(3.51) .45 .12 .11


Verbal Fluency COWAT

g (total score)

Mean (SD) 39.64

(9.90)

45.00

(11.55)

43.86

(11.05) <.001 .50 .10

Inhibition Stroop Task (seconds to

complete)


range)

173.50

(44.00)

165.50

(56.00)

156.50

(54.00)

.02 a

.17 .23

Cognitive flexibility TMT

c (Ratio score)


range)

2.37

(1.09)

2.58

(1.29)

2.44

(0.86)

.43 a

.28

.17

Key:

a Analyses were performed on transformed variables for these tasks. Medians and interquartile ranges were therefore considered more appropriate descriptive

measures. bSDMT = Symbol Digit Modalities Test (Smith, 1982);

cTMT

= Trail Making Test (R. Reitan, M);

dKHMT = Kaufman Hand Movement Test (Kaufman &

Kaufman, 1983); eMCG = Medical College of Georgia Complex Figures(Meador et al.);

fRAVLT = Rey Auditory Verbal Learning Test (Rey, 1964);

gCOWAT =

Controlled Oral Word Association Test (Benton et al., 1994). (n = 28).

131

Test-retest was low to adequate for most measures from baseline to 1 month, with

correlations ranging from 0.32 (TMT ratio) to 0.82 (KHMT), and all but one correlations

were significant at p <.01. Similarly, the test-retest reliability remained consistent from 1

month to 3 months with the exception of two measures (TMT Part A, MCG copy). From 3

to 12 months, the correlations for several measures remained significant although scores for

a number of measures were non-significant (see Table 5.3, p. 132).

Inter-form Reliability

The inter-form reliability was explored by obtaining Pearson correlations or Spearman’s

Rho, for the four alternate versions of the MCG complex figure, RAVLT and SDMT, and

the two alternate forms of the COWAT collapsed across assessment time.

The inter-form reliability ranged from ρ = .17 to r = .90. With the exception of the MCG

complex figures, inter-form reliability was generally acceptable (see Table 5.4. p. 133).

The strongest correlation was observed for the Symbol Digit Modalities Test.

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Table 5.3.

Test-retest reliability for cognitive battery across time.

baseline-1 month

n = 34

1 month-3 months

n = 28

3 months-12m

n = 9

Cognitive domain Variable Baseline

Mean

(SD)

1 month

Mean (SD)

r or

ρ

1

month

Mean

(SD)

3 months

Mean

(SD)

r or ρ

3

month

s Mean

(SD)

12m

Mean

(SD)

r or ρ

SDMTb

(total written

score) 46.59

(9.09)

48.59

(10.75) .76**

47.68

(11.03)

48.39

(9.84) .76**

40.11

(11.07)

38.56

(10.60) .79* Speed of Processing

TMTc Part A (seconds)

34.32

(11.54)

30.03

(12.24) .50**

28.39

(9.92)

28.82

(10.67) .32

42.78

(17.61)

35.67

(9.67) .41

Working Memory KHMTd (total correct) 13.38

(3.39)

14.62

(3.57) .82**

14.50

(3.42)

15.21

(3.19) .80**

13.78

(3.99)

13.78

(3.56) .94**

Visuospatial Skill MCG e

(copy total) 33.88

(1.96)

33.59

(2.09) .47**

33.68

(2.13)

34.02

(1.34) .29

33.78

(1.20)

33.28

(2.68) -.34

Visuospatial Memory MCG e

(delayed recall) 19.60

(5.72)

19.63

(6.18) .59**

19.89

(6.03)

20.57

(5.10) .65**

20.61

(5.81)

19.28

(7.35) .63

Verbal learning RAVLT

f (total words,

trials 1-5)

46.85

(9.70)

48.74

(9.14) .62**

48.64

(9.23)

49.79

(10.25) .66**

47.44

(11.79)

45.67

(16.53) .92**

Verbal Delayed

Recall

RAVLT f

(total number

of words: delayed recall)

8.85

(2.81)

9.18

(3.08) .52**

9.36

(3.07)

9.71

(3.51) .62**

9.11

(4.23)

8.56

(2.51) .86**


Verbal Fluency

COWAT

g (total score)

40.76

(9.60)

45.44

(10.85)

.67**

45.00

(11.55)

43.86

(11.05)

.86**

40.22

(8.12)

41.33

(12.36)

.80**

Inhibition Stroop Task (seconds to

complete)

178.94

(43.86)

168.85

(40.04) .75**

173.57

(41.13)

164.75

(34.21) .88**

171.22

(40.91)

182.89

(31.62) .82**

Cognitive Flexibility TMTc (Ratio score)

2.32

(0.78)

2.48

(0.79) .32

2.62

(0.77)

2.47

(0.64) .48*

2.30

(0.84)

2.56

(0.99) .90**

** denotes p < .01; * denotes p < .05; Key: aSDMT = Symbol Digit Modalities Test (Smith, 1982)

bTMT

= Trail Making Test (Reitan, 1958);

cKHMT

= Kaufman Hand Movement Test (Kaufman & Kaufman, 1983); dMCG = Medical College of Georgia Complex Figures(Meador et al.);

eRAVLT = Rey

Auditory Verbal Learning Test (Rey, 1964); fCOWAT = Controlled Oral Word Association Test (Benton et al., 1994).

133

Table 5.4.

Inter-form reliability: Pearson’s r and Spearman Rho (ρ) across parallel versions of each

task collapsed across time

Parallel Version

Cognitive domain Variable Mean (SD) A B C D

SDMTa A 45.22 (9.4) 1

B 44.21 (9.52) .89** 1

C 49.34 (10.24) .90** .88** 1

Speed of

Processing

D 49.21 (10.33) .75** .70** .85** 1

MCGb copy A 33.75 (1.85) 1

B 33.72 (1.72) .37 1

C 32.98 (2.2) .31 .56** 1

Visuospatial Skill

D 34.71 (1.53) .17 .52* .34 1

MCGb delay A 19.92 (6.51) 1

B 20.34 (5.99) .77** 1

C 18.02 (5.47) .77** .66** 1

Visuospatial

Memory

D 19.85 (5.09) .40 .39 .43 1

RAVLTc total A 47.75 (11.90) 1

B 48.54 (9.76) .48* 1

C 47.13 (10.63) .58** .45* 1

Verbal Learning

D 45.93 (9.42) .79** .55** .56** 1

A 9.22 (3.53) 1 RAVLTc

delayed recall B 8.84 (2.70) .48* 1

C 9.25 (3.04) .66** .67** 1

Verbal Delayed

Recall

D 8.79 (3.23) .73** .51* .64** 1

COWATd PRW

CFL 43.25 (11.46) .85**

Verbal Fluency

PRW 43.61 (10.12)

** denotes p < .01; * denotes p < .05; aSDMT = Symbol Digit Modalities Test (Smith, 1982);

bMCG = Medical College of Georgia Complex Figures (Meador et al.);

cRAVLT = Rey

Auditory Verbal Learning Test (Rey, 1964); dCOWAT = Controlled Oral Word Association

Test (Benton et al., 1994).

134

Discussion

While cross-sectional studies may provide us with some information about cognitive

differences among individuals, a longitudinal approach is necessary when the interest

involves changes within individuals over time. The measurement of cognitive change

requires repeat neuropsychological assessment. However, even when test reliability is

perfect, prior exposure to neuropsychological assessments can result in improved scores in

the absence of intervention or neurological insult. These improvements, known as practice

effects, can occur across relatively protracted re-test intervals, and might vary as a function

of individual differences in ability, task difficulty, and cognitive domain. Despite the

importance of understanding these issues for valid interpretation of longitudinal studies or

repeat neuropsychological assessment, they are poorly understood and remain largely

ignored.

The current study sought to examine the learning effects in healthy, mature adult volunteers

on a range of neuropsychological measures tapping a number of cognitive domains. Within

the broader thesis, this investigation served two aims. Firstly, to better characterise the

effect of practice on neuropsychological assessment, and secondly, to provide a set of

‘normative’ data against which to compare the surgical groups test performances post-

operatively.

Participants were followed up 4 to 6 weeks (1 month), and again at 3 months after the

initial assessment. Given the small sample available for testing at 12 months, analyses of

practice effects were limited to the earlier sessions (baseline, 1 month, and 3 months). As

135

predicted, even within this relatively small sample of neurologically healthy individuals,

significant practice effects were observed over the three test sessions.

It was hypothesised that practice effects would occur on repeated neuropsychological test

administrations. Consistent with this, there were significant improvements in test

performances over three serial neuropsychological assessments. Also as predicted, the

magnitude of these improvements varied across assessment times and cognitive measures.

Due to the available sample at the 12 month follow-up, it was only possible to examine the

magnitude of improvements across the first two follow-up sessions, limiting the

conclusions that could be drawn regarding the persistence of the observed practice effects.

However, for many of the tasks, performance gains were greatest from baseline to the first

follow-up (1 month); in partial support for a possible plateau on some measures.

Specifically, in the current study, scores increased across each test session for the Kaufman

Hand Movement Test and the Stroop Interference task. This indicates that relatively stable

practice effects occur for verbal working memory and response inhibition; either by

automatisation or development of strategies. In contrast, improvements only occurred

across the first and second session for Part A of the TMT and the Controlled Oral Word

Association Test.

In addition, results showed that significant and moderately large improvements occurred on

four of the core neuropsychological measures; Stroop Interference, COWAT, KHMT, and

TMT. This suggests that verbal fluency, response inhibition, verbal working memory, and

psychomotor speed are subject to significant practice effects. Others have also found

136

differential patterns of practice across tasks (Beglinger et al., 2005; DesRosiers &

Kavanagh, 1987; McCaffrey et al., 1993; Rabbitt et al., 2004).

Several tasks (RAVLT, MCG figures, SDMT, and TMT ratio), however, yielded non-

significant changes. Ceiling effects (particularly the MCG figures), and inadequate sample

size may account for the lack of significant findings for these variables. Alternatively, the

non-significance in selected measures could be the result of attenuated practice effects

through use of alternate versions. Indeed alternate versions were used for five of the six

variables that showed non-significant effects. A third possibility was that test-retest

reliability interacted with rates of improvement. While this was not explicitly evaluated,

inspection of Table 5.2 (p. 130) suggests that this was not the case. For example, absence

of significant re-test gains were observed for measures with both poor reliability (e.g. TMT

ratio score, MCG figure copy) as well as moderate to high reliability (e.g. RAVLT total).

Alternate forms have been proposed as a viable method for avoiding practice effects in

serial neuropsychological assessment. However, the fact that significant gains have

reportedly occurred with use of alternate forms (Beglinger et al., 2005; Benedict &

Zgaljardic, 1998; Crawford et al., 1989; DesRosiers & Kavanagh, 1987; Shapiro &

Harrison, 1990) indicates that practice can occur through familiarity with test-procedures

(test-specific practice effects). Significantly reducing or ameliorating practice effects

through use of alternate measures suggests that familiarity with specific test-items/stimuli

underpins improvement on some tasks (i.e. item-specific practice effects). Indeed alternate

forms may reduce the influence of item-specific, but not-necessarily test-specific factors

(Benedict & Zgaljardic, 1998; Crawford et al., 1989). In the present study, significant

137

practice effects were not observed for any of the tasks for which alternate versions were

administered at each retest (MCG figures, RAVLT, or SDMT). However, significant

improvements in test performance occurred from baseline to 1 month for the COWAT,

despite the fact that two alternate versions of this task were used. This might suggest that

some tasks, particularly those with more executive demands, are amenable to strategy

development to optimise performance.

Of the measures showing significant improvement with prior exposure, the practice effect

was greatest for the COWAT, a measure of verbal fluency. On this task, significant gains

were made (on average six additional words generated) from baseline to 1 month, followed

by a plateau from one to 3 months. A similar pattern of marked initial gain, and subsequent

plateau was observed for Part A of the TMT, a measure of psychomotor processing speed.

In contrast, improvements continued to occur, in a relatively stable manner, across all three

sessions for measures of verbal working memory (KHMT), and response inhibition (Stroop

Interference task).

This pattern of differential practice effects across tasks that employed alternate versions,

would also lend partial support to Benedict and Zgaljardic’s (1998) suggestion that tasks

dependent on novelty, graphomotor responding, or visuospatial learning will be most

vulnerable to test-specific, rather than item-specific practice. Such tasks are least likely to

benefit from alternate forms.

Tasks tapping verbal learning and memory would seem highly vulnerable to item-specific

practice. Given this, one might hypothesise that alternate forms would be effective at

138

attenuating practice effects in such tasks (Benedict & Zgaljardic, 1998; Crawford et al.,

1989). This was certainly the case in the current study, where no significant gains were

reported for alternate versions of RAVLT or MCG figure recall across the three sessions.

While this stands in contrast to the findings of Shapiro and Harrison (1990), it replicates

findings by Geffen et al. (1994).

The evidence regarding the effect of repeat administration for timed tasks involving rapid

psychomotor or information processing responses is mixed. Consistent with the findings of

the current study, McCaffrey et al. (1992) reported the absence of practice effect for the

SDMT. However, significant gains were observed on another processing speed task in the

current study (TMT Part A).

In addition, test-retest reliability coefficients for all but one measure (copy trial of the MCG

complex figures) were acceptable, and ranged from .52 to .96. As would be expected with

use of standardised measures, the observed reliability coefficients were in keeping with

previous work (Geffen et al., 1994; Kneebone et al., 1998). However, it is important to

reiterate the need to better understand the relationship between reliability and practice

effects, and adequately address this in any analyses that seek to determine whether

meaningful change has occurred following insult or intervention.

The inter-form reliability across parallel versions was also mostly acceptable, with the

exception of the last form of the MCG figure task (both copy and delayed recall trials),

which did not correlate significantly with any of the other three figures. Obtained

correlations between the alternate versions were consistent with previous work (Geffen et

139

al., 1994; Shapiro & Harrison, 1990), and provide further evidence of the equivalence and

worth of parallel forms.

The present findings need to be considered in the context of a number of possible

limitations. Firstly, limited sample size is likely to have influenced the detection of

significant changes for some measures in the current study, though effect sizes were

generally medium to large for most of the findings. Additionally, although the current

study was not designed to specifically tease apart the interaction of reliability and practice

gains, it is possible that the observed rates of change and re-test scores were confounded by

differences in test-retest reliability. Equally, high variability may provide pseudo-random

fluctuation in parameters and lead to erroneous conclusions about practice effects.

However, previous work has demonstrated that, in addition to the influence of test

reliability, test scores are also modulated by practice effects (Chelune et al., 1993;

Kneebone et al., 1998). Moreover, there did not appear to be a consistent relationship

between practice gains and reliability in the current findings. It is also possible that high

initial scores on certain tasks restricted the degree of improvement that was possible;

thereby precluding detection of significant practice effects. Avoidance of such ceiling

effects through appropriate test selection is therefore crucial in longitudinal studies where

improvement is anticipated or possible.

In addition, it was beyond the scope of this study to clearly delineate the potential

contributions item-specific practice, increased automatic processing, and strategy

development on re-test effects. This may be achieved by employing a randomised, cross-

over study design, and through the utilisation of dual-task methodologies and suppression.

140

The results of the current investigation provide further evidence that in study designs that

use repeat testing a number of issues arise. Pre-baseline testing, use of alternate forms, or a

single correction factor across individuals or measures, while partially useful, do not

adequately deal with the complexity of repeat testing, particularly when multiple cognitive

domains are assessed. Consequently, the only method to control for the many issues is to

compare changes within any experimental group to that of a group of appropriate controls.

This highlights the need for inclusion of neurologically healthy control samples, when

attempting to tease apart the effects of injury, disease, or intervention from methodological

factors associated with serial neuropsychological assessment.

141

CHAPTER 6 : Pre-surgical Neuropsychological Sequelae Among CABG Surgery Patients

Overview

Within the CABG literature, neuropsychological studies have focused on the post-operative

complications that might occur as a result of surgery. While surgery is the central

candidate for the neurological changes that are argued to occur in these patients, it is also

possible that factors including pre-existing vascular disease (such as hypertension, history

of heart attack) might have already placed patients at risk of reduced cerebral blood flow or

embolism, manifest as reduced cognitive performance (Rankin et al., 2003; Petitti &

Buckwalter, 2003; Vingerhoets, Van Nooten, & Jannes, 1997). This study seeks to

examine the neuropsychological profile of candidates for CABG surgery, and the

possibility that presurgical cognitive deficits are not only the consequence of elevated

anxiety, stress or depressed mood among such patients (hypothesis 2).

To do so, the current study will test heart-diseased patients, scheduled for CABG surgery,

on a number of cognitive measures across a range of domains prior to surgery. Their

performance will be compared to an age-matched healthy control sample. To examine the

possible relationship between mood on pre-surgical cognitive functioning, partial

correlations will be conducted between self-reported symptoms of depression, anxiety and

stress, and performance on cognitive measures.

On the basis that cardiovascular disease itself is likely to compromise cerebral integrity and

cause subtle cognitive impairments, presurgical deficits would be anticipated within the

domains of speed of information processing, executive functioning and memory. Moreover,

142

although an association with mood might be expected, the deficits would occur independent

of the influence of mood.

Background

To briefly recap on the relevant review presented in chapter 2 (pages 7-38), severe

hypertension that is common among patients with severe coronary artery disease is

associated with hemodynamic instability, cerebral ischemia, white matter damage and

lacunae (Adams et al., 1993; Fearn et al., 2001; Fisher, 1982; Mäntylä et al., 1999). Such

structural insults can give rise to functional impairments, including cognitive dysfunction

(Jokinen et al., 2006; Kramer, 2002; Longstreth et al., 1996; Reed, 2006; Ylikoski et al.,

1993). On this basis, it might be expected that individuals with severe cardiac illness (such

as those scheduled for CABG surgery) would show neuropsychological impairments

(Ernest, Murphy, et al., 2006; Fitzgibbons et al., 2002; Rankin et al., 2003; Selnes,

Goldsborough, Borowicz, & McKhann, 1999).

From the review of the literature presented in chapter 2, we know that basal ganglia,

cerebellum, hippocampus, parietotemporal cortex, and cerebral white matter are

particularly vulnerable to hemodynamic and metabolic disruption (Moody, Bell, & Challa,

1990; Small & Buchan, 1996). The extent of damage and precise location of associated

ischemic/hypoxic pathology is likely related to the patient’s vascular anatomy (Mäntylä et

al., 1999).

143

Given that the aim of much of the existing research has been to examine the effects of

intervention, studies have focused almost entirely on post-operative neuropsychological

status or changes from pre-surgical function. However, as discussed in chapter 3,

individual differences in ability (for example IQ, or baseline performance) can interact with

other test factors and influence the patterns of change over time. This is likely to

complicate the interpretation of such change. Therefore, neuropsychological performance

at baseline is equally important when untangling the likely multifaceted influences on

cognition associated with CABG surgery. Compromised test scores at baseline (either as a

result of some factor associated with the disease itself, or elevated stress, anxiety, or

depression), will undoubtedly influence the interpretation of post-surgical deficits and post-

surgical changes in neuropsychological performance. Despite this, only a small subset of

the published CABG studies has specifically addressed the question of presurgical

cognitive dysfunction.

Recently, Selnes et al. (2009) reported generalised cognitive impairment, on a composite

score, among three cardiovascular diseased groups (presurgical patients scheduled for on-

and off-pump CABG, non-surgical cardiac diseased) compared to well matched healthy

controls. In earlier work, Keith, Puente, Malcolmson, Tartt, Coleman, and Marks (2002)

reported CABG patients had impaired verbal memory, relative to age-matched healthy

controls prior to surgery. Similarly, Rankin, Kochamba, Boone, Petitti, and Buckwalter,

(2003) identified pre-surgical deficits in composite scores of both verbal memory and

perceptuomotor speed, with patients scoring below the fifth percentile on both measures.

Whilst Selnes et al. did not observe specific deficits, the overlap in the pattern of pre-

surgical deficits in these two latter studies is difficult to ignore, and on the surface provides

144

support for the idea that cardiovascular disease, itself, may be associated with

neuropsychological impairment.

An alternative explanation is that these pre-surgical deficits are a consequence of elevated

anxiety and or depression. Indeed, it is widely accepted that depression and anxiety impede

neuropsychological test performance. Not surprisingly, CABG patients have been shown

to be significantly more anxious, compared with non-surgical healthy controls prior to, but

not after surgery (Keith et al., 2002; Tsushima et al., 2005). Consequently, within the

CABG literature, it has been suggested that elevated levels of depression and anxiety at

baseline may lower pre-surgical cognitive performance, thereby influencing the degree of

post-surgical change (Brown et al., 1994; Duits et al., 1998). Given that neither Keith et al.,

nor Rankin et al. examined this possibility in their analysis it is difficult for this alternative

explanation to be definitively ruled out.

Others, however, have suggested that this is unlikely (McKhann, Borowicz , et al., 1997;

Tsushima et al., 2005), which suggests that elevated pre-surgical anxiety and depression

has little or no bearing on neuropsychological status. For example, Tsushima, Johnson, Lee,

Matsukawa, and Fast (Tsushima et al., 2005) found that scores on the Beck Depression

Inventory II (BDI-II:Beck, Steer, & Brown, 1996), and State-Trait Anxiety Inventory

(STAI: Spielberger, Gorsuch, & Luchens, 1970), were unrelated to neuropsychological test

performance in their sample of 60 CABG patients. This was despite “substantial”

symptoms of anxiety (p. 669) in their sample.

145

The present study examined the neuropsychological profile of cardiovascular diseased

patients scheduled to undergo CABG, and its relationship with self-reported symptoms of

anxiety, stress, and depression. This study attempted to 1) determine whether significant

cardiovascular disease (that is severe enough to warrant surgical revascularisation) was

associated with cognitive deficits independent of the effects of psychological factors 2)

describe the nature of any neuropsychological deficits among CABG candidates.

Hypothesis

CABG candidates will have pre-existing vascular compromise and chronic cerebral

hemodynamic insufficiency that will have affected neuropsychological functioning.

Specifically it is predicted that;

1. CABG candidates will show neuropsychological deficits prior to

surgery, independent of the potential effect of psychological factors. That is,

controlling for potential effects of mood and demographic variables, CABG

patients will demonstrate poorer neuropsychological test performance compared to

controls at initial baseline assessment.

2. Pre-surgical neuropsychological impairments will be most pronounced in

domains tapping areas vulnerable to ischemic damage; speed of information

processing, verbal memory, and executive functioning. That is, CABG patients

would show significantly poorer performance than their healthy counterparts

(control group) on such measures.

146

Method

The methodology for this study has been presented in chapter 4 (from p. 71) and will be

briefly summarised here. Figure 6.1. (p. 147) outlines the relevant sections of the

longitudinal study that will be examined in this chapter. Briefly, data from 53 patients

scheduled to undergo CABG surgery, and 46 age-matched controls were included in the

current study. Participants were administered a series of neuropsychological measures as

described in chapter 5. Mean performances of the CABG and control groups for eight

neuropsychological variables were compared using ANCOVA. Demographic variables (age,

gender, education, premorbid IQ, and current fluid reasoning ability) as well as DASS

scores (depression, anxiety & stress) were used as covariates in these analyses to control for

the potential influence of differences in sample characteristics and psychological factors on

test performance.

147

Figure 6.1. Flowchart of participation relevant to the study reported in the current chapter.


study

(N =108)

Controls

(n = 46)


n = 62





baseline

(n = 53)

148

Results

On average, the surgical group and healthy controls were of a similar age (see Table 6.1., p.

149), F (1, 95) = .53, p = .24. However the control group, was significantly more educated

than the surgical group, F (1, 95) = 6.47, p = .01, and demonstrated significantly better

performance on the Ravens Standard Progressive Matrices, F (1, 94) = 5.44, p = .02.

Participant's Full Scale IQ's (FSIQ) were calculated from the NART according to

standardised procedures (Nelson, 1991). Two CABG and two control participants failed to

read more than 10 words and were excluded from the analyses given that the NART was

used as a predictor variable in later analyses. The mean estimated IQ was in the average

range (mean = 110.47, SD = 6.80, range: 96-121) for the surgical group and in the high

average range for healthy controls (mean = 114.27, SD = 6.34, range = 102-126). This

resulted in a significant group difference in estimated FSIQ, F (1, 93) = 7.83, p < .01.

Demographics and Covariates

Data were screened for normality and outliers. Two outliers (± 3.29) were identified in the

surgical group for the number of days from baseline to surgery. One outlier was identified

(control) for total score on Ravens Standard Progressive Matrices. Outliers were replaced

with their respective group means for each variable. Following this, all demographic

variables were normally distributed.

Group differences between groups were examined using ANOVA for continuous variables,

and Chi squared analyses for categorical data (see Table 6.1., p. 149). Table 6.1. shows the

149

demographic characteristics of the combined surgical group, as well as sample of age

matched healthy controls.

Table 6.1.

Demographic characteristics of the surgical and healthy control samples at initial visit.

CABG Control p

N 53 44

Male/femaleǂ 40/13 23/21 .02

Age in years

Mean (SD) min-max

63.51

(9.42) 43-77

62.2

(8.51) 47-79 .48

Years of education


range) Range

11.0 (3.1) 6-17 12.7 (3.4) 7-21 .01

Estimated FSIQ

Mean (SD) Range

110.47

(6.80) 96-121

114.27

(6.34) 102-126 <.01

Ravens Standard

Progressive Matrices

Score

Mean (SD) Range

28.31

(7.31) 7-44

31.59

(6.31) 16-42 .02

Handednessǂ

% Right

90.6

83.7

.24

ǂ Chi Squared analyses; FSIQ = Estimated Full Scale Intelligence Quotient.

There were no significant differences for self-reported handedness between the surgical and

control groups, χ2 (1, N = 97) = 1.02, p >.05, and consistent with the general population,

150

more participants claimed to be right handed (87.5%), compared to left-

handed/ambidextrous (12.5%), χ2 (1, N = 97) = 54, p <. 001. The gender distribution

across two groups varied considerably, with the percentage of males in the surgical group

75.5% compared to only 52.3% male participants in the control sample, χ2 (1, N = 97) =

5.68, p <. 05.

Cognitive Performance

Data were screened for normality and outliers. Two outliers were identified for Part A of

the Trail Making Test (TMTa), and two outliers were identified for the Stroop Interference

task. These scores were replaced with their respective group means for each variable. Four

of the cognitive variables deviated from normality, and therefore required transformation

prior to analyses. The distribution for TMTa was positively skewed and showed

leptokurtosis, which was effectively normalised with a log transformation. The positively

skewed TMT ratio score was normalised with a square root transformation. A log

transformation normalised the positively skewed and kurtotic distribution for the Stroop

Interference task. Finally, the negatively skewed SDMT was reflected and normalised by

taking its square root.

Univariate Analyses of Covariance were conducted to examine group differences in

baseline cognitive variables, with demographic variables (Gender, Age, Education, NART

error score, Ravens Standard Progressive Matrices) as covariates. When demographic

factors were statistically controlled, significant group differences emerged for verbal

151

memory (delayed recall trial of the RAVLT), F (1, 89) = 8.21, p = .04, with the control

group outperforming the surgical group on this task. A trend in the same direction was also

observed for verbal learning (RAVLT total score), F (1, 89) =3.64, p = .06 (see Figure 6.2.

p. 151 & Figure 6.3. p. 151).

0

2

4

6

8

10

12

CABG Control

Group

Me

an

nu

mb

er

of

wo

rds

rec

all

ed

(R

AV

LT

de

lay)

Figure 6.2. Group differences in verbal memory (RAVLT delayed recall) at baseline.

Note * = p < .05. Error bars represent 95% confidence intervals.

0

10

20

30

40

50

60

CABG Control

Group

Mea

n n

um

ber

of

wo

rds

rec

all

ed

(R

AV

LT

to

tal)

Figure 6.3. Group differences in verbal learning (RAVLT total) at baseline.

Error bars represent 95% confidence intervals.

*

152

In addition, the group difference in verbal memory recall remained significant when

depression, anxiety and stress scores were added as additional covariates, F (1, 86) = 4.04,

p = .05. Furthermore, the addition of the DASS scores (see relationship between symptoms

of current mood and cognitive performance from p. 154) revealed an additional significant

difference between controls and surgical participants for a measure of cognitive flexibility

(TMT ratio score), F (1, 86) = 4.62, p = .03.

Table 6.2. (p. 153) shows that gender was a significant covariate for verbal learning, F (1,

89) = 8.23, p < .01; verbal memory, F (1, 89) = 5.96, p = .02; and verbal fluency, F (1, 89)

= 4.55, p = .04. Age was a significant covariate for verbal learning, F (1, 89) = 13.05, p

< .01; verbal memory, F (1, 89) = 7.01, p = .01; both speed of processing measures (TMT

Part A), F (1, 89) = 6.78, p = .01, (SDMT), F (1, 89) = 6.12, p = .02; inhibition (Stroop

Interference), F (1, 88) = 15.27, p < .01; and working memory, F (1, 89) = 4.66, p = .03.

Estimated premorbid intellect (NART) was associated with verbal fluency, F (1, 89) = 5.59,

p = .02; and working memory, F (1, 89) = 5.88, p = .02. Finally, current fluid reasoning

(RSPM) was a significant covariate for verbal learning, F (1, 89) = 6.05, p = .02; both

processing speed measures (TMT Part A), F (1, 89) = 9.60, p < .01, (SDMT), F (1, 89) =

21.26, p <.001; inhibition, F (1, 88) = 7.16, p < .01; verbal fluency, F (1, 89) = 3.93, p = .05;

and working memory, F (1, 89) = 9.78, p < .01. Education was not a significant covariate

for any of the baseline cognitive scores.

153

Table 6.2.

Results from ANCOVA. Relationship between demographic (covariates) and independent variable (group) cognitive performance.

Key: aSDMT, Symbol Digit Modalities Test (Smith, 1982);

bTMT, Trail Making Test

(Reitan, 1958);

cKHMT, Kaufman Hand Movement Test (Kaufman & Kaufman,

1983); dRAVLT, Rey Auditory Verbal Learning Test (Rey, 1964);

eCOWAT, Controlled Oral Word Association (Benton et al., 1994);

a NART, National Adult

Reading Test (Nelson, 1991.); gRSPM, Ravens Standard Progressive Matrices (Raven).

Cognitive Domain

Variable

Group Gender Age Education NARTf RSPM

g

Speed of processing

SDMTa F (1, 89) = 2.08, p = .15 F (1, 89) = .28, p =.60 F(1, 89) = 6.12, p = .02 F(1, 89) = 1.57, p = .21 F(1, 89) = .04, p = .84 F(1, 89) = 21.26, p < .01

TMTba F (1,89) =. 00, p = .99 F (1, 89) = .29, p = .59 F (1, 89) = 6.78, p = .01 F (1, 89) = .003, p = .96 F (1, 89) = 1.64, p = .20 F (1, 89) = 9.60, p < .01

Working Memory

KHMTc

F(1, 89) = .002, p = .97

F(1, 89) = 1.47, p = .23

F(1, 89) = 4.66, p = .03

F(1, 89) = .04, p = .85

F(1, 89) = 5.88, p = .02

F(1, 89) = 9.78, p < .01

Memory

RAVLTd total F (1,89) =3.64, p = .06 F (1, 89) = 8.23, p < .01 F (1, 89) = 13.05, p < .01 F (1, 89) = .46, p = .50 F (1, 89) = 1.63, p = .21 F (1, 89) = 6.05, p = .02

RAVLTd delay F (1, 89) = 8.21, p = .04 F (1, 89) = 5.96, p = .02 F (1, 89) = 7.01, p = .01 F (1, 89) = .12, p = .73 F (1, 89) = .21, p = .65 F (1, 89) = .56, p = .46

Executive Functioning

Stroop Task F(1,88) = .84, p = .36 F(1, 88) = .31, p = .58 F(1, 88) = 15.27, p < .001 F(1, 88) = .03, p = .86 F(1, 88) = 1.73, p = .19 F(1, 88) = 7.16, < .01

COWATe

F(1,89) = 1.13, p = .29

F(1, 89) = 4.55, p = .04 F(1, 89) = 2.85, p = .10 F(1, 89) = .002, p = .96 F(1, 89) = 5.59, p = .02 F(1, 89) = 3.93, p = .05

TMTb ratio F(1,89) =3.15, p = .08 F(1, 89) = .44, p = .51 F(1, 89) = 1.23, p = .27 F(1, 89) = .53, p = .47 F(1, 89) = .78, p = .38 F(1, 89) = 3.05, p = .08

154

Mood State and its Relationship to Cognitive Performance

Eight outliers were identified across the three measures of mood (depression, anxiety,

stress). For symptoms of depression, four participants from the surgical group, and two

controls scored in the severe range, two surgical participants scored in the moderate

range, while the remaining participants rated symptoms of depression in the mild-

normal range. The frequency of responses across these classifications did not differ

between the surgical and healthy control samples, χ2 (2, N = 97) = 2.15, p = .54.

For symptoms of anxiety two surgical, and one control participant scored in the

extremely severe range, three participants from the surgical and one from the control

group scored in the severe range, while eight surgical and two control participants

scored in the moderate range. The remaining participants recorded mild-normal

symptoms of anxiety. These group differences in the frequency of responses across

these classifications were significant, χ2 (2, N = 97) = 15.14, p < .01.

Elevated stress symptoms, in the extremely severe range, were observed in one

participant from the control group. In addition, three surgical patients, and one control

participant reported symptoms of stress in the severe range. Moderate levels of stress

were reported in four surgical participants and two controls, and the remaining

participants reported symptoms of stress, which placed them in the mild-normal ranges.

The frequency of responses across these classifications did not differ between the

surgical and healthy control samples, χ2 (2, N = 97) = 3.66, p = .45.

155

As a consequence of non-normal extent mood disturbance, all three variables were

significantly positively skewed and showed kurtosis. These were normalised using log

transformations.

Overall mean levels of self-reported symptoms of anxiety were significantly lower in

the control sample relative to the surgical group, F (1, 95) = 27.47, p < .001. The

groups did not differ significantly on self-reported symptoms of depression or stress.

To examine the magnitude of any relationships between current symptoms of

depression, anxiety and stress and the cognitive variables were explored using partial

correlations within each group while demographic factors were held constant. For the

control sample, there were no significant correlations between any of the cognitive

scores and measures of mood. In the surgical group, however, one processing speed

measure (Part A of the Trail Making Test) correlated significantly, and positively, with

depressed mood (r = .33, p = .03) and anxiety (r = .43, p < .01). These data are

presented in Table 6.3. (p. 156).

0

0.5

1

1.5

2

2.5

3

CABG Control

Group

Me

an

TM

T r

ati

o s

co

re

Figure 6.4. Group differences in cognitive flexibility (Trail Making Test ratio) at

baseline. Note * = p < .05. Error bars represent 95% confidence intervals.

*

156

Table 6.3.

Partial correlations between DASS scores and baseline cognitive scores in the CABG group.

Variable

Mood Variables

pr (r) Control Variables

r Cognitive

Domain Depression Anxiety Stress Age Education Gender RSPM

f FSIQ

g

Speed of

Processing SDMTa

(total written score)

.21

(.15)

.18

(.20)

-.01

(-.07) .43** -.40** .08 -.61** .14

TMTa

b (seconds)

.33*

(.23) .43**

(.38)**

.26

(.14) .41** -.29* .24 -.52** .15

Working

Memory KHMTc

(total correct)

-.18

(-.12)

-.27

(-.25)

-.15

(-.07) -.31* .32* .02 .57** -.38**

Memory

Learning RAVLT

d Total (total

words, trials 1-5)

.02

(.04)

-.06

(-.11)

-.08

(-.02) -.44** .27* .00 .34* -.19

Delayed

Recall

RAVLTd delay (total

number of words: delayed

recall)

.10

(.14) -.15

(-.10)

-.01

(.05) -.41** -.03 .19 .05 -.03

Executive

Function Fluency COWAT

e (total score)

.13

(.08)

.04

(-.05)

.03

(.01) -.13 .36** .25 .33* -.43**

Inhibition Stroop Task (seconds)

.15

(.08)

.14

(.15)

.11

(.00) .52** -.30 .14 -.55** .20

Cognitive

Flexibility TMTbratio (Ratio score)

-.07

(-.07)

-.09

(-.03)

-.03

(-.03) .09 -.18 -.04 -.30* .34*

Note n = 53; * denotes p < .05; ** denotes p < .01; ^ denotes a trend (p<.06) aSDMT, Symbol Digit Modalities Test (Smith, 1982);

bTMT

, Trail Making Test

(Reitan, 1958); cKHMT, Kaufman Hand Movement Test (Kaufman & Kaufman, 1983);

dRAVLT, Rey Auditory Verbal Learning Test (Rey, 1964);

eCOWAT,

Controlled Oral Word Association Test (Benton et al., 1994); f RSPM, Ravens Standard Progressive Matrices (Raven);

gFSIQ, Estimated Full Scale IQ.

Zero-order correlations are reported in parentheses.

157

However, the group difference in verbal memory (discussed earlier), remained

significant when anxiety, depression and stress were added as covariates the model, F (1,

86) = 4.04, p = .05. In addition, a group difference in cognitive flexibility (Trail

Making Test ratio score) emerged as a consequence of controlling for differences in

mood, F (1, 86) = 4.62, p = .03 (see Figure 6.4. p. 155) with stronger performance in

controls over CABG candidates.

Discussion

The current study, as part of a longitudinal investigation into the neuropsychological

sequelae of CABG surgery, sought to examine the pre-surgical neuropsychological

functioning in cardiovascular diseased patients due to undergo CABG surgery.

Importantly, the current investigation sought also to examine, and account for the likely

effects of emotional state in the surgical group on their test performance.

As predicted, CABG patients showed pre-surgical neuropsychological deficits relative

to age-matched controls that were over and above those expected because of depression,

anxiety or stress. Although there were differences in gender distribution, level of

education and intellect between the age-matched controls and the surgical patients (see

Table 6.1., p. 149), these differences were statistically controlled in the analysis to limit

their influence. Furthermore, the fact that these results are in close agreement with

those observed in Keith et al. (2002) and Rankin et al. (2003), would suggest that these

demographic factors were adequately accounted for.

Specifically, CABG patients showed significantly poorer performance for the delayed

recall trial of the RAVLT, relative to the healthy control group, with a similar trend

158

apparent for the RAVLT total score. This suggests a specific impairment in verbal

memory among coronary heart-diseased patients who are scheduled to undergo CABG

surgery. An additional finding, of better performance on the TMT ratio among the

controls relative to the CABG candidates occurred once the DASS scores were

statistically controlled. This might indicate that elevated anxiety, stress, or depression

somehow optimised performance on this task, and that partialling this out of the

analyses revealed an underlying weakness. In the CABG candidates, elevated scores on

the DASS Anxiety and Depression subscales correlated with poorer performance on

Part A, but not Part B of the TMT. The partialling out of this influence may therefore

have had the effect of increasing the ratio between Parts A and B of the TMT and

revealing an impairment in cognitive flexibility.

Given that cardiovascular disease factors – such as hypertension and cardioemboli - are

associated with ischemic brain damage (Adams et al., 1993; Fisher, 1982; Mäntylä et al.,

1999), and reduced cerebral hemodynamics and metabolism (Reed et al., 2006),

impairments were considered most likely in areas vulnerable to ischemic damage.

Frontal and hippocampal structures were identified as the most at risk. In addition,

reduced oxygen supply, and associated subtle ischemia has been linked to diffuse

cerebral white matter changes. These observed deficits in verbal memory and cognitive

flexibility, are consistent with pathological changes within these areas (Kramer, 2002;

Longstreth et al., 1996; Ylikoski et al., 1993).

Mood state is another known influence on neurocognitive function and has been offered

as a potential explanation for the neuropsychological performance prior to surgery

(Brown et al., 1994; Duits et al., 1998). Several studies, however, have failed to

incorporate measures of mood in their testing, and therefore account for its possible

159

impact on change in neuropsychological performance. In the present study, elevated

anxiety was observed in the CABG group, compared to controls. In addition, four

CABG participants scored in the severe range for depression, and five scored in the

severe or extremely severe range for anxiety. Overall levels of self-reported depression

and stress, however, were undifferentiated between the groups.

An association between mood and cognitive performance was observed in the current

study, although only within the surgical group. Specifically, elevated anxiety and

depression in this sample were associated with reduced performance on a speed of

processing task. Consequently, mood variables were added to the analyses, to control

for their influence and determine whether effects of group remained. Importantly, the

group differences in verbal memory remained significant, and an additional group

difference in cognitive flexibility emerged when the influence of depression, anxiety

and stress were controlled for. This provides further evidence that disease factors,

rather than non-organic factors, contribute to cognitive impairments. That is, not all the

variance in cognitive test performance in cardiovascular patients can be explained by

elevated anxiety, or depressed mood.

Others have failed to show an association between self-reported symptoms of anxiety

and depression with neuropsychological functioning in CABG patients (Tsushima et al.,

2005). For example, Tshushima et al. found very small correlations (ranging from 0.01

– 0.25) between mood measures and neuropsychological performance. In the current

study, both elevated anxiety and depression were associated with slower speed of

processing in the surgical group (see p. 155). Important differences in the severity of

depression, as well as chosen measures of mood and cognition between the current

study and Tsushima et al.’s study may have contributed to the discrepant findings. In

160

addition, the correlations between mood and cognitive functioning reported by

Tsushima et al. may have been confounded by the reported significant relationship

between demographic factors (age and education) and cognition.

However, it is important to note that within the current study, there were differences in

the relationship between mood and cognition across the two samples. Specifically,

mood variables were only significantly correlated with one cognitive variable within the

surgical group (Table 6.3., p. 156). There are several possible explanations for this

finding. The first relates to cognitive resources, and the notion that those with vascular

compromise may have reduced processing resources available. Therefore, dysfunction

may be more apparent in these patients under situations where the processing demands

are higher, or there are additional factors competing for these resources (such as

intrusive thoughts associated with mood disturbance). Additionally, differences in the

severity of depressive symptoms may have also contributed to the discrepant findings

between these groups. In support of this, a recent meta-analysis by McDermott and

Ebmeier (2009) identified a significant relationship between severity of mood

disturbance and performance on timed and executive tasks.

Alternatively, a different gender balance within each group may be another explanation

for the different pattern of results among CABG candidates and healthy controls. The

control sample comprised almost 50% female, whereas females were underrepresented

in the cardiovascular diseased CABG surgery patients (see Table 6.1., p. 149). Of note,

gender was found to be a significant covariate for verbal learning and verbal fluency

(see Table 6.2., p. 153).

161

There has been considerable controversy over the existence of gender differences in

neuropsychological abilities (Hobson, 1961; Jackson, 2006; Lachance, 2006; Rizk-

Jackson, 2006). Stable sex differences across a range of cognitive domains in

neurologically healthy older adults were found by de Frias, Nilsson, & Herlitz (2006).

They report stronger episodic recall, fact and verbal recognition and semantic fluency in

women compared with men, and a male preference for visuospatial abilities. In the

current study, gender differences were potentially a significant concern. Consequently,

gender was included as a predictor variable in the regression analyses, in an attempt to

minimise this possibility. Therefore, it is unlikely that the observed differences between

our samples can be attributed to gender effects.

The principle finding in this study is that cardiovascular diseased patients due to

undergo CABG surgery show specific impairments in verbal memory and cognitive

flexibility. Importantly, these impairments are independent of demographic or mood

state factors. This finding provides further evidence that cardiovascular disease may

cause, or place people at risk of neurological impairments. Given the profile of

impairments, the locus of damage is highly likely to include metabolically vulnerable

mesial temporal structures such as the hippocampus (Yonelinas, 2004), in addition to

more diffuse white matter changes that may disrupt fronto-subcortical networks

(Cummings, 1995).

It would appear, from the present findings, that severe cardiovascular disease

warranting surgical revascularisation could be associated with neuropsychological

deficits. Such deficits might indicate that neural is compromised with CVD, either

directly via some mechanism of reduced blood flow, or as a result of more widespread

vascular disease that might include carotid artery, or cerebrovascular disease.

162

These results highlight the importance of examining, and incorporating, pre-surgical

measures of functioning in any study that aims to examine post-surgical changes in

neuropsychological function.

163

CHAPTER 7 : Acute Neuropsychological Sequelae of On- vs. Off-pump CABG: A

Prospective Randomised Trial

Overview

As outlined in chapter 2, there are several unanswered questions regarding the

neuropsychological sequelae associated with CABG surgery. In particular, whether the

use of the pump is the cause of neuropsychological impairment; whether specific

cognitive processes or all areas of cognitive functioning, if any, are at risk during

CABG surgery; and whether any such changes are transient or persisting. This chapter

examines the acute cognitive changes, at 1 and 3 months after on- or off-pump CABG.

A sample of cardiovascular diseased patients were randomly allocated to either on- or

off-pump CABG and assessed on a battery of neuropsychological measures before and

at 1 and 3 months post-operatively. For each task, pre-surgical performance, along with

a range of control variables, was used to predict post-operative test scores using

regression equations built from age-matched controls. Cognitive impairment was

assumed to have occurred when an observed score was significantly poorer than the

predicted performance on a given task. For comparison, corrected Reliable Change

Indices (RCIs) were also calculated as an alternative method to determine impairment.

Under this method, impairment was deemed to have occurred when scores fell outside

the range of scores expected on the basis of test reliability and practice.

Background

To summarise the literature presented in the introductory chapters, CABG surgery in

general appears to be associated with important neurological consequences, which range

164

in severity from subtle changes to frank stroke (Roach et al., 1996; Selnes,

Goldsborough, Borowicz, & McKhann, 1999; Taggart & Westaby, 2001). While the

more subtle declines have been attributed to the use of cardiopulmonary bypass (CPB)

(BhaskerRao et al., 1998; Newman et al., 2001; Roach et al., 1996), research findings

are yet to conclusively support this view. Despite a relatively large literature

investigating post-CABG neurological dysfunction, the magnitude of changes,

incidence of impairment, their temporal nature, and the brain regions affected remains

uncertain. Furthermore, how these translate into functional cognitive changes, whether

potential impairments are global or affect specific cognitive domains is unclear.

The evidence regarding the acute neuropsychological deficits following CABG is

inconclusive and has been compounded by failure to account for 1) differential practice

effects across measures and individuals, 2) statistical/psychometric factors such as

regression to the mean and imperfect test reliability, and 3) the impact of mood.

However, the most commonly reported pattern is of initial early decline and subsequent

recovery (Browne et al., 2003; Jacobs et al., 1998; Mahanna et al., 1996; Newman et al.,

2001; Selnes, Goldsborough, Borowicz, & McKhann, 1999; Diederik. van Dijk et al.,

2000)

The introduction of CABG surgery performed on the beating heart (off-pump) has

enabled researchers to examine whether the cognitive deficits following CABG occur

directly as a result of using cardiopulmonary bypass. Claiming that the pump (CPB) is

the main cause for post-operative cognitive decline in CABG surgery, many researchers

argue that off-pump surgery should reduce the risk of neurological damage

(BhaskerRao et al., 1998; Taggart et al., 1999).

165

There are demonstrated neurological advantages of the off-pump over the on-pump

method including decreased embolic activity (BhaskerRao et al., 1998; Bowles, 2001;

Sylivris et al., 1998), less cerebral oedema (Anderson, Li, Hindmarsh, Settergren, &

Vaage, 1999), and better cerebral perfusion and oxygenation (Chernov et al., 2005;

Diegler et al., 2000), which are allied with decreased risk of compromised cerebral

integrity and function. Therefore, avoiding the use of CPB (on-pump), by performing

CABG off-pump, should result in improved neuropsychological outcome.

Since the introduction of off-pump, non-experimental observational studies comparing

these techniques argue that off-pump surgery is associated with better

neuropsychological outcomes compared to traditional CABG. In particular researchers

suggest that differences are most evident within the domains of executive function

(BhaskerRao et al., 1998; Selnes et al., 2001), verbal memory (Selnes et al., ; Taggart et

al., 1999), and speed of information processing (Selnes, McKhann, Borowicz, & Grega,

2006; D. P. Taggart et al., 1999). However, support for the off-pump method is not

universal and evidence from randomized trials comparing on and off-pump CABG is

largely conflicting. While some studies report enhanced cognitive outcome in off-pump

relative to on-pump (Diegler et al., 2000; Lee et al., 2003; Motellebzadeh, 2007; Van

Dijk et al., 2002), others report no differences (Fitzgibbons et al., 2002; Hernandez et al.,

2007; Lloyd et al., 2000; Lund et al., 2003; Tully et al., 2008), and one reports better

outcome in on- compared to off-pump (Zamvar et al., 2002). Few studies, however

have adequately accounted for the impact of stress, anxiety and depression, which is

known to influence neurocognitive function (Brown et al., 1994; Duits et al., 1998;

Eysenck, 1985).

166

To date, two research groups have performed meta-analytic studies of the published

randomised controlled trials. On a composite neuropsychological score from six

randomised trials, Takagi et al. (2007) reported a statistically significant reduction in

incidence of decline among the off-pump patients compared to on-pump patients at the

1 month to 3 month follow-up. While these authors examined a general composite

measure of neuropsychological functioning, Marasco et al. (2008) analysed results

across five specific cognitive domains within eight trials (N = 892). In Marasco et al.

off-pump CABG was associated with improved performance on one task (Trail Making

Part A), a measure of processing speed, at both short and long-term postoperative

follow-ups. Moreover, a similar pattern occurred in the early postoperative period for an

additional speeded measure (Digit Symbol) when one outlier study was removed from

the meta-analysis. Collectively, the results of these meta-analytic findings provide

marginal support for a neuropsychological benefit of off-pump CABG over traditional

on-pump, in the acute postoperative period.

Studies have rarely attempted to evaluate which cognitive domains may be

compromised during CPB and whether these cognitive domains are impaired as a result

of the physiological changes caused by on-pump surgery, or whether there are other

explanations for any observed changes. In addition, few studies have adequately

accounted for the impact of stress, anxiety and depression which is known to influence

neurocognitive function (Brown et al., 1994; Duits et al., 1998; Eysenck, 1985).

Furthermore, differential rates of practice effects, both across individuals and

neuropsychological measures, are likely to impact on the interpretation of any post-

operative change, although are yet to be adequately, and consistently dealt with.

167

The existence and nature of cognitive deficits is also influenced by the criteria used to

determine whether deterioration or dysfunction has occurred. A range of methods have

been employed in the existing research, making it difficult to directly compare across

studies. This will impact on the incidence and, therefore, the capacity to draw sensible

conclusions from even the more powerful meta-analytic studies. Typically, a change

between pre- and post-operative performance is evaluated using some criteria to

determine whether the difference is abnormal and thus reflects impairment. The

definition and identification of post-operative (in this case post-CABG) cognitive

dysfunction is therefore intrinsically linked to the statistical, but often arbitrary rules

that have been applied (Kneebone et al., 1998; Lewis et al., 2006). Most of the

approaches can be criticised because they fail to take in to consideration issues such as

practice effects, regression to the mean, test reliability or differential patterns of change

(influenced by individual differences, age or other factors).

Many traditional parametric statistics are not properly equipped to deal with the issues

of practice effects, individual trajectories, or multiple influences on change. Stump,

James and Murkin (2000) raised the possibility that individual trajectories may offset

one another and therefore produce a very misleading overall group average, thereby

potentially reducing the chances of detecting change. Similarly, multiple influences of

change may be superimposed, again resulting in a possible masking of the change

attributable to the effect of interest (Keith et al., 2002; Rabbitt et al., 2001). For

example, improvements from practice associated with repeated assessment may offset

potential deterioration associated with neurological impairment. These complicating

factors highlight the need for careful design and consideration of appropriate statistical

analyses.

168

In sum, the literature to date has not yet untangled the complex story of the

neuropsychological sequelae associated with CABG surgery. This is likely due to

conflicting findings among barely comparable studies that have mostly employed

arbitrary definitions of cognitive impairment and have often failed to account for the

influence of psychometric properties, mood, differential trajectories of change or other

factors associated with repeat testing. It remains unclear whether on-pump results in

cognitive dysfunction, and whether this dysfunction is global or is limited to specific

cognitive processes in the acute post-operative phase.

Recognising the need for a sound statistical approach for determining

neuropsychological change, Kneebone, Andrew, Baker and Knight (1998) proposed

Reliable Change Index (RCI) adjusted for practice. Briefly, the RC index establishes an

interval within which an individual’s score may fall given the observed practice effects

and measurement error of the instrument. This interval provides a defensible, rather than

arbitrary, cut-off on which to determine whether a patient’s performance has changed.

Lewis et al. (2006) state that “systematic error is likely to affect the whole sample in a

uniform way” and advocate for the use of RCI with a constant correction factor to

control for practice effects. However, there is sufficient evidence within the broader

neuropsychological literature to suggest that practice effects may not be constant.

Rather, trajectories of change vary as a function of age, ability, and nature of the task its

self (Rabbitt et al., 2004; Rabbitt et al., 2001; Rabbitt & Lowe, 2000; Rabbitt et al.,

2008). Therefore, while RCI’s will alleviate some of the pitfalls associated with repeat

neuropsychological assessment, there is scope for even more precise and defensible

statistical methods to calculate cognitive change.

169

One approach that has the potential to simultaneously deal with measurement error and

differential practice effects is to build regression equations to predict follow-up scores,

which can then be compared to individuals’ actual obtained performance (Crawford &

Garthwaite, 2006; Crawford & Howell, 1998b). When an obtained score is

substantially lower than the predicted score, cognitive deterioration or impairment can

be inferred (Crawford & Garthwaite, 2006; Crawford & Howell, 1998b).

The current study uses a method based on a similar approach outlined by Crawford and

colleagues (Crawford & Garthwaite, 2006; Crawford & Howell, 1998b), to predict

patients’ performances on eleven measures at follow-up (1 and 3 months). Data from

the control sample were used to derive the regression equations for each test at follow-

up with baseline performance, age, gender, education, NART error score, and Ravens

Standard Progressive Matrices as predictor variables. These equations were then used

to calculate predicted scores for each surgical patient which where then compared to

patients obtained test performance to determine whether patients were performing at,

below, or beyond expectation at each follow-up. In addition, RCI’s were also calculated,

correcting for practice gains using data from the control group, across each measure as

an alternative method of defining impairment.

A similar standardised regression-based approach has been employed by Kneebone and

colleagues (Tully et al., 2008), who have extended their previous work which used the

RCI method (Kneebone et al., 1998) in the investigation of post-CABG

neuropsychological impairment. Tully et al. built regressions using a healthy control

sample using baseline test performance, age, gender and IQ as predictors of post-

operative test performance. The discrepancy between predicted and obtained

postoperative test scores was then standardised by dividing by the standard error of the

170

estimate from the control regression equations. This standardisation approach is

appropriate when examining predicted scores from individuals who were part of the

original sample used to derive the regression equation, however, it doesn’t account for

the additional error that arises from using a separate sample to construct regression

coefficients (Crawford & Howell, 1998b). Therefore it will likely underestimate the

confidence limits and result in a less stringent criteria for impairment. This is

particularly relevant in small sample sizes, such as those typical in CABG randomised

controlled trials such as the study by Tully et al. (2008). Therefore, whilst the technique

used by Tully et al. (2008) is the most considered approach within the published

literature, it would be more correct to adjust the standard error when evaluating

members from a group other than the regression sample(Crawford & Garthwaite, 2006;

Crawford & Howell, 1998b).

To deal with this additional error, Crawford and colleagues (Crawford & Howell, 1998;

Crawford & Garthwaite, 2006) have derived an inferential method for use at an

individual case-study level.

Using Crawford et al.’s method, this study examined the neuropsychological outcomes

between two types of coronary artery bypass graft (CABG), namely on and off-pump at

1 and 3 months. This study attempts to 1) determine whether off-pump CABG results

in superior neuropsychological outcome compared to on-pump at 1 and 3 months post

surgery; and 2) describe the nature of any neuropsychological deficits occurring in the

acute phase after CABG surgery.

171

Hypotheses

As outlined in chapter 4 (see hypotheses 3-5, from p. 69), it is hypothesised that, if CPB

is the cause of neuropsychological impairment, over and above other non-specific

effects of surgery, then patients on off-pump CABG will show less cognitive decline

compared to traditional on-pump CABG.

Secondly, from a neuropathologic standpoint, the consequences arising from the use of

CPB (such as hypoperfusion, showers of microemboli, and temperature changes) are

likely to result in ischemia and possibly mild hypoxia. While such cerebral insults

produce widespread defects, the hippocampal and frontal regions are highly vulnerable

to hemodynamic and metabolic disruptions. Therefore, it is anticipated that the specific

deficits in the functions underpinned by these areas (memory, and executive functioning)

will be superimposed on more diffuse global impairments (speed of information

processing) in the on-pump, but not the off-pump group. Additionally, while it has been

previously assumed that emboli favour the pathway leading from the right

brachiocephalic trunk (Jacobs et al., 1998 ), there is no difference in microembolic load

between the left and right middle cerebral arteries (Bowles et al., 2001). As such, it is

predicted that verbal and visual aspects of memory and executive function will not be

differentially affected.

Finally, while some authors report chronic disturbances in cognitive performance

following CABG, the effect appears to be most pronounced in the acute phase and more

subtle over the long-term. Given the pattern of early cognitive decline, followed by

recovery reported in the CABG literature (Murkin et al., 1995; Selnes, Goldsborough,

Borowicz, Enger, et al., 1999), it is anticipated that group differences in

neuropsychological functioning, evident at 1 month, will resolve by 3 months.

172

Method

The methodology for the study is described in detail in chapter 4. Briefly, this study

focuses on the acute neuropsychological outcomes following CABG surgery. A sample

of patients who randomised to on-pump or off-pump CABG were neuropsychologically

assessed approximately one week before surgery, and again at 1 and 3 months post-

operatively. Figure 7.1. (p. 173) presents the sections of the overall thesis study and

associated participation information relevant for this current chapter. The sample

characteristics are presented in Table 7.3. (p. 180) and Table 7.8. (p. 189).

A standardised neuropsychological battery comprising seven tasks, tapped a broad

range of cognitive domains. Due to the poor reliability of the Medical College of

Georgia Complex Figures (reported in chapter 5) the data from this task were excluded

from analyses at follow-up. As such, from 10 principal cognitive measures derived (see

p. 99), 8 are reported in this chapter.

Two methods of measuring post-operative cognitive impairment were applied to the

CABG data utilising data from an age-matched control group who had been assessed on

the same battery over similar re-test intervals (see Figure 7.1., p. 173.). In the

predicted-obtained approach, regression equations built from the control sample (see

Table 7.1., p. 176 & Table 7.2., p. 177 for these results), were used to predict post-

operative performance from baseline scores and a range of demographic variables.

Neuropsychological impairment was considered to have occurred when obtained test

scores were significantly lower than predicted.

173

Figure 7.1. Flow chart of participation at baseline, 1 month and 3 months.


study

(N =108)


(n = 32)


(n = 30)

Completed 1 month

assessment

(n = 24)

Completed 1 month

assessment

(n = 22)

Completed 3 month

assessment

(n = 24)

Completed 3 month

assessment

(n = 24)

Completed 1 month

assessment

(n = 34)

Completed 3 month

assessment

(n = 30)



- unwell (n = 1)

- developed angina and

breathlessness during assessment

(n = 1)



Controls

(n = 46)


n = 62





baseline

(n = 53)

174

Analyses were performed using mean predicted-obtained discrepancy scores, and the

incidence of impairment was also calculated using both this approach and a corrected

RCI method for comparison. The RCI method allows for the construction of an index

within which an individual’s score on a given task may vary given measurement error

and mean practice effects. Tables of the RCI’s for each follow-up, based on the data

from the control groups, are presented in Appendix A.

A matched control group were examined over the same intervals, allowing for

regression equations as well as reliable change indices (RCIs) to be derived for each

neuropsychological variable. The approach to primary data analyses is represented in

Figure 7.2. (below).

Figure 7.2. Schematic representation of the data analyses for chapters 7 and 8.

Predicted-Obtained Method

Predicted-obtained scores

(surgical group)

Control Regressions

Mean

discrepancy

Incidence

Whole

surgical

group

Whole

surgical

group

On-pump Off-pump On-pump Off-pump

Reliable Change Index Method

Incidence

Whole surgical

group

On-pump Off-pump

χ2

χ2

T-

test

χ2 ANCOVA

Test-retest reliability

coefficients (control data)

175

The test-retest reliability, and mean practice gains have been previously reported

(chapter 5), though tables of the corrected RCIs at each follow-up is included in

Appendix A.

Results

Control Data: Regression Analyses

Standard multiple regressions were performed between each cognitive follow-up score

as the dependent variable and baseline test score, gender, age, education, NART error,

and ravens standard progressive matrices as independent variables. Variables were first

examined for normality and outliers, resulting in the need to transform three baseline

variables (TMTa, TMT ratio, SDMT) with square root and log transformations.

For the simultaneous multiple regressions R2 ranged from .07 to .87 (Table 7.1., p. 176,

and Table 7.2., p. 177) indicating that, overall, a large proportion of the variance in

cognitive performance at follow-up was predicted by the combination of baseline

cognitive and control variables. Sequential regressions were employed to determine if

the addition of control predictors (gender, age, education, premorbid and current IQ),

improved prediction of follow-up performances beyond that afforded by differences in

baseline performance alone. When compared to the model where baseline performance

was primary predictor, the addition of the other predictors added significantly to the

regressions in most cases. These results are presented in Table 7.1. (p. 176) and Table

7.2. (p. 177).

176

Table 7.1.

Results of the regression analyses of controls at 1 month.

B (SE) R2 R

2 change Cognitive

Domain Dependents Intercept

Baseline Gender Age Education NART RSPM 1 2 F p

Speed of

Processing SDMT

a (total written

score) 37.55

.71**

(.11)

-1.86

(1.62) -.44**

(.10)

.89**

(.30)

-.01

(.13)

-.08

(.14) .69** .87** 7.26 <.01

TMTa

b (seconds)

-13.61 .59 **

(.19)

3.86

(3.22)

.31

(.20)

-.02

(.61)

.17

(.26)

.14

(.31) .54** .61* .89 .50

Working

Memory KHMT

c (total

correct) 4.00

.75 **

(.09)

-1.85**

(.55)

-.05

(.03)

.15

(.10)

.01

(.04) .12*

(.04) .67** .87** 7.67 <.01

Memory

Verbal

Learning

RAVLTd Total

(total words, trials 1-

5)

43.32 .23

(.15)

-1.17

(2.49)

-.28

(.15)

.53

(.42)

-.18

(.18)

.33

(.20) .38** .65** 4.01 <.01

Delayed

Recall

RAVLTd delay

(total number of

words: delayed recall) 4.30

.42*

(.15)

-1.19

(.91)

-.06

(.05)

.21

(.16)

.02

(.07)

.12

(.07) .27** .55** 3.19 .02

Executive

Function

Fluency COWAT

e (total

score)

-.39

.81**

(.10)

-.16

(2.09)

-.16

(.13)

1.56**

(.39)

.59**

(.16)

-.25

(.17)

.59**

.80**

5.35

<.01


49.38 .67**

(.14)

-14.38

(9.10)

.83

(.59)

.72

(1.67)

.87

(.70) -1.60*

(.71) .76** .83** 2.11 .10

Cognitive

Flexibility TMT

bratio (Ratio

score) 4.04

.20

(.16)

-.53

(.27)

.00

(.02)

-.03

(.05)

.00

(.02)

.03

(.02) .10 .38* 2.33 .07

Key: 1 denotes Bivariate regression; 2 denotes multivariate regression. B (SE) denotes regression coefficients with standard error;* denotes p < .05. ;

** denotes p < .01. aSDMT, Symbol Digit Modalities Test (Smith, 1982);


(Reitan, 1958);

cKHMT, Kaufman Hand

Movement Test (Kaufman & Kaufman, 1983); dRAVLT, Rey Auditory Verbal Learning Test (Rey, 1964);

eCOWAT, Controlled Oral Word

Association Test (Benton et al., 1994);

177

Table 7.2.

Results of the regression analyses of controls at 3 months.

Cognitive

Domain

B (SE) R2 R

2 change

Dependents Intercept


Speed of

Processing SDMT

a (total written

score) 27.64

.59**

(.14)

-1.13

(2.13)

-.20

(.13)

.02

(.39)

-.12

(.17)

.29

(.19) .68** .76** 1.52 .23

TMTa

b (seconds)

47.12 .25

(.23)

-5.17

(4.00)

.24

(.25)

-.06

(.76)

-.36

(.32) -.83*

(.39) .34** .56** 2.22 .09

Working

Memory KHMTc

(total correct) 11.08

.56**

(.16)

-.76

(.97)

-.04

(.06)

-.11

(.18)

-.06

(.08)

.09

(.08) .48** .55** .68 .64

Memory

Verbal

Learning RAVLT

d Total (total

words, trials 1-5)

.08 .51**

(.18)

.03

(3.01)

.15

(.18) 1.17*

(.51)

-.05

(.21)

.09

(.24) .45** .63** 2.21 .09

Delayed

Recall

RAVLTd delay (total

number of words:

delayed recall) -9.86

.57**

(.19)

-.06

(1.19)

.11

(.07)

.10

(.21)

.07

(.09)

.17

(.09) .33** .47* 1.17 .35

Executive

Function

Fluency COWATe

(total score)

-6.30

.77**

(.15)

-.49

(3.17)

.08

(.20)

.52

(.59)

.37

(.25)

.04

(.26)

.55**

.60**

.53

.75


28.59 .54**

(.11)

-10.08

(8.00)

.72

(.51)

1.92

(1.47)

.53

(.62) -.70*

(.65) .66** .74** 1.31 .30

Cognitive

Flexibility TMT

bratio (Ratio

score) 3.07

.15

(.19)

.06

(.31)

-.01

(.02)

-.04

(.06)

.00

(.02)

.00

(.03) .02 .07 .26 .93

Key: 1 denotes Bivariate regression; 2 denotes multivariate regression. B (SE) denotes regression coefficients with standard error;* denotes p < .05. ;

** denotes p < .01. aSDMT (Smith, 1982);

bTMT

(Reitan,1958);

cKHMT (Kaufman & Kaufman, 1983);

dRAVLT (Rey, 1964);

eCOWAT (Benton et

al., 1994);

178

Surgical Data: Screening

As documented in the study flow-chart (p. 173) 46 surgical patients returned for follow-

up assessment at 1 month. Reasons for missing data included failure to attend (1), could

not be contacted (4), patient unwell (1). A further five cases could not be entered into

the regression equations used to predict follow-up performance on the cognitive

measures due to missing predictor variables. In addition, one patient completed a partial

assessment due to symptoms of angina and breathlessness, which resulted in missing

data for four variables (RAVLT delayed recall, SDMT, KHMT, COWAT). An

additional patient declined to complete one particular test (COWAT). Missing data

were not imputed, given the possibility that patients who were unable to return for

assessment at follow-up were sicker, less able individuals. Data from 48 participants

was available for analysis at 3 months. Five cases were missing due to failure to attend

(2), travelling or living considerable distance from Perth (3).

Prior to analysis, the primary data (predicted minus obtained difference scores) were

examined using SPSS for missing values, the presence of outliers, and normality.

Outliers were defined as standardised scores >± 3.29 (Tabachnick & Fidell, 2001).

Four outliers across three variables (TMT Part A, TMT ratio, Stroop Interference task)

were identified in the 1 month data, and four outliers across three variables (RAVLT

total score, TMT Part A, Stroop Interference task) at 3 months. These extreme scores

were not considered representative of the sample and were therefore replaced with the

group mean for each respective variable.

Data were then screened for normality using the Skewness and Kurtosis statistics.

Distributions were considered to deviate from normality when either the Skewness or

179

Kurtosis statistic exceeded ±2.33, corresponding to a probability of < .01 that the scores

are normally distributed. One variable violated this assumption at 3 months (TMT ratio),

and analyses were performed on the square-root transformation of these data. For the 1

month follow-up, there were two incidences where the predicted score exceeded the

maximum available score for the KHMT. These predicted variables were changed to

reflect the ceiling on that measure (maximum of 21).

Surgical data: One Month Follow-up

On average, the 1 month follow-up took place 44 days from baseline (mean = 44.18, SD

= 12.52). The number of days from baseline to 1 month follow-up differed significantly

across the groups, F (2, 77) = 4.74, p = .01, because the control sample happened to be

tested earlier (mean = 39.81, SD = 9.73) than the on-pump group (mean = 49.54, SD =

14.27), but not the off-pump group (mean = 45.09, SD = 12.37). The 1 month follow-

up time was not significantly different between the on-pump and off-pump groups.

Due to the attrition of the sample, the demographic variables were reanalysed to ensure

that the dropout did not alter the pattern of findings. Table 7.3. (p. 180) shows the

demographic characteristics of the surgical samples, as well as a small sample of age

matched healthy controls at 1 month. Importantly, there were no significant differences

between the CABG groups on demographic variables including years of education,

estimated Full Scale Intelligence Quotient (FSIQ), and current fluid reasoning ability

(score on the Ravens Standard Progressive Matrices test). However, the control group

reported higher-levels of education, and obtained greater scores on measures of

estimated IQ and fluid reasoning relative to the on-pump group.

180

Table 7.3.

Demographic characteristics of the surgical and healthy control samples at 1 month.

Off-pump On-pump Control p

N 22 24 34

Male/femaleǂ 17/5 16/8 16/17 .08

Age in years

Mean (SD) Range

64.32

(7.29) 53-76

64.83

(10.50) 43-77

62.74

(9.13) 47-79 .76

Years of

education

Mean (SD) Range

12.1

(3.3) 7-17

10.0

(2.4) 6-15

13.2

(3.5) 8-21 <.01

Estimated FSIQ

Mean (SD) Range

112.55

(6.86)

97-

121

108.19

(6.64)

96-

120

114.62

(6.22) 103-126 <.01

Ravens Standard

Progressive

Matrices Score

Mean (SD) Range

30.32

(5.72) 21-42

26.63

(8.83) 7-44

31.49

(7.79) 20-41 .06

Handednessǂ

% Right

86.40

91.70

90.60

.82


Combined surgical group: overall neuropsychological deficits.

As described previously, participants test scores were subtracted from those predicted

from the regression equations to address issues of differential practice effects and

imperfect test reliability. To examine whether CABG surgery in general resulted in a

deterioration in neuropsychological functioning, the groups’ data were combined and an

independent samples t-test were conducted comparing predicted – obtained difference

scores to zero (i.e. reflecting no difference from scores predicted using the control data).

Within the combined surgical group, obtained performance was significantly poorer

than predicted for three of the outcome variables at 1 month (Table 7.4., p.181).

181

Table 7.4.

Predicted-obtained difference scores for combined surgical group at 1 and 3 months.

Scores reported are the Mean and SD of the predicted-obtained discrepancies. Note that positive scores reflect poorer than predicted

performance. Key: aSDMT (Smith, 1982);

bTMT

(Reita, 1958);


dRAVLT (Rey, 1964);

eCOWAT

(Benton et al., 1994);#Values for the TMT ratio at three months are square root transformations of the original, heavily skewed, raw data.

1 month 3 months

Cognitive

Domain Variable

N

Mean predicted-

obtained difference

(SD)

p N

Mean predicted-obtained

difference

(SD)

p

SDMTa

(total written

score) 44 0.89 (6.17) .35 48 1.44 (5.81) .09 Speed of

Processing

TMTab

(seconds) 46 1.20 (10.05) .42 48 1.03 (9.49) .45

Working Memory KHMTc

(total correct) 45 0.01 (2.84) .98 48 0.42 (2.41) .23

Verbal Memory

Learning RAVLT

d Total (total

words, trials 1-5) 46 4.70 (8.07) <.001 48 4.38 (7.67) <.001

Delayed Recall RAVLT

d delay (total


recall) 45 1.51 (2.65) <.001 48 1.80 (2.53) <.001

Executive Function

Fluency COWATe

(total score)

45

4.53 (9.46)

<.01

48

2.98 (6.99)

<.01

Inhibition Stroop Task (seconds) 46 -9.63 (21.17) <.01 47 -5.71 (26.22) .14

Cognitive Flexibility TMTbratio (Ratio score) 46 -0.20 (0.75) .07 48

1.80 (0.21) #

<.001

182

Specifically, at 1 month obtained performance was significantly lower than predicted

performance for verbal learning, t (45) = 3.95, p < .001; verbal memory, t (44) = 3.83, p

< .001; and verbal fluency, t (44) = 3.21, p < .01. In addition, significantly better than

predicted performances were observed for inhibition, t (45) = - 3.09, p < .01, while no

significant impairments were observed for working memory, t (44) = .03, p = .98; or either

of the processing speed tasks (TMT Part A), t (45) = .81, p = .42, (SDMT), t (43) = .95, p

= .35, or cognitive flexibility, t (45) = -1.83, p = .07. These data are presented in Table 7.4

(p. 181).

Combined surgical group: incidence of neuropsychological impairment.

As shown in Table 7.5 overleaf, analyses of the incidence of impairment using the

predicted-obtained revealed that working memory and verbal learning, followed by verbal

fluency were the domains most susceptible to post-operative impairment, with 17.78%,

17.40%, and 13.33% of CABG patients classified as impaired at 1 month. Overall, the RCI

tended to classify fewer participants as impaired than the predicted-obtained method (see

Table 7.5. , p.183), though significance was only achieved for the verbal learning task.

183

Table 7.5.

Number (%) of CABG patients classified as impaired across two methods at 1 month.

Method

Cognitive

Domain Variable N

Predicted-

Obtained

Count (%)

RCI

Count

(%)

χ2 p

Speed of

Processing

SDMTa

(total written

score)

44 3

(6.82)

2

(4.55)

.43 .52

TMTab

(seconds) 46 3

(6.52)

4

(8.70)

.31 .58

Working

Memory

KHMTc (total correct) 45 8

(17.78)

4

(8.89)

1.64 .20

Verbal

Memory

Learning

RAVLTd Total (total

words, trials 1-5)

46

8

(17.39)

2

(4.35)

4.15

.04

Delayed Recall RAVLTd delay (total


recall)

45 2

(4.44)

5

(11.11)

1.55 .21

Executive

Function

Fluency

COWATe (total score)

45

6

(13.33)

3

(6.67)

1.24

.27

Inhibition Stroop Task (seconds) 46 2

(4.35)

2

(4.35)

0.26 .61

Cognitive

Flexibility

TMTbratio (Ratio score) 46 1

(2.17)

4

(8.70)

2.12 .15


bTMT

, Trail Making Test

(Reitan,

1958); cKHMT, Kaufman Hand Movement Test (Kaufman & Kaufman, 1983);

dRAVLT, Rey

Auditory Verbal Learning Test (Rey, 1964); eCOWAT, Controlled Oral Word Association Test

(Benton et al., 1994); Where expected frequencies fell below 1, Fisher’s exact test was used.

Yates correction was applied with cell counts less than 5.

184

On- versus off-pump: overall neuropsychological deficits.

Predicted-obtained difference scores were entered into univariate ANOVAs with surgical

group (on- and off-pump) as the independent variable. At 1 month post-surgery, the on-

pump groups performance was disproportionately lower than predicted in comparison to

the off-pump group for verbal fluency, F (1, 43) = 6.37, p = .02 (see Figure 7.3. p. 186).

Furthermore, obtained scores were significantly lower than predicted for this task for the

on-pump group, t (22) = 4.48, p < .001, but not the off-pump group, t (20) = .15, p = .89.

That is, impaired performance was specifically observed in the on-pump group, while

performance in the off-pump group was not significantly different from their predicted

performance. A trend in the opposite direction, was observed for verbal memory (delayed

recall on the RAVLT), F (1, 43) = 3.98, p < .06 (see Figure 7.4. 186). Examination of the

raw cognitive data, presented in Table 7.6. (p. 185) confirms this pattern of findings.

When depression, anxiety and stress scores were added as covariates, the group difference

for verbal fluency remained significant F (1, 40) = 6.42, p = .02, and the difference for the

delayed verbal memory became significant, F (1, 40) = 5.09, p = .03.

185

Table 7.6.

Raw cognitive descriptive statistics at the 1 month follow-up.

Overall CABG

n = 46

On-pump

n = 24

Off-pump

n = 22

Controls

n = 34 Cognitive

Domain Variable

Baseline 1 month Baseline 1 month Baseline 1 month Baseline 1 month

Speed of

Processing SDMT

a (total

written score) 40.61

(11.06)

42.43

(10.10)

37.96

(11.02)

38.96

(10.81)

44.18

(9.05)

45.14

(8.70)

46.30

(9.07)

48.06

(10.46)

TMTab

(seconds) 36.67

(11.30)

34.83

(16.14)

38.79

(9.68)

38.96

(15.50)

32.86

(9.48)

29.41

(12.84)

34.70

(11.51)

30.42

(12.20)

Working

Memory KHMT

c (total

correct) 12.35

(3.08)

13.42

(3.72)

11.75

(3.17)

12.50

(2.90)

13.00

(2.96)

14.64

(3.97)

13.27

(3.38)

14.48

(3.54)

Verbal Memory

Learning RAVLT

d Total

(total words, trials

1-5)

39.35

(9.22)

39.13

(11.01)

39.21

(9.49)

39.21

(11.56)

40.23

(7.95)

40.00

(9.48)

46.79

(9.85)

48.55

(9.22)

Delayed Recall

RAVLTd delay

(total number of

words: delayed

recall)

6.72

(2.99)

6.36

(3.23)

7.29

(3.20)

7.17

(3.33)

6.09

(2.58)

5.73

(2.55)

8.88

(2.85)

9.12

(3.11)

Executive

Function

Fluency COWAT

e (total

score)

36.35

(10.25)

37.22

(10.11)

33.13

(9.91)

32.13

(9.43)

37.59

(10.82)

41.50

(9.14)

41.21

(9.38)

45.48

(11.01)


186.33

(49.52)

176.50

(56.56)

197.75

(54.51)

187.92

(55.33)

176.00

(38.31)

131.46

(35.70)

178.76

(44.53)

169.03

(40.64)

Cognitive

Flexibility TMT

bratio (Ratio

score) 2.56

(0.70)

2.59

(0.98)

2.79

(0.93)

2.58

(0.72)

2.46

(0.67)

2.68

(1.21)

2.31

(0.78)

2.47

(0.80)

Key: aSDMT (Smith, 1982);

bTMT

(Reitan, 1958);


dRAVLT (Rey, 1964);

eCOWAT (Benton et al., 1994);

Values presented are Mean and SD.

186

-4

-2

0

2

4

6

8

10

off on

Group

Me

an

pre

dic

ted

-ob

tain

ed

sc

ore

CO

WA

T

Figure 7.3. Mean predicted-obtained discrepancy by group for verbal fluency (COWAT )

at 1 month. Note * = p < .05. Error bars represent 95% confidence intervals.

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

off on

Group

Mean

pre

dic

ted

-ob

tain

ed

sco

re

RA

VL

T d

ela

yed

recall

Figure 7.4. Mean predicted-obtained discrepancy by group for verbal memory (RAVLT

delayed recall) at 1 month. Error bars represent 95% confidence intervals.

*

187

Table 7.7.

Comparison of adjusted RCI method and Predicted-obtained method for classifying patients as impaired at 1 month.

Predicted-Obtained Method RCI Method Comparison Cognitive

Domain Variable

On-pump Off-pump χ2 On-pump Off-pump χ2 χ2 p

Speed of

Processing

SDMTa

(total

written score) 3 (13.64) 0 (0) 2.50 1 (4.55) 1 (4.55) 1.05 0.73 .39

TMTab

(seconds) 2 (8.33) 1 (4.55) 0.44 3 (12.50) 1 (4.55) 0.37 1.37 .24

Working

Memory

KHMTc

(total

correct) 7 (30.43) 1 (4.55) 4.85* 4 (17.39) 0 (0) 3.65 1.12 .29

Verbal

Memory

Learning

RAVLTd Total


1-5)

3 (12.50) 5 (22.73) 0.53 1 (4.17) 1 (4.55) 1.04 1.20 .27

Delayed Recall RAVLTd delay

(total number of

words: delayed

recall)

1 (4.35) 1 (4.55) 1.05 2 (8.70) 3 (13.64) 0.17 1.37 .24

Executive

Function

Fluency

COWATe

(total

score)

4 (17.39)

2 (9.09)

0.29

2 (8.69)

1 (4.55)

0.40

1.13

.29

Inhibition Stroop Task (seconds) 2 (8.33) 0 (0) 0.87 2 (8.33) 0 (0) 0.87 - 1.00

Cognitive

Flexibility TMT

bratio (Ratio

score) 0 (0) 1 (4.55) 0.93 3 (12.50) 1 (4.55) 0.37 0.73 .39


bTMT

, Trail Making Test

(Reitan, 1958);

cKHMT, Kaufman Hand Movement

Test (Kaufman & Kaufman, 1983); dRAVLT, Rey Auditory Verbal Learning Test (Rey, 1964);


Association Test (Benton et al., 1994); Where expected frequencies fell below 1, Fisher’s exact test was used. Yates correction was applied

with cell counts less than 5. note *, p < .05. ** p < .01. Percentages are in parentheses.

188

On- versus off-pump: incidence of neuropsychological impairment.

As can be seen in Table 7.7. (p. 187) significantly more on-pump compared off-pump

patients group were classified as impaired on the KHMT using the predicted-obtained

method. There was, however, a similar trend was observed using the RCI approach for this

task. Overall, the predicted-obtained method was not significantly more likely to indicate

impairment in the on-pump participants than the RCI method, suggesting that these

methods detected cognitive impairment at a consistent rate.

Three Month Follow-up

On average, the three groups were tested 99 days from baseline (mean = 99.01, SD =

17.76). The number of days from baseline to three month follow-up did not differ

significantly across the on-pump (mean = 99.70, SD = 16.25), off-pump (mean = 98.21, SD

= 11.91), and control sample (mean = 99.10, SD = 22.63), F (2, 75) = .04, p = .96.

The demographic characteristics of the final sample used in the 3 month analyses are

presented in Table 7.8. (p. 189). The analyses were repeated to ensure that the dropout did

not alter the pattern of findings. Importantly, the on-pump and off-pump groups did not

differ significantly in terms of demographic characteristics. The significant group

differences arose from higher-levels of education and estimated FSIQ, in the control group

relative to the on-pump participants. In addition, of the participants that completed the 3

month follow-up, both the control and the off-pump participants, however, also exhibited

better performance than the on-pump participants on the RSPM.

189

Table 7.8.

Demographic characteristics of the surgical and healthy control samples at 3 months.

off-pump on-pump Control p

N 24 24 30

Male/femaleǂ 19/5 16/8 16/14 .14

Age in years

Mean (SD) Range

63.83

(7.86) 52-76

65.46

(10.08) 46-77

63.60

(8.67) 47-79 .79

Years of education

Mean (SD) Range

12.1

(3.3) 7-17

9.9

(2.5) 6-15

13.1

(3.6) 8-21 <.01

Estimated FSIQ

Mean (SD) Range

112.33

(6.90) 97-121

108.37

(6.85) 96-120

115.49

(6.40) 103-126 <.01

Ravens Standard

Progressive

Matrices Score

30.58

(5.15) 21-42

25.88

(8.05) 7-40

31.21

(5.15) 20-41 <.05

Handednessǂ

% Right

87.50 91.70 90.0 .90


Combined surgical group: overall neuropsychological deficits.

When the data for the surgical groups was combined, obtained performance was

significantly poorer than predicted for three variables at 3 months (see Table 7.4. p. 181).

Consistent with the pattern of results at 1 month, for the overall surgical group obtained

performance at 3 months was significantly lower than predicted for verbal learning, t (47)

= 3.96, p <.001; verbal memory (delayed recall), t (47) = 4.92, p <.001; and the verbal

fluency, t (47) = 2.95, p <.01.

190

Significantly better than predicted performance was observed for one aspect of executive

function; cognitive flexibility, t (47) = -60.79, p <.001, although inhibition was no longer

significantly higher than predicted at the 3 months follow-up, t (46) = -5.71, p= .14. In

addition, speed of processing and working memory continued to show no significant

impairment at 3 months.


The incidence of post-operative decline for the overall surgical sample is presented in Table

7.9. (overleaf). Again, the highest incidence of impairment occurred within verbal

learning, with just over 10 % of patients producing scores that were significantly poorer

than their expected scores. However, cognitive impairment was not significantly more

likely to be indicated with the predicted-obtained method than the RCI method.

On- versus off-pump: overall neuropsychological deficits.

Table 7.10. (p. 193) presents the descriptive statistics for the raw cognitive data from this

sub-sample. At 3 month, the on-pump group’s speed of processing performance (Part A of

the TMT) was disproportionately lower than their predicted performance relative to the off-

pump group, F (1,46) = 6.75, p = .01. This represented a significant impairment in the on-

pump (mean difference = 4.39, SD = 9.81), t (23) = 2.20, p = .04, but not the off-pump

group (mean difference = -2.33, SD = 8.02), t (23) = -1.42, p = .17 (see Figure 7.5., p. 192).

191

Table 7.9.

Number (%) of CABG patients classified as impaired across two methods at 3months.

Method

Cognitive

Domain Variable N

Predicted-

Obtained

Count (%)

RCI

Count

(%)

χ2 p

Speed of

Processing

SDMTa

(total written

score)

48 3

(6.25)

0

(0)

2.41 .12

TMTa

b (seconds) 48 2

(4.17)

1

(2.08)

0.34 .56

Working

Memory

KHMTc

(total correct) 48 2

(4.17)

5

(10.42)

1.08 .30

Verbal

Memory

Learning

RAVLTd Total (total

words, trials 1-5)

48

5

(10.42)

5

(10.42)

0.00

1.00



recall)

48 2

(4.17)

4

(8.33)

0.36 .55

Executive

Function

Fluency

COWATe (total score)

48

1

(2.08)

4

(8.33)

1.48

.22

Inhibition Stroop Task (seconds) 47 2

(4.26)

1

(2.13)

0.34 .56

Cognitive

Flexibility

TMTbratio (Ratio score) 48 3

(6.25)

0

(0)

2.41 .12


bTMT

, Trail Making Test

(Reitan,

1958); cKHMT, Kaufman Hand Movement Test (Kaufman & Kaufman, 1983);

dRAVLT, Rey

Auditory Verbal Learning Test (Rey, 1964); eCOWAT, Controlled Oral Word Association Test

(Benton et al., 1994); Where expected frequencies fell below 1, Fisher’s exact test was used.

Yates correction was applied with cell counts less than 5.

192

-10

-8

-6

-4

-2

0

2

4

6

8

10

off on

Group

Mean

Pre

dic

ted

-ob

tain

ed

TM

Ta

Figure 7.5. Mean predicted-obtained discrepancy for speed of processing (Part A of the

TMT), by surgical group. Note that a positive score reflects a larger predicted-obtained

discrepancy. * = p < .05. Error bars represent 95% confidence intervals.

As shown in Figure 7.6. (p. 195), inhibition was significantly poorer in the on-pump

relative to the off-pump group, F (1, 45) = 4.06, p = .05. This group effect arose because of

significantly faster than predicted performance in the off-pump group (mean difference = -

13.01, SD = 23.98), t (23) = -2.66, p = .01, and a non-significant difference between

predicted and obtained performance in the on-pump group (mean difference = 1.91, SD =

26.78), t (22) = .34, p = .74. The effect of surgical procedure was no longer significant for

verbal fluency at 3 months, F (1, 46) = 1.64, p =. 21. The group differences in one

processing speed measure (TMT Part A), F (1, 43) = 6.46, p = .02, and one executive

function measure (Stroop Interference), F (1, 42) = 6.07, p = .02, remained significant

when levels of depression, anxiety and stress were controlled for.

*

193

Table 7.10.

Raw cognitive descriptive statistics at the 3 month follow-up.

Overall CABG

n = 48

On-pump

n = 24

Off-pump

n = 24

Controls

n = 30 Cognitive

Domain Variable

Baseline 3 months Baseline 3 months Baseline 3 months Baseline 3 months

Speed of

Processing SDMT

a (total written

score) 39.63

(10.27)

41.21

(10.83)

35.08

(9.69)

38.33

(11.53)

44.17

(8.87)

44.08

(9.46)

46.70

(9.05)

48.20

(9.53)

TMTab

(seconds) 35.90

(11.57)

34.08

(12.06)

40.38

(11.71)

39.42

(12.97)

31.42

(9.73)

28.75

(8.36)

31.24

(6.11)

30.63

(13.17)

Working

Memory KHMT

c (total correct)

12.48

(3.20)

13.96

(3.46)

11.67

(3.40)

13.33

(3.35)

13.29

(2.82)

14.58

(3.54)

13.63

(3.12)

15.37

(9.83)

Verbal Memory

Learning RAVLT

d Total (total

words, trials 1-5)

39.23

(9.06)

39.58

(10.49)

38.13

(10.21)

37.50

(10.85)

40.33

(7.80)

41.67

(9.91)

47.20

(9.29)

49.97

(9.92)

Delayed Recall RAVLT

d delay (total

number of words:

delayed recall)

6.75

(2.95)

6.77

(2.96)

7.25

(3.27)

7.17

(3.54)

6.25

(2.56)

6.38

(2.26)

9.20

(3.00)

9.80

(3.44)

Executive

Function

Fluency COWATe

(total score)

36.88

(10.12)

38.42

(9.51)

35.63

(9.73)

36.58

(9.66)

38.13

(10.56)

40.25

(9.20)

40.43

(10.16)

44.17

(10.79)


183.63

(50.26)

179.32

(98.29)

194.71

(57.94)

205.39

(131.35)

172.54

(39.35)

154.33

(38.56)

179.78

(34.63)

165.47

(33.69)

Cognitive

Flexibility TMT

bratio (Ratio

score) 2.51

(0.90)

2.25

(1.10)

2.63

(0.78)

2.49

(1.27)

2.32

(0.89)

2.20

(1.16)

2.37

(1.14)

2.33

(0.91)


bTMT

, Trail Making Test

(Reitan, 1958);

cKHMT, Kaufman Hand Movement Test (Kaufman & Kaufman,

1983); dRAVLT, Rey Auditory Verbal Learning Test (Rey, 1964);

eCOWAT, Controlled Oral Word Association Test (Benton et al., 1994); Values presented are Mean

and SD.

194

Table 7.11.

Comparison of adjusted RCI method and Predicted-obtained method for classifying patients as impaired at 3 months.

Variable Predicted-Obtained Method RCI Method Comparison Cognitive

Domain On-pump Off-pump χ2 On-

pump Off-pump χ2 χ2 p

Speed of

Processing SDMT

a (total

written score) 1 (4.17) 2 (8.33) 0.36 0 (0) 0 (0) - - 1.00

TMTa

b

(seconds) 1 (4.17) 1 (4.17) 1.04 1 (4.17) 0 (0) 1.02 2.63 .11

Working

Memory KHMT

c (total

correct) 1 (4.17) 1 (4.17) 1.04 4 (16.67) 1 (4.17) 1.56 1.09 .30

Verbal Memory

Learning

RAVLTd Total


1-5)

4 (16.67)

1 (4.17)

1.56

3 (12.50)

2 (8.33)

0.22

0.48

.49


(total number of

words: delayed

recall)

0 (0) 2 (8.33) 1.04 3 (12.50) 1 (4.17) 0.55 1.50 .22

Executive

Function

Fluency COWAT

e (total

score)

0 (0)

1 (4.17)

1.02

2 (8.33)

2 (8.33)

0.55

1.77

.18


2 (8.33) 0 (0) 0.96 1 (4.17) 0 (0) 1.07 - 1.00

Cognitive

Flexibility TMT

bratio

(Ratio score) 2 (8.33) 1 (4.17) 0.36 0 (0) 0 (0) - - 1.00


bTMT

, Trail Making Test

(Reitan, 1958);

cKHMT, Kaufman Hand Movement Test (Kaufman

& Kaufman, 1983); dRAVLT, Rey Auditory Verbal Learning Test (Rey, 1964);

eCOWAT, Controlled Oral Word Association Test (Benton et al., 1994);

Where expected frequencies fell below 1, Fisher’s exact test was used. Yates correction was applied with cell counts less than 5. note *, p < .05. ** p

< .01. Percentages are in parentheses.

195

-25

-15

-5

5

15

25

off on

Group

Mean

pre

dic

ted

-ob

tain

ed

Str

oo

p In

terf

ere

nce s

co

re

Figure 7.6. Mean predicted-obtained discrepancy for inhibition (Stroop Interference), by

surgical group. Note that a positive score reflects a larger predicted-obtained discrepancy.

* = p < .05. Error bars represent 95% confidence intervals.


Table 7.11. (p. 194) shows the number of patients classified as impaired across each

surgical method using both the RCI and the predicted-obtained methods. At this follow-up,

the incidence of impairment did not differ significantly across groups (on versus off-pump),

and nor were there any significant differences in the frequency of impairment across the

two statistical approaches (predicted-obtained and RCI).


Seven outliers were identified across the three measures of current mood (depression,

anxiety and stress) at 1 month. At 3 months, there were two outliers for the depression

*

*

196

subscale, one for the anxiety subscale, and one for the stress subscale. As a consequence,

all three mood variables (depression, anxiety and stress) were heavily positively skewed

with extensive kurtosis at both 1 and 3 months and as such deviated significantly from

normality. Log transformations effectively normalised all three distributions and reduced

the effect of extreme values at 1 month, and a square root transformation normalised the

distribution of stress scores, while reciprocal transformations normalised the distributions

for depression and anxiety at 3 months.

Frequency of elevated depression, anxiety, and stress scores at 1 month.

Participants’ scores on the depression, anxiety and stress subscales within the DASS were

categorized as either normal, mild, moderate, severe, or extremely severe, according to the

DASS manual (Lovibond & Lovibond, 1995). For symptoms of depression, anxiety and

stress at 1 month, majority of participants scored in the normal range. Elevated depressive

symptomatology was observed in 10.26% of all participants, with 14.29% of the off-pump

patients and 12.5% of the on-pump sample, whilst only 6.06% of controls reporting

depressive symptoms exceeding the normal range. The frequency of responses across these

levels of depression (normal, mild, moderate, severe, extremely severe) did not differ

between groups, χ2 (8, N = 80) = 5.87, p = .44.

Elevated anxiety symptoms were reported in 33.33% of off-pump patients, 45.85% of on-

pump patients, and 12.12% of the control sample at 1 month. The frequency of responses

across levels of anxiety, however, did not differ significantly across the three groups, χ2 (8,

N = 80) = 13.31, p = .10.

197

Some stress symptomatology was reported in approximately 20% of all study participants

at 1 month (off-pump = 19.04%, on-pump = 20.83%, control = 18.18%). One control

participant reported extremely severe levels of stress and one member of the on-pump

group reported severe stress levels while the remaining participants’ stress symptoms fell in

the normal to moderate range. The frequency of these ratings did not differ significantly

across groups, χ2 (8, N = 80) = 4.85, p = .77.

Mean DASS scores and partial correlations with cognitive test performance at 1

month.

At 1 month, both surgical groups’ reported anxiety was slightly, but significantly elevated

(on-pump median = 4.0, interquartile range = 5, off-pump median = 3.0, interquartile range

= 4) compared to controls (median = 1, interquartile range = 3.5), F (2, 75) = 6.05, p <. 01.

In contrast, the overall degree of depressive symptomatology, F (2, 75) = 2.91, p = .06, and

stress symptoms, F (2, 75) = 0.10, p = .91, did not differ across the three groups. This

pattern is consistent with the reported levels of anxiety, stress and depression across the

three groups at baseline as presented in chapter 5.

Partial correlations were used to examine the magnitude of any relationships between post-

operative cognitive performance and current symptoms of depression, anxiety, or stress,

whilst controlling for demographic variables. At 1 month, few of the zero-order correlation

coefficients between mood and post-operative cognitive test performance were strong,

though there were significant relationships between the control variables and cognition (see

Table 7.12., p. 200 and Table 7.13. p. 201). When these were factored into the correlations

between mood and cognition, only two large and significant correlations emerged within

198

the off-pump group. Specifically, increased anxiety symptomatology was associated with a

greater number of words recalled across the five learning trials within the RAVLT. In

addition, higher ratings of stress symptoms were associated with slower processing

(SDMT).

Frequency of Elevated Depression, Anxiety and Stress scores at 3 months.

At 3 months, some depressive symptomatology was reported in around 12% of all

participants, comprising 8% of the off-pump, 20.69% of the on-pump, and 6.67% of the

control participants. Ratings in the severe or extremely severe range were observed in six

participants. Four of these were members of the on-pump group, while the remaining two

were from the control sample.

Overall, group differences in extent of anxiety symptoms did not reach significance.

Approximately 22% of participants reported some anxiety-related symptoms, with 20% of

the off-pump, 34.48% of the on-pump, and 10% of controls ratings above the normal level.

Five on-pump participants also reported severe or extremely severe symptoms of anxiety,

and one control participant reported severe levels of anxiety.

Again, around 22% of the entire sample reported some stress symptomatology. The

incidence of elevated stress levels was fairly consistent across the three groups, with 20%

of the off-pump, 31.04% of the on-pump, and 16.67% of the control sample scoring above

the normal range. Five members of the on-pump group, and one control participant

reported severe or extremely severe stress levels. The remaining participants rated their

199

levels of depression, anxiety or stress either in the normal, mild or moderate range. The

frequency of these ratings did not differ across groups for depression, χ2 (8, N = 78) = 6.24,

p = .62, anxiety, χ2 (8, N = 78) = 10.84, p = .21, or stress, χ

2 (8, N = 78) = 9.95, p = .27.


months.

At 3 months, there was a significant effect of group for levels of anxiety, F (2, 73) = 4.47, p

= .02, arising from lower levels of reported anxiety symptoms in controls (median = 1.0,

interquartile range = 2) relative to the on-pump group (median = 2.5 interquartile range = 6).

There were no significant group differences in the mean levels of reported stress, F (2, 73)

= 0.65, p = .53, or depression, F (2, 73) = 0.24, p = .79.

At 3 months, again few of the zero order correlations between mood and cognitive test

performance were significant in the on-pump group. By comparison, the off-pump group’s

performance on the SDMT correlated strongly with all three subscales from the DASS (see

Table 7.15., p. 203). In addition, lower depression scores, and elevated stress ratings were

associated with faster response times on Part A of the TMT in this group (see Table 7.14. p.

202). There continued to be significant and sizeable relationships between many of the

control variables and cognitive test performance. Even controlling for these, significant

associations between mood and cognition remained in the off-pump group (see Table 7.15.,

p. 203).

200

Table 7.12.

Partial correlations between DASS scores and 1 month post-operative cognitive scores in the on-pump group.

Cognitive

Domain Variable

Mood Variables


r

Depression Anxiety Stress Age Education Gender RSPMf FSIQ

g

Speed of

Processing SDMT

a (total

written score) -.17

(.07)

.06

(-.13)

.08

(.38) -.45* .12 -.11 -.71** .18

TMTab

(seconds) -.03

(-.19)

-.17

(.03)

-.13

(-.41)* .48* -.16 -.08 -.65** .01

Working

Memory KHMT

c (total

correct) .05

(.11)

.25

(-.15)

.04

(.05) -.11 .22 .10 .59** .51*

Memory

Learning

RAVLTd Total


5)

-.10

(.10)

-.16

(-.36)

.08

(.02) -.43* .21 .36 .43* .47*

Delayed Recall

RAVLTd delay

(total number of

words: delayed

recall)

-.16

(-.05)

-.30

(-.45)*

-.23

(-.17) -.23 .14 .45* .44* .40

Executive

Function Fluency

COWATe

(total

score)

.39

(.41)^

.21

(.02)

.47^

(.38) -.28 .34 .28 .54** .26


.11

(-.03)

-.05

(.12)

.17

(-.19) .37 -.01 .13 -.53** -.12

Cognitive

Flexibility TMT

bratio (Ratio

score) .13

(.05)

-.03

(.10)

.23

(.05) .35 .04 -.23 -.24 -.05


bTMT

, Trail Making

Test (Reitan, 1958);

cKHMT, Kaufman Hand Movement Test (Kaufman & Kaufman, 1983);



f RSPM, Ravens Standard Progressive Matrices (Raven);

gFSIQ,

Estimated Full Scale IQ. Zero-order correlations are reported in parentheses.

201

Table 7.13.

Partial correlations between DASS scores and 1 month post-operative cognitive scores in the off-pump group.

Cognitive

Domain Variable

Mood Variables

pr (r)

Control Variables

r

Depression Anxiety Stress Age Education Gender RSPMf FSIQ

g

Speed of

Processing SDMT

a (total

written score) -.10

(-.19)

-.25

(-.25) -.57*

(-.51)* -.32 .63** -.19 .49* .39

TMTab

(seconds) -.03

(.05)

.11

(.08)

.44

(.44)* -.30 -.33 .12 -.35 -.06

Working

Memory KHMT

c (total

correct) .11

(.17)

-.13

(.12)

-.25

(-.09) -.20 .53* -.00 .62** .56**

Memory

Learning

RAVLTd Total


1-5)

.28

(.15)

.51*

(.30)

.21

(.10) -.36 .65** -.05 .54* .37

Delayed Recall

RAVLTd delay

(total number of

words: delayed

recall)

.10

(.06)

.48

(.31)

.47

(.29) -.33 .65** .11 .53* .48*

Executive

Function Fluency

COWATe

(total

score)

.02

(.12)

-.02

(.17)

-.21

(-.06) .08 .21 .19 .34 .50*


-.03

(-.00)

.29

(.15)

.50^

(.36) .20 -.60** .11 -.61** -.53*

Cognitive

Flexibility TMT

bratio (Ratio

score) .21

(.03)

.07

(.14)

-.37

(-.39) .50* -.20 .04 -.14 -.11

Note n = 21; * denotes p < .05; ** denotes p < .01; ^ denotes a trend (p<.06); aSDMT, Symbol Digit Modalities Test (Smith, 1982);

bTMT

, Trail Making






gFSIQ,


202

Table 7.14.

Partial correlations between DASS scores and 3 month post-operative cognitive scores in the on-pump group.

Cognitive

Domain Variable

Mood Variables


r

Depression Anxiety Stress Age Education Gender RSPM f FSIQ

g

Speed of

Processing SDMT

a (total

written score) .07

(.20)

.10

(.18)

-.23

(-.11) -.41* .34 .11 .67** .07

TMTab

(seconds) .27

(-.02)

.12

(-.08)

-.21

(-.18) .36 -.22 -.04 -.70** .02

Working

Memory KHMT

c (total

correct) -.06

(.14)

.25

(.36)

-.03

(-.04) -.18 .21 -.18 .66** .30

Memory

Learning

RAVLTd Total


1-5)

-.05

(.15)

.18

(.18)

.08

(.00) -.46** .20 .43* .51* .17

Delayed Recall

RAVLTd delay

(total number of

words: delayed

recall)

.10

(.09)

.07

(.07)

-.04

(-.03) -.36 .27 .32 .45* .38

Executive

Function

Fluency COWAT

e (total

score)

-.18

(.02)

-.19

(.02)

.06

(.07) -.44* .30 .25 .60** .23


-.41

(-.41)^

-.29

(-.34)

.45

(.39) .20 -.17 -.11 -.41^ -.20

Cognitive

Flexibility TMT

bratio (Ratio

score) -.25

(-.12)

-.30

(-.44)*

.41

(.31) .37 .16 -.06 -.21 -.32


bTMT

, Trail Making






gFSIQ,


203

Table 7.15.

Partial correlations between DASS scores and 3 month post-operative cognitive scores in the off-pump group.

Cognitive

Domain Variable

Mood Variables

pr (r)

Control Variables

r

Depression Anxiety Stress Age Education Gender RSPM f FSIQ

g

Speed of

Processing SDMT

a (total

written score) .69**

(.49)*

.61**

(.65)**

-.61**

(-.43)* -.43* .50* -.01 .33 .31

TMTab

(seconds) -.57*

(-.51)*

-.05

(-.31) .58**

(.45)* .60** -.36 .37 -.27 -.14

Working

Memory KHMT

c (total

correct) .36

(.22)

.14

(.21)

-.33

(-.18) -.21 .60** -.03 .67** .53**

Memory

Learning

RAVLTd Total


1-5)

.29

(.26)

-.35

(-.04)

-.14

(-.10) -.38 .60** -.19 .57** .33

Delayed Recall

RAVLTd delay

(total number of

words: delayed

recall)

.01

(.08) -.56*

(-.22)

.28

(.23) -.46* .19 -.18 .32 .16

Executive

Function Fluency

COWATe

(total

score)

.24

(.06)

.08

(.15)

-.09

(.01) -.01 .31 .20 .23 .59**


-.47*

(-.43)*

-.38

(-.44)*

.35

(.30) .28 -.39^ .21 -.42* -.40^

Cognitive

Flexibility TMT

bratio

(Ratio score) .39

(.36)

.02

(-.03)

-.24

(-.26) .12 -.24 -.10 -.36 -.21

Note n = 24; * denotes p < .05; ** denotes p < .01; ^ trend (p<.06); aSDMT, Symbol Digit Modalities Test (Smith, 1982);

bTMT

, Trail Making Test





gFSIQ,


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Discussion

The current study sought to determine whether there is any cognitive benefit to avoiding

the use of cardiopulmonary bypass, and performing surgery on the beating heart. Post-

operative cognitive performance at 1 and 3 months was expected to differ between groups

assigned to on-pump versus off-pump CABG.

Post-operative Neuropsychological Sequelae: Differentiation of Impairments Across On-

versus Off-pump CABG

As predicted, there were important group differences in cognitive outcome after surgery.

Specifically, based on the predicted-obtained difference scores, relative to the off-pump

group patients who received the on-pump procedure demonstrated impairments, or weaker

than expected performances on the verbal fluency (COWAT), inhibition (Stroop

Interference), and one measure of processing speed (TMT Part A). Examination of the raw

cognitive data supports the pattern of findings scores with a decline in verbal fluency total

score among on-pump but not off-pump patients, and greater rates of improvement within

the off-pump group for the two speeded tasks (Trail Making Test and Stroop Interference).

This indicates that deficits in executive functioning (verbal fluency and inhibition) and

psychomotor processing speed are more likely following on-pump than off-pump CABG.

An additional finding of a trend towards a relative weakness in verbal memory in the off-

pump group was revealed after the influence of post-operative mood on cognitive

performance had been accounted for. However, in terms of the verbal learning (RAVLT

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total score) both groups scores remained relatively stable over time, compared with a noted

improvement within the control sample. This indicates that symptoms of mood either

minimised the discrepancy between predicted and obtained performance in the on-pump

group, or emphasised this discrepancy in the off-pump group. Given that many previous

studies have not employed measures of mood, or accounted for these in their analysis of

cognitive change, this is an important finding.

Impairments in executive functioning could relate to disruptions to the frontostriatal

networks, underpinned by specific damage within the frontal cortex, basal ganglia, or white

matter tracts that are known to be selectively vulnerable to anoxic events (Bigler & Alfano,

1988; Cummings et al., 1984; Petito, 1987). Generalised ischemic changes are also

understood to result in diffuse white matter change (Filley, 1998), which may account for

the observed reduction in general proficiency (processing speed), within the on-pump

group.

There was partial support for the second prediction under hypothesis 4, that the incidence

of cognitive impairment would be greater following on-pump compared to off-pump

CABG; with impairment in working memory (KHMT) occurring significantly more

frequently in the on-pump group at 1 month.

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Post-operative Neuropsychological Sequelae: General CABG

Irrespective of surgical technique, performance was better than predicted for two executive

measures at 1 (inhibition) and 3 months (cognitive flexibility). This unexpected finding

warrants further attention. Examination of the raw means for these variables, shows that the

CABG sample had slightly depressed scores on these tasks at baseline, and for the measure

of cognitive flexibility, they exhibited greater absolute gains at follow-up. This might

suggest that surgery, and improved vascularisation, led to an enhancement of prior slightly

reduced cognition. It is important to note that this post-surgical rebound effect was not

observed for delayed verbal memory (RAVLT delayed recall) despite the poor performance

on this task among CABG patients at baseline. Two potential explanations are posited for

this.

Firstly, in light of the multiple comparisons performed at baseline, it is acknowledged that

the significant finding of low RAVLT scores at baseline was potentially due to chance.

Alternatively, the absence of improvement in verbal memory may be attributable to

residual cerebral dysfunction. Given that memory was the only significantly reduced score

pre-surgically it is possible that the neural mechanisms, which underpin memory

consolidation (e.g. hippocampal formation), were compromised to a greater extent than

those systems involved in the aspects of executive function assessed. Despite the potential

benefit of re-vascularisation the damage had been done.

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Relationship Between Mood State and Post-operative Neuropsychological Functioning in

CABG Patients

As was expected, there were important associations between psychological variables and

post-operative cognitive performance in the CABG samples at both 1 and 3 months.

Specifically, elevated anxiety was associated with reduced verbal memory, and enhanced

cognitive flexibility in the on-pump group at 1 and 3 months respectively. Within the off-

pump group, anxiety correlated positively with processing speed, and negatively with

verbal memory and inhibition at the 3 month follow-up. While there were significant

associations between processing speed performances and stress in both the on- and off-

pump groups at 1 and 3 months, the direction of these correlations was divergent.

Specifically within the on-pump group, higher stress levels correlated significantly with

faster performance on a measure of processing speed at 1 month, while in the off-pump

group, stress was negatively associated with speeded performances at both 1 and 3 months

post-operatively. The only significant findings for depression, occurred within the off-

pump sample at 3 months; with negative associations between depressive ratings and two

executive tasks (verbal fluency and inhibition), and a positive association with processing

speed.

While cognitive effects of psychological phenomena are well documented (Wright &

Persad, 2007), the current pattern of findings is not entirely typical. In particular, increased

depressive symptomatology would ordinarily not be associated with enhanced performance

on timed tasks. Given that the mean post-operative levels of anxiety and stress were

relatively low (falling in the normal range) it is plausible that the adrenergic system and

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associated catecholamine activation enhanced cognitive functioning (McEwen & Sapolsky,

1995).

Comparison of the Methods of Identifying Neuropsychological Impairment.

When examining the two methods for identifying post-operative cognitive impairment, in

the overall CABG group, the predicted-obtained method classified more patients as

impaired than the RCI method on a measure of verbal learning at 1 month. However, these

approaches performed similarly when comparing across the on- and off-pump techniques.

Previously, the adjusted RCI approach has been shown to produce a better estimate of

incidence than other standard approaches which do not account for retest effects and

measurement error (Kneebone et al., 1998). Specifically, Kneebone et al. demonstrated

that the RCI classified significantly more patients as impaired over the standard deviation

method. The current comparisons of the adjusted RCI and predicted-obtained regression

approaches suggest that both techniques produce fairly consistent incidence rates. However

when the data for whole CABG group were combined the predicted-obtained method

classified more individuals as impaired on one task at 1 month. That both methods give

similar results provides converging evidence for post-CABG cognitive dysfunction.

Additionally, there would not appear to be any dramatic improvement in the sensitivity to

detect impairment using the regression-based approach over the RCI.

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Methodological Strengths and Limitations

As already mentioned, several studies have reported improved post-operative cognitive

outcomes in off-pump compared to on-pump CABG (Chernov et al., 2005; Diegler et al.,

2000; Ernest et al., 2005; Ernest, Worcester, et al.; Motellebzadeh, 2007; Schmitz et al.,

2002; Van Dijk et al., 2002; Zamvar et al., 2002), though this is not a universal finding

(Baker et al., 2000; Jensen et al., 2006; Stroobant et al.; Stroobant, van Nooten, De Bacquer,

Van Belleghem, & Vingerhoets, 2008; Tully et al., 2008). However, the interpretation of

the findings within many of these studies has often been clouded by methodological

shortfalls, and the widely criticized diverse criteria used to define cognitive impairment

within the CABG literature (Mahanna et al., 1996; Roach et al., 1996).

Importantly, the current study employed conservative and methodologically defensible

statistical techniques to determine whether change in cognitive performance reflected

meaningful deterioration or impairment. The strength in the regression-based approach lies

in the fact that is simultaneously accounts for the influence of test-reliability, statistical

artefacts such as regression to the mean, and the effect of individual differences on the

trajectory of change over time (including practice effects). Therefore, it provides a more

controlled indication of change. Moreover, with the exception of verbal memory (RAVLT

delayed recall), the finding essentially remained unchanged when anxiety, depression, and

stress were fitted to the analyses comparing the on- and off-pump groups. Thus, one can be

reasonably confident that the observed effects do in fact reflect the impact of the

intervention (CABG surgery), rather than a secondary effect of mood. Indeed Andrew et al.

(2000) found that the extent of post-operative mood disturbance, or change in mood from

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presurgical status, is only minimally related to the incidence of neuropsychological

impairment.

By comparison, the RCI approach also accounts for measurement error and a correction

factor can be applied to adjust for practice effects. As such, the RCI approach provides a

more suitable benchmark for comparison with the predicted-obtained than traditional

classification methods. In comparing the predicted-obtained and RCI method there was

only one statistically significant difference in the percentage of patients within the overall

surgical group who showed post-operative impairment. Overall, these methods tended to

provide similar estimates of incidence across the cognitive measures used, and more

importantly, consistent patterns of impairment across the two surgical techniques.

For most individual measures, the incidence of cognitive impairment among CABG

patients was low (ranging from 2.17% to 17.78% of the sample at 1 month, and from 0% to

10.42% at 3 months). This would suggest that, on many measures, the rate of impairment

was no greater than would be expected based on the theoretical normal distribution of a

group of individuals tested over two occasions. However, there were domains of higher

incidence (e.g. measures of verbal memory, verbal fluency, and working memory) which

exceed this expectation and imply a true effect.

While the observed impairment in speed of information processing following on-pump

CABG is in accordance with previous work (Baker et al., 2000; Chernov et al., 2005;

Zamvar et al., 2002), none of the previous studies that measured verbal fluency, have

reported a specific decline in this measure (Lund et al., 2003; Murkin, Boyd, Ganapathy,

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Adams, & Peterson, 1999; Rankin et al., 2003; Taggart et al., 1999; Zamvar et al., 2002).

Most recently, Ernest et al. (2006) observed that patients who were randomized to off-

pump, showed significantly greater improvement in COWAT scores than those randomized

to on-pump. Additionally, when scores were compared with published normative data,

there was a higher incidence of impaired performance on this measure (according to their

criteria of > 1.5 standard deviations below the mean) in on- compared to off-pump.

It is unclear whether Lund et al. (2003), Murkin et al. (1999) and Zamvar et al.(2002), who

each employed the COWAT, used available alternate versions to minimise item-specific

practice. Both Rankin et al. (2003) and Ernest et al. (2003) administered the same version

of their verbal fluency measures to patients at baseline and follow-up. Importantly none of

these studies specifically accounted for the improvement in verbal fluency scores that

occurs with repeat administration.

While reliable, verbal fluency measures are highly susceptible to practice gains (Ruff et al.,

1996) in the order of approximately three words. As demonstrated in chapter 5, gains of

five words occurred with one repeat assessment after a 1 month delay. Furthermore, this

was despite the use of equivalent versions of the task. These improvements may counteract,

and therefore underestimate any negative effects that arise from an intervention. Perhaps

more importantly, in both the Rankin et al. and the Stroobant et al. studies; there were

differences (in excess of three words) between their on- and off-pump groups at baseline.

Theoretically, such a difference may influence rates of improvement, as a consequence of

differential rates of practice across more and less able individuals (Lowe & Rabbitt, 1998),

or regression to the mean (Barnett et al., 2005; Browne et al., 1999). As such, the rates of

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improvement within each group (on- and off-pump) in previous studies may not have been

of equivalent magnitude, thereby clouding interpretation of post-operative scores.

The current study expected, and specifically controlled, the influence of these factors at

follow-up. Moreover, each individual’s performance was compared to his or her expected

performance based on a number of additional factors known to impact on

neuropsychological test performance and modulate change in neuropsychological test

scores. This revealed a differential deficit in verbal fluency following on-, but not off-

pump CABG, that has been previously underestimated or masked by other factors. In

addition to the findings reported in chapter 5, further evidence for the differential rates of

change can be seen in the descriptive statistics for the raw cognitive data, and also in the

consistent significant associations between the control variables (most notably Age,

Education, and Fluid Reasoning ability) and post-operative cognitive functioning (see

Tables 7.12-7.15, pp. 200-203).

Returning to the main cognitive outcome, there are a number of cognitive processes

involved in performing verbal fluency tasks (Lezak, Howieson, Loring, Hannay, & Fischer,

2004). Thus, a number of cognitive defects can result in impaired verbal fluency

performance on tasks such as the COWAT. As well as executive components (initiation,

generativity), it is a timed measure, requiring quick and efficient retrieval of stored verbal

material. It is, therefore possible that a core deficit in cognitive processing speed underpins

the observed impaired performance in the current study. This would be consistent with the

weaker timed performances observed in the on-pump group at 3 months, although cannot

213

explain why this impairment resolved, or why other timed performances were seemingly

unaffected. Further work should examine this possibility.

Several previous studies point towards relatively poorer verbal learning or verbal memory

following on-pump surgery (Chernov et al., 2005; Lee et al., 2003; Taggart et al., 1999;

Van Dijk et al., 2002). In contrast to these findings, the present study found an unexpected

relative weakness in delayed recall on the RAVLT, only among those in the off-pump

group, once the influence of post-operative mood had been statistically controlled.

Previously, Baker, Andrew, Ross, and Knight (2000) highlighted a similar post-operative

vulnerability for verbal memory deficits in their patients who were randomly assigned to

the off-pump (n = 12) method. These results lend support to the suggestion raised by

Taggart and Westaby (2001) that off-pump surgery may, itself, induce separate

pathophysiological changes that manifest as cognitive dysfunction. Others, who have

observed no difference in neuropsychological outcome between on- and off-pump CABG,

have also supported the idea that general or hemodynamic changes may also occur as a

consequence of off-pump CABG (Stroobant et al., 2002; Taggart & Westaby, 2001).

Indeed, transient hemodynamic deterioration has been observed in off-pump CABG,

particularly for grafting the posterior descending and circumflex arteries (Watters et al.,

2001). The clinical relevance of this hemodynamic change is questionable, although it does

not appear to be associated with reduced mean arterial pressure, heart rate, or indication of

neurological injury (Watters et al., 2001).

In addition to the specific deficits associated with on-pump CABG, there seemed to be a

fairly widespread dampening across several cognitive domains, irrespective of surgical

214

technique. Within the combined surgical group, 1 month performance was weaker than

expected for the total and delayed recall scores on the RAVLT and the COWAT. That is, in

addition to the effects associated specifically with on-pump CABG, heart surgery or

surgery in general seems to reduce aspects of cognitive performance including verbal

learning, memory, and higher-level executive functioning (verbal fluency). Moreover,

these general effects are sustained over several months following surgery, with lower than

predicted scores on these tasks over time.

Although cognitive deterioration is frequently observed following both on- and off-pump

CABG, methodological weaknesses in studies to date have made it difficult to reconcile

these findings (Baker et al., 2000; Browne et al., 2003; Chernov et al., 2005; Lloyd et al.,

2000; Malherios et al., 2002; Stroobant et al., 2002; Taggart et al., 1999; Van Dijk et al.,

2002). The present results support that, irrespective of surgical technique, CABG surgery

precipitates deterioration across a range of cognitive domains.

However, it is important to note that improvements on some measures of executive

function produced scores that were better than predicted scores at both 1 and 3 months. On

the surface this is puzzling given that predictions were made based on individual

characteristics and baseline functioning. This apparent post-CABG cognitive enhancement

may have arisen from the fact that the regression equations were built using physically

healthy and slightly less anxious individuals who did not undergo any intervention.

Improvements in executive function, therefore, exceeded the rates of change observed in

healthy participants. This may reflect a restoration or recovery of functioning associated

215

with alleviated symptoms of heart disease and possible restoration of adequate blood flow,

and / or resolution of preoperative anxiety.

The observed improvement on some tasks, exceeding expected performance, is not without

precedent. For example, despite using a correction factor to account for practice, Andrew

et al. (2000) reported improvements across most measures in a small proportion of their

CABG patients. In their study, the highest incidence of post-operative improvement was

reported for an executive measure of cognitive flexibility, with 6.2% of their patients

showing improved performance on this task. This was followed closely by verbal learning

and psychomotor processing speed, with 6.1% and 5.5% of patients demonstrating

improvements on these tasks after surgery. Interestingly, the authors reported a negative

practice effect (i.e. deterioration on follow-up) in their control sample one of these tasks

(California Verbal Learning Test), which might explain the relative improvement in some

patients. However, it is also acknowledged that based on the theoretical normal distribution

of change, some degree of improvement would be expected using the RCI methodology.

Given that the current control sample did not show negative practice effects (see chapter 5),

it is unlikely that improvements observed on some executive tasks arose as a consequence

of such phenomena. There are a number of alternative possibilities to explain this

improvement in the CABG patients.

Firstly, these data may reflect recovery from subclinical weaknesses at baseline that can be

attributed to changes in their physical condition, restoration of adequate blood flow, and

alleviation of symptoms. In partial support of this, chapter 6 showed presurgical

impairment in cognitive flexibility once the influence of mood had been accounted for.

216

Secondly, while the present analysis takes presurgical cognitive status as well as important

individual differences into consideration of post-operative neuropsychological performance,

it has not accounted for the possible influence of preoperative mood disturbance, or change

in mood. Andrew et al. (2000) observed important relationships between mood symptoms

and neuropsychological disturbance in their sample of 147 cardiac patients. Moreover,

they showed that preoperative mood status predicted post-operative neuropsychological

deficits in attention, verbal learning and verbal memory. Not accounting for the potential

impact of presurgical mood on post-operative neuropsychological performance could be

considered a limitation in the present study. It is worthy to note, however, that presurgical

mood exerted minimal influence (and did not remove any significant effects) on the

cognitive performance of the current CABG sample, presurgically. Moreover, that

presurgical cognitive performance was included in the analysis of post-operative cognitive

functioning, should account for at least some of the variance in cognition that could

plausibly be accounted for by preoperative mood.

The general consensus within the CABG literature seems to be that neuropsychological

deficits are most pronounced in the acute phase (particularly at discharge from hospital),

and resolve within the first few months (Browne et al., 2003; Jacobs et al., 1998; Mahanna

et al., 1996; Murkin et al., 1995; Newman et al., 2001; Selnes, Goldsborough, Borowicz,

Enger, et al., 1999; Selnes, Goldsborough, Borowicz, & McKhann, 1999; van Dijk et al.,

2000). Therefore, it was hypothesised that impairments would resolve by 3 months.

Contrary to expectation, group differences did not entirely resolve by 3 months. The on-

pump group remained more affected than the off-pump group, on measures of psychomotor

speed and inhibition. However, using the criteria that obtained performance must be

217

significantly lower than predicted performance only the speed of processing measure could

be considered differentially impaired for the on-pump group. Additionally, the effect of

surgical procedure was no longer significant for the verbal fluency measure, which was

selectively impaired in the on-pump group at 1 month. While on first glance, these results

seem somewhat consistent with the previous literature, it is important to note that the

combined CABG sample demonstrated residual impairments across several cognitive

domains at 3 months.

The apparent global dampening of cognition, irrespective of surgical group, might reflect

some non-specific effect of surgery or post surgical care. One possible explanation is the

effect of undergoing general anaesthesia, which is known to impede aspects of basic

cognitive functioning (Imre, Fokkema, Den Boer, & Ter Horst, 2006; Passiea, Karstb,

Wiesec, Emricha, & Schneidera, 2005), particularly in the aged (Culley, Baxter,

Yukhananov, & Crosby, 2003). An alternative explanation is that, rather than the effects of

surgery per se, the global impairments could reflect a neurologic inefficiency that relates to

cardiovascular disease itself. The findings outlined in chapter 6, and also those reported by

Rankin et al. (2003), would lend support for this perspective.

An additional finding in the current study was the significant discrepancy in self-reported

symptoms of depression, anxiety and mood between CABG patients and healthy controls.

The observed elevation in reported anxiety symptoms in both surgical groups might relate

to the confronting nature of major heart surgery, although mood disturbances might be

expected to dissipate after surgery (Andrew et al., 2000). This is only the second CABG

study to use the DASS as a measure of current mood status. In Andrew et al. (2000), the

218

authors suggested that their high incidence (45%) of post-operative anxiety symptoms

might have related to the overlap between the seven-day time reference of the DASS and

the fact that their follow-up occurred one week after surgery. This cannot explain the

persisting symptoms of anxiety observed at 1- and 3 months in the current study. It is

possible, that some of the somatic symptoms on the symptom checklist (i.e. “I was aware

of dryness of my mouth”, “I had a feeling of faintness”) were endorsed because they may

reflect symptoms that are associated with cardiovascular disease itself, or the side effects of

pharmacotherapies. Consistent with this explanation, Andrew et al. also indicated that the

members of their sample with low to moderate anxiety symptoms tended to endorse the

items reflecting autonomic arousal and involvement of skeletal musculature. These

findings might suggest that the observed persisting elevations in anxiety reflect physical

complaints rather than an underlying mood disorder.

On review of the available evidence, off-pump appears to offer some significant

pathophysiologic advantages including cerebral protection (reduced microemboli,

inflammation, and enhanced cerebral perfusion). Some controversy exists, however, as to

whether these advantages translate into tangible neuropsychological benefits that would

warrant revision of standardised operating procedures in Australian hospitals. The current

findings support the view that off-pump CABG offers some protection against neurological

insult, and that there are neuropsychological costs associated with on-pump CABG.

Fortunately, the deficits associated with on-pump CABG are largely resolved by 3 months,

although CABG procedures were associated with a global dampening that lasted across

both 1 and 3 months.

219

CHAPTER 8 : Chronic Neuropsychological Sequelae of On- vs. Off-pump CABG

Overview

So far in this thesis it has been established that cognitive deficits are evident in CABG

candidates prior to surgery and that additional cognitive deficits are observed during the

acute phase of post-operative recovery. Specifically, chapter 6 concluded that important

cognitive impairments are observed among CABG candidates prior to surgery, which are

independent of elevated stress, anxiety or depression. This suggests that disease factors,

which have largely been ignored in the literature, may at least contribute to some of the

impairments reported post-operatively. In addition to these coronary heart disease-related

impairments, important cognitive deficits within executive functioning and speed of

information processing associated with on-pump CABG were revealed in chapter 7. Using

the methodology and statistical approach as outlined in chapters 4, the study presented in

this chapter seeks to extend these findings and examine the longer-term neuropsychological

sequelae of on- and off-pump CABG.

Background

Given that there was a dedicated review of the literature in the introductory chapters the

following section will highlight only relevant aspects in order to establish the rationale and

specific aims and hypotheses for this final empirical chapter. A brief summary of the

general pattern of reported findings within studies that have examined chronic

neuropsychological changes will be followed by a discussion of the major limitations and

220

variability in methodology that can account for discrepancies across the published findings

to date.

The typical reported pattern of neuropsychological change after bypass is one of

pronounced deficits in the early post-operative stage (particularly at discharge), followed by

apparent recovery of function (Browne et al., 2003; Jacobs et al., 1998; Murkin et al., 1995;

Newman et al., 2001; Selnes, Goldsborough, Borowicz, Enger, et al., 1999; Selnes,

Goldsborough, Borowicz, & McKhann, 1999; van Dijk et al., 2000). However, relatively

few studies have examined the long-term cognitive outcomes following CABG, and

findings are mixed. For example, several studies have documented chronic impairments

(Bruggemans et al., 1995; Newman et al., 2001; Selnes et al., 2001; Stygall et al., 2003),

whilst others have reported no change, or improved neuropsychological functioning at long

-term follow-up (Fearn et al., 2001; McKhann et al., 2005; Müllges et al., 2002; Newman et

al., 2001; Selnes et al., 2003 ; Selnes et al., 2001; Townes et al., 1989; Vingerhoets, Van

Nooten, Vermassen, et al., 1997).

There are four central methodological concerns that, collectively, have diminished

confidence in these findings. These are to 1) failure to acknowledge or appropriately

manage the complex issues associated with serial neuropsychological assessment (e.g.

practice effects, test reliability and regression to the mean), 2) differences in re-test

intervals, 3) ignoring the impact of mood on post-operative test performance, and 4) use of

varying criteria to define “impairment”.

221

Effects of serial neuropsychological assessment.

As outlined in the previous chapters, the general approach to investigating cognitive

changes following CABG has been to assess patients before and after surgery using a

battery of tests. While there are distinct advantages to examining intra-individual change,

most studies have either ignored, or inadequately dealt with several very important issues

associated with serial neuropsychological assessments. In brief, in the absence of a true

effect, scores on cognitive tests may vary as a consequence of measurement error,

regression to the mean, or practice. Furthermore, practice effects have been demonstrated

to vary across measures and cognitive domains, assessment times, and as a function of age

and intellectual ability (Collie et al., 2003; McCaffrey et al., 1992; Rabbitt et al., 2004;

Rabbitt et al., 2001; Rabbitt et al., 2008). Theoretically, this should not pose a significant

problem in trials where patients have been randomly assigned to a particular procedure,

although it will affect the classification of patients as “impaired” when normative

comparisons are used. That is, failing to account for such influences on test scores will

undoubtedly affect the interpretation of performance at follow-up.

Despite this, very few studies have attempted to account for the possibility that practice

effects may, in fact, mask other changes. To highlight, improvements or an absence of

change in test performance are frequently noted in observational (McKhann, Goldsborough,

et al., 1997; McKhann et al., 2005; Müllges et al., 2002; Newman et al., 2001) and

controlled studies (Hlatky et al., 1997; Selnes et al., 2003; Vingerhoets, Van Nooten,

Vermassen, et al., 1997). Moreover, CABG patients show reduced performance over time

when compared with non-diseased controls (spouses) (Bruggemans et al., 1995) or urologic

controls (Fearn et al., 2001). In the absence of an appropriate control group, gains due to

222

practice effects are likely to be interpreted as either recovery of functioning, or evidence for

intact cognition.

Within randomised trials, failure to acknowledge improvements, and simply examine only

deterioration in test scores can also lead to very conflicting results. For example, using a

criterion of 20% decline on 20% of the neuropsychological measures to signify impairment,

a similar percentage of patients were classified as impaired one year after surgery in Lee et

al.’s (2003) study. The on-pump group, however, showed no improvement in their test

performance over time, while the off-pump group improved significantly on some

measures. A similar pattern of findings was also observed by Van Dijk et al. (2002).

The lack of a significant difference in the reported incidence, in light of the significant

group differences in rate of improvement (practice effect), demonstrates how failure to

account for practice effects in analyses might mask important changes and muddy

interpretation of results.

Additionally, test scores can vary due to imperfect reliability. One consequence of this is

that individuals with extreme scores tend to have less extreme scores at follow-up; i.e.

regression to the mean (Barnett et al., 2005; Raymond et al., 2005). If presurgical

performance is impaired, follow-up scores will likely increase based on this principle alone.

Such ‘artefactual change’ could account for some of the previous CABG findings (Newman

et al., 2001; Selnes et al., 2001). For example, cognitive decline at follow-up was predicted

by high preoperative scores in Newman and colleagues (2001) study, while those with poor

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baseline performance in both Selnes et al.’s (2001) and Rankin et al.’s (2003) studies

improved.

Influence of mood.

The impact of mood on changes in test performance is also rarely accounted for, despite an

abundance of research that has documented a clear relationship between emotional factors

and cognitive test performance. For example, elevated anxiety and depressed mood have

been associated with increased cognitive impairment in neurologically intact individuals

(see Howieson, Loring, & Hannay, 2004), and mood disturbance can mimic dementia in

older persons (for a review see Wright & Persad, 2007). Despite this, few studies have

employed methods to objectively measure, or account for the possible impact of pre- and

post-surgical changes in mood, on cognitive test scores.

For example, many of the studies that have examined long-term changes in cognition

following CABG surgery have included measures of depression in their assessments, but

have not specifically reported how this interacted with changes in cognitive test scores at

follow-up (McKhann et al., 2005; Selnes et al., 2001; Vingerhoets, Van Nooten, Vermassen,

et al., 1997).

Typically, CABG patients (both on and off-pump) provide higher ratings of depressive

symptomatology compared to non-surgical controls (Brown et al., 1994; Duits et al., 1998)

with the exception of one study, that employed the patients spouses as controls

(Bruggemans et al., 1995). Although correlations between depression and cognitive

224

changes both before (Ernest et al., 2007), and after CABG (McKhann, Borowicz , et al.,

1997) appear negligible, improvements in mood have coincided with improvements in

cognitive test scores at follow-up (Lee et al., 2003). Moreover, controlling for changes in

mood, using ANCOVA, has been shown to remove differences between the groups at long-

term follow-up (Townes et al., 1989). For these reasons, to accurately interpret cognitive

changes it is essential to examine and account for the impact of mood-state in CABG

patients on their test performances across time.

Timing of post-operative assessment.

Conclusions about the temporal nature of cognitive changes are also limited by the

enormous variability across studies in the timing of post-operative assessments. Marked

cognitive dysfunction is reported among studies that have examined only early changes

(Bendszus et al., 2002; Jacobs et al., 1998; Kneebone et al., 1998; Müllges et al., 2000;

Rasmussen et al., 1999), but to a lesser extent among studies that did not examine cognition

in the acute phase (McKhann, Goldsborough, et al., 1997; McKhann et al., 2005; Selnes,

Goldsborough, Borowicz, Enger, et al., 1999; Selnes et al., 2001). While several studies

have extended assessments beyond 3 months, few have attempted to control for the effects

of repeat assessment using a healthy control group. Unfortunately, these controlled studies

have produced mixed findings and it remains unclear whether post-operative decline occurs

following CABG. For example CABG patients in Bruggemans and colleagues (1995) study

demonstrated persisting deficits in attention and speed of information processing when

compared with their spouses at a 7 months follow-up. In contrast, neither Townes and

225

colleagues (1989) or McKhann and colleagues (2005) observed any significant differences

between their CABG samples and healthy control groups at 7 and 12 months respectively.

Within the randomized controlled trials, six did not examine post-operative changes beyond

the acute recovery phase. The remaining five studies reported mixed findings, making it

difficult to draw any firm conclusions about chronic outcomes.

Definition of decline.

Many studies dichotomise patients as either impaired or unimpaired, at follow-up. This has

involved comparison with published normative data (Ernest et al., 2006; Fitzgibbons et al.,

2002) or decline from baseline scores to exceed some predetermined cut-off (Lee et al.,

2003). Others have contrasted the group’s relative performance or changes in scores over

time without taking into account the relative influence of test reliability and practice effects

(Van Dijk et al., 2002). In accordance with recommendations outlined in the consensus

statement on defining dysfunction (Murkin, Stump, Blumenthal, & McKhann, 1997),

dichotomising patients as impaired or not using individual change scores seems to be the

favoured approach. While there are distinct advantages to examining intra-individual

change, most studies have either ignored, or inadequately dealt with several very important

issues associated with measuring cognitive changes in serial neuropsychological

assessment. In brief, in the absence of a true effect, scores on cognitive tests may vary as a

consequence of measurement error, regression to the mean, or practice. Furthermore,

practice effects will impact on the classification of patients as “impaired” or not when

226

normative comparisons are used and will undoubtedly influence interpretation of scores at

follow-up.

In summary, there have been relatively few studies that have examined the long-term

neuropsychological changes after CABG surgery, and even fewer have directly compared

these outcomes after on- and off-pump techniques. Furthermore, their findings have been

inconsistent. It is likely that this is due to methodological differences, and differences in

criteria used to define impairment. Specifically, studies have varied in their follow-up

times, their choice of cognitive domains and measures, and in their definition of meaningful

decline - factors which clearly influence reported rates of impairment (Kneebone et al.,

1998; Mahanna et al., 1996). Therefore, it is difficult to draw definitive conclusions from

the literature to address the questions about the existence of, cause, characteristics, and

temporal nature of cognitive changes following CABG. As such, there are several

unanswered questions regarding the neuropsychological sequelae associated with CABG

surgery.

The results in chapter 6 demonstrated presurgical deficits in CABG candidates, while

chapter 7 showed specific deficits or weaknesses within the domains of executive

functioning (verbal fluency, and inhibition), and speed of processing associated with on-,

but not off-pump CABG. Furthermore, these specific deficits were superimposed on more

general cognitive impairments that were evident in both groups (on- and off-pump) at 1-

and 3 months post-operatively. It remains to be seen whether CABG leads to long-term

cognitive impairment.

227

Building on the previous studies, the current study employed a regression-based method to

measure cognitive change in order to examine the long-term outcomes of on- and off-pump

bypass. An RCI method, corrected for practice, was also used to compare the outcomes for

this new technique.

The current study examined the neuropsychological outcomes between on and off-pump

CABG at 12 months post-operatively and attempted to 1) determine whether off-pump

CABG results in superior neuropsychological outcome compared to on-pump at 12 months;

and 2) describe the nature of any chronic neuropsychological deficits occurring after CABG

surgery.

Hypotheses

To briefly recap the relevant hypotheses as presented in chapter 4 (see from 71), it was

expected that persisting cognitive deficits (in the domains of information processing speed,

working memory, and memory) would be observed in the combined surgical group.

However, it was also anticipated that the previous differentiation of neuropsychological

functions between the two surgical techniques - in particular specific impairments

following on-pump CABG - would no longer be evident at the 12 month follow-up.

228

Method

The study methodology has been outlined previously (chapter 4), and was summarised in

the previous chapter. Briefly, the current study examined neuropsychological data from

participants who returned for follow-up neuropsychological assessment at 12 months after

the initial baseline assessment. Figure 8.1. (p. 229) outlines the relevant subset of data used

in the current study and Table 8.1. presents the sample characteristics.

Eight principal cognitive outcome measures were derived from a battery of

neuropsychological measures and included in the analyses. Two methods of measuring

post-operative cognitive impairment were applied to the CABG data utilising data from an

age-matched control group who had been assessed on the same battery over similar re-test

intervals (see Figure 8.1. p. 229) for a schematic representation). According to the

regression based approach, neuropsychological impairment was deemed to have occurred

when participants’ obtained test scores were significantly lower than those predicted on the

basis of regression equations built from the control sample (see Table 8.2., p. 232 for these

results). A RCI approach was used for comparison. Tables of the RCI’s for each follow-up,

based on the data from the control groups, are presented in Appendix A.

229

Figure 8.1. Flow chart of participation at 12 months.


study

(N =108)


(n = 32)


(n = 30)

Controls

(n = 46)


n = 62





baseline

(n = 53)

Completed 12 month

assessment

(n = 11)

Completed 12 month

assessment

(n = 20)

Completed 12 month

assessment

(n = 21)




- unwell (n = 1)

230

Results

Sample Characteristics

As shown in Figure 8.1. (p. 229), 43 CABG and only 11 controls participants returned

for assessment at 12 months. Sample characteristics for each group are presented in

Table 8.1 below. Of those who remained in the study at 12 months, significant

differences were observed on a number of demographic variables (Table 8.1. below).

Table 8.1.

Demographic characteristics of the surgical and healthy control samples.

off-pump on-pump Control p

N 20 21 11

Male/femaleǂ 15/5 15/6 9/2 .86

age in years

Mean (SD) Range

64.70

(8.08) 52-76

63.29

(11.00) 43-77

68.73

(7.14) 53-79 .61

Years of

education^

Mean (SD) Range

11.8

(3.3) 7-17 9.6 (2.2) 6-15

11.2

(2.8) 8-16 .04

Estimated FSIQ

Mean (SD) Range

111.73

(6.07) 97-120

106.93

(7.45) 91-120

114.04

(7.96) 104-126 .02

Ravens Standard

Progressive

Matrices Score

Mean (SD) Range

30.00

(5.13) 21-39

26.67

(8.91) 7-44

26.82

(9.27) 22-38 .22

Handednessǂ

% Right

90 100 72.50 .05

Key: ǂ

Chi Squared analyses; ^ ANOVA on transformed variable; FSIQ denotes Estimated Full

Scale Intelligence Quotient.

231

On average, the on-pump group reported lower levels of education compared with both

the off-pump, t (39) = 2.23, p < .05, and control groups, t (30) = 2.06, p < .05. A similar

pattern was observed for estimated FSIQ with the off-pump group, t (39) = 2.16, p < .05,

and controls, t (30) = 2.50, p < .05, outperforming the on-pump group.

In addition, the three groups returned for follow-up at significantly different intervals, F

(2,48) = 3.57, p = .04, with controls (Mean = 403.80, SD = 56.83) assessed 3 weeks

later than the on-pump group (Mean = 383.80, SD = 16.38), and 1 month later than the

off –pump group (Mean = 375.20, SD = 10.94).

Control Data: Regression Analyses

Standard multiple regressions were performed between each cognitive follow-up score

as the dependent variable and baseline test score, gender, age, education, NART error,

and ravens standard progressive matrices as independent variables.

For the simultaneous multiple regressions R2 ranged from .50 to .98 (Table 8.2., p. 232)

indicating that, on the whole, a large proportion of the variance in cognitive

performance at follow-up was predicted by the combination of baseline cognitive and

control variables. Stepwise regressions examined whether the inclusion of the control

predictors (gender, age, education, premorbid and current IQ), improved prediction of

follow-up performances beyond that afforded by differences in baseline performance

alone. Contrary to the results at 1 and 3 months, the inclusion of these variables did not

232

Table 8.2.

Results of the regression analyses of controls at 12 months.

B (SE) R2 R

2 change Cognitive

Domain Dependents Intercept


Speed of

Processing SDMT

a (total


1.05*

(.35)

3.07

(5.47)

-.44

(.42)

.19

(.96)

.11

(.26)

-.11

(.33) .89* .92* .34 .87

TMTab

(seconds) -49.17 .13

(.23)

.60

(5.20) 1.23*

(.63)

-1.06

(.95)

.21

(.28)

.09

(.47) .51* .93* 4.4

3 .09

Working

Memory KHMT

c (total

correct) 18.43

.08

(.17)

.85

(1.75)

-.05

(.11)

-.11

(.31) -.27*

(.08)

.08

(.09) .32 .88 3.6

9 .12

Memory

Verbal

Learning

RAVLTd Total


1-5)

-7.26 .13

(.44)

5.54

(10.84)

.09

(.69)

-.24

(1.89)

.18

(.50)

1.14

(.68) .43* .69 .70 .65

Delayed

Recall

RAVLTd delay

(total number of

words: delayed

recall)

.64 .48*

(.16)

3.92

(1.61)

-.08

(.11)

.22

(.28)

.41

(.07)

-.01

(.09) .44* .82 1.6

1 .33

Executive

Function

Fluency COWAT

e (total

score)

12.00

.83

(.35)

-5.76

(7.31)

-.21

(.37)

.46

(1.06)

.26

(.32)

.35

(.34) .69*

* .88

1.3

0 .41


57.27 .61**

(.10)

-2.33

(6.12)

-.27

(.40)

1.30

(1.21)

.42

(.27)

.16

(.69) .96*

* .98**

1.2

7 .42

Cognitive

Flexibility TMT

bratio

(Ratio score) 10.48

.10

(.36)

.70

(.87)

-.10

(.06)

-.05

(.16)

-.02

(.05)

-.05

(.06) .15 .50 .56 .73

Key: 1 denotes Bivariate regression; 2 denotes multivariate regression. B (SE) denotes regression coefficients with standard error;* denotes

p < .05. ; ** denotes p < .01. aSDMT, Symbol Digit Modalities Test (Smith, 1982);

bTMT

, Trail Making Test

(Reitan, 1958);

cKHMT ,

Kaufman Hand Movement Test (Kaufman & Kaufman, 1983); dRAVLT, Rey Auditory Verbal Learning Test (Rey, 1964);

eCOWAT,

Controlled Oral Word Association Test (Benton et al., 1994);

233

significantly improve the prediction over and above the baseline score alone (see R2 change

statistics, Table 8.2.).

Surgical Data: Twelve Month Follow-up

In total, two outliers were identified across the eight predicted-obtained difference scores.

These extreme scores were replaced with their respective group mean for each variable.

All predicted-obtained variables were normally distributed. The raw cognitive data (at

baseline and 12 month follow-up) are presented in Table 8.3 (p. 234).

Combined surgical group: overall cognitive deficits.

Single sample t-tests compared mean predicted and obtained discrepancy scores to zero (no

difference) across measures to investigate hypothesis 5, that significant post-operative

deficits would be observed within the overall CABG group (most likely within the domains

of speed of processing, working memory, and memory). Partly consistent with expectation,

predicted performance was significantly poorer than expected for verbal leaning (RAVLT

total score) t (40) = 2.54, p = .02, verbal memory (RAVLT delayed recall), t (40) = 4.54, p

< .01, and one measure of speed of processing (SDMT) t (40) = 2.93, p <.01. However,

Performance was significantly better than predicted for verbal working memory (KHMT) t

(40) = -2.46, p =.02; cognitive flexibility (TMT ratio), t (40) = -14.23, p < .01; and another

timed measure of psychomotor speed (TMTa), t (40) = -8.61, p < .01 (see Table 8.4., p.

235).

234

Table 8.3.

Raw cognitive descriptive statistics at the 12 month follow-up

Overall CABG

n = 41

On-pump

n = 21

Off-pump

n = 20

Controls

n = 11 Cognitive

Domain Variable

Baseline 12

months

Baseline

12

months

Baseline

12

months Baseline

12

months

Speed of

Processing SDMT

a (total


(10.93)

40.00

(10.04)

36.81

(11.81)

37.05

(10.97)

44.05

(8.75)

43.10

(8.10)

40.36

(10.65)

40.81

(13.01)

TMTa

b

(seconds) 35.51

(11.50)

34.43

(17.30)

39.86

(12.10)

39.00

(21.51)

30.95

(9.02)

29.65

(9.78)

38.09

(17.72)

35.09

(13.01)

Working

Memory KHMT

c (total

correct) 12.29

(3.36)

13.63

(3.40)

11.67

(3.60)

12.81

(2.91)

12.95

(3.04)

14.50

(3.72)

12.27

(4.57)

13.36

(3.39)

Verbal

Learning

RAVLTd Total

(total words,

trials 1-5)

38.88

(8.01)

39.98

(8.54)

38.81

(9.81)

39.91

(10.02)

38.95

(5.83)

40.05

(6.91)

40.45

(12.95)

41.46

(13.21)

Verbal

Delayed

Recall

RAVLTd delay

(total number of

words: delayed

recall)

6.88

(3.05)

6.98

(3.24)

7.67

(3.31)

7.62

(3.26)

6.05

(2.59)

6.30

(3.15)

8.27

(4.05)

8.27

(2.49)

Executive

Function

Fluency COWAT

e (total

score)

36.05

(10.10)

39.56

(9.46)

34.33

(9.52)

37.67

(9.95)

37.85

(10.62)

41.55

(8.73)

40.82

(8.92)

43.09

(11.44)


180.83

(35.76)

175.29

(44.01)

188.43

(33.88)

185.43

(47.32)

172.85

(36.77)

164.65

(38.58)

186.45

(52.20)

176.46

(30.96)

Cognitive

Flexibility TMT

bratio

(Ratio score) 2.65

(0.69)

2.69

(0.84)

2.71

(0.78)

2.73

(0.88)

2.59

(0.59)

2.66

(0.82)

2.88

(1.16)

2.61

(0.84)



(Reitan, 1958);




Scores reported are the Mean and SD raw scores at baseline and 12 months.

235

Table 8.4.

Predicted-obtained difference scores for combined surgical group at 12 month



(Reitan, 1958);




Association Test (Benton et al., 1994); Scores reported are the Mean and SD of the predicted-obtained discrepancies. Note that positive

discrepancy scores reflect poorer than predicted performance.

Combined Surgical group off-pump CABG on-pump CABG Cognitive

Domain Variable

N = 41 p

n = 20 n = 21 p

SDMTa

(total written

score) 3.53 (7.72) <.01 3.63 (6.26) 3.44 (9.05) .94

Speed of Processing TMTa

b (seconds) -19.68 (14.64) <.01 -22.73 (10.88) -16.74 (17.25) .19


(total correct) -1.32 (3.43) .02 -1.38 (3.87) -1.26 (3.06) .91

Verbal Learning RAVLT

d Total (total

words, trials 1-5) 4.15 (10.49) .02 5.18 (10.38) 3.18 (10.77) .55

Verbal Delayed

Recall

RAVLTd delay (total


recall)

2.21 (3.11) <.01

2.15 (3.12) 2.27 (2.99) .90

Executive Function

Fluency COWATe

(total score) 1.90 (7.47) .11 1.69 (7.90) 2.08 (7.23) .87

Inhibition Stroop Task (seconds) -3.76 (21.48) .27 -6.81 (24.35) -0.85 (18.47) .38

Cognitive Flexibility TMTbratio (Ratio score) -3.10 (1.39) <.01

-3.13 (1.06) -3.07 (1.68) .44

236

The notable attrition within the control group may have influenced the interpretation of

these findings by introducing an artefact into the regression predictions. It was therefore

necessary to examine whether there was, indeed an improvement in functioning within the

CABG surgery sample after the acute postoperative period, and stable performance among

controls. This was achieved by conducting a repeated measures ANOVA’s (group x time)

across the 3 month and 12 month raw cognitive data for the sub-sample who returned at

both follow-up times. These data are presented in Table 8.5. (p. 237). These analyses

showed significant improvements from 3 to 12 months for one processing speed measure

(TMTa), F (1, 44) = 4.24, p < .05, and two executive function tasks (TMT ratio), F (1, 44)

= 4.10, p < .05, (Stroop Interference), F (1, 44) = 5.43, p < .05. None of the Group x Time

interactions were significant, suggesting the trajectory of change from 3 to 12 months did

not differ significantly across the CABG and control samples. The CABG group had a

significantly lower verbal learning score at the three month follow-up, F (1,44) = 3.90, p

< .05.


The incidence of impairment within the CABG group was compared across methods using

chi-squared statistic. As shown in Table 8.6. (p. 238). The RCI method classified

significantly fewer patients as impaired than the predicted-obtained approach on two

measures; the RAVLT delayed recall and the Stroop Interference task.

237

Table 8.5.

Repeated measures ANOVA for CABG and Controls from 3 to 12 months.

Overall CABG

n = 37

Controls

n = 9

Repeated Measures ANOVA

Cognitive

Domain Variable

3 months 12 months

3 months 12 months

Time Group Time x

Group

SDMTa

(total written

score) 41.00

(10.49)

40.27

(9.34)

40.11

(11.07)

38.56

(10.60) 1.54 .13 .20

Speed of

Processing TMTa

b (seconds)

34.76

(11.97)

33.35

(15.75)

42.78

(17.61)

35.67

(9.67) 4.24* 1.17 1.90

Working

Memory KHMT

c (total correct)

13.54

(3.32)

13.81

(3.51)

13.77

(3.99)

13.87

(3.56) .10 .01 2.79

Verbal

Learning RAVLT

d Total (total

words, trials 1-5)

39.14

(10.03)

39.65

(8.63)

47.44

(11.79)

45.67

(16.53) .21 3.90* .68

Verbal

Delayed

Recall

RAVLTd delay (total

number of words:

delayed recall)

6.62

(2.99)

6.84

(3.37)

9.11

(4.23)

8.56

(2.51) .14 3.58^ .70

Executive

Function

Fluency COWATe

(total score)

38.32

(10.08)

40.35

(9.45)

40.22

(8.12)

41.33

(12.36) 2.07 .17 .18


165.08

(43.14)

172.87

(43.48)

171.22

(40.91)

182.89

(31.62) 5.43* .29 .22

Cognitive

Flexibility TMT

bratio (Ratio

score) 2.25

(1.06)

2.57

(0.77)

2.21

(1.32)

2.64

(1.82) 4.10* .32 .00

Key: * = p < .05, ^ = p < .06. aSDMT, Symbol Digit Modalities Test (Smith, 1982);


(Reitan, 1958);

cKHMT, Kaufman Hand

Movement Test (Kaufman & Kaufman, 1983); dRAVLT, Rey Auditory Verbal Learning Test (Rey, 1964); eCOWAT, Controlled Oral Word Association

Test (Benton et al., 1994); Scores reported are the Mean and SD raw scores at 3 month and 12 months, TMT ratio scores are reported as median and

interquartile ranges.

238

Table 8.6.

Number (%) of CABG patients classified as impaired across two methods at 12 months.

Method

Cognitive

Domain Variables

Predicted-

Obtained

Count (%)

RCI

Count

(%)

χ2 p

SDMTa

(total written

score) 2

(4.88)

3

(7.32)

0.21 .65 Speed of

Processing

TMTab

(seconds) 4

(9.76)

1

(2.44)

1.49 .22

Working

Memory

KHMTc

(total correct) 1

(2.44)

1

(2.44)

1.02 .31

Memory

Verbal Learning

RAVLTd Total (total

words, trials 1-5)

0

(0)

0

(0)

-

1.00



recall)

7

(17.07)

1

(2.44)

4.70 .03

Executive

Function

Fluency

COWATe

(total score)

0

(0)

2

(4.88)

1.02

.31

Inhibition Stroop Task (seconds) 11

(26.83)

1

(2.44)

9.53 <.01

Cognitive

Flexibility

TMTbratio (Ratio score) 0

(0)

0

(0)

- 1.00

Key: n = 42.

aSDMT, Symbol Digit Modalities Test (Smith, 1982);


(Reitan, 1958); cKHMT, Kaufman Hand Movement Test (Kaufman & Kaufman, 1983); dRAVLT,

Rey Auditory Verbal Learning Test (Rey, 1964); eCOWAT, Controlled Oral Word Association Test

(Benton et al., 1994); Fisher’s exact statistic was used where expected frequencies were less than 1.

Yates correction was applied for cell counts less than 5.

239

Table 8.7.

Comparison of adjusted RCI method and Predicted-obtained method for classifying patients as impaired at 12 months.

Variable Predicted-Obtained Method RCI Method Comparison Cognitive

Domain On-pump Off-pump χ2 On-

pump Off-pump χ2 χ2 p

Speed of

Processing SDMT

a (total

written score) 2 (9.52) 0 (0) 0.86 2 (9.52) 1 (5.00) 0.46 1.77 .18

TMTa

b

(seconds) 3 (14.29) 1 (5.00) 0.35 1 (4.76) 0 (0) 1.12 3.59 .06

Working

Memory KHMT

c (total

correct) 0 (0) 1 (5.00) 0.93 1 (4.76) 0 (0) 1.12 2.00 .16

Verbal Memory

Learning

RAVLTd Total


1-5)

0 (0)

0 (0)

-

0 (0)

0 (0)

-

-

1.00


(total number of

words: delayed

recall)

3 (14.29) 4 (20.00) 0.04 1 (4.76) 0 (0) 1.12 1.14 .29

Executive

Function

Fluency COWAT

e (total

score)

0 (0)

0 (0)

-

0 (0)

2 (10.00)

1.26

-

1.00


6 (28.57) 5 (25.00) 0.22 1 (4.76) 0 (0) 1.12 1.47 .23

Cognitive

Flexibility TMT

bratio

(Ratio score) 0 (0) 0 (0) - 0 (0) 0 (0) - - 1.00


bTMT

, Trail Making Test

(Reitan, 1958);




Where expected frequencies fell below 1, Fisher’s exact test was used. Yates correction was applied with cell counts less than 5. note *, p < .05. ** p

< .01. Percentages are in parentheses.

240

On- versus off-pump: predicted-obtained discrepancy.

Consistent with expectation, there were no statistically significant differences between

patients randomised to on- or off-pump on any of the cognitive measures at the 12 month

follow-up (see Table 8.4., p. 235). When scores of current mood were included in the

model as covariates, group differences remained non-significant for all predicted-obtained

difference scores.


The relative incidence of impairment across each group was calculated using the predicted-

obtained method and the adjusted RCI approach, allowing for comparison across groups

and statistical methods. There were no significant differences in the frequency with which

patients from the on-pump group or off-pump group were classified as impaired (see table

8.7., p. 239).

There was a trend for on-pump patients to be classified as impaired more frequently using

the predicted-obtained method compared to RCI approach for one task at 12 months

(TMTa).


At 12 months, all three measures of mood were heavily skewed, and the depression and

anxiety data also had significant kurtosis. Square root transformations effectively

241

normalised distributions prior to analyses. There were no significant group differences in

mean severity of reported symptoms of depression, anxiety, or stress.

Frequency of elevated depression, anxiety, and stress scores at 12 months.

Using self-ratings from the DASS (Lovibond & Lovibond, 1995), most participants scored

in the normal range for symptoms of depression, anxiety and stress. Elevated depressive

symptomatology was observed in 6.82% of all participants, with 5% of the off-pump

patients and 9.5% of the on-pump sample, and only none of controls reporting depressive

symptoms exceeding the normal range. The frequency of responses across these levels of

depression (normal, mild, moderate, severe, extremely severe) did not differ between

groups, χ2 (4, N = 53) = 3.88, p = .69.

Elevated symptoms of anxiety were reported in 29.55% of participants overall, made up of

25% of the off-pump group, 38.1% of the on-pump group, and none of the controls. Again,

the frequency of responses was not significantly different across groups, χ2 (4, N = 53) =

7.43, p = .49. Similarly, 18.18% of participants reported some symptoms of stress, with

25% of the off-pump sample, 19.05% of the on-pump, and no controls, reporting symptoms

of stress exceeding the normal range. These differences were not statistically significant, χ2

(4, N = 53) = 3.46, p = .49.

242


months.

At 12 months, the average severity of reported depression, anxiety, and stress symptoms

was relatively similar across groups. Specifically, levels of depression in the off-pump

group (median = 3.0, interquartile range = 5.75), on-pump group (median = 2.0,

interquartile range = 3.5), and control group (median = 1.0, interquartile range = 1.0) were

not significantly different, F (2, 50) = 1.08, p = .35. Similarly, differences in anxiety

symptoms between the off-pump (median = 3.0, interquartile range = 4.25), on-pump

(median = 4.0, interquartile range = 5.0), and control group (median = 1.5, interquartile

range = 2.75), were non-significant, F (2, 50) = 1.50, p = .23. As were the overall levels of

self-reported stress in the off-pump (median = 6.0, interquartile range = 8.5), on-pump

(median = 6.0, interquartile range = 8.0), and control group (median = 5.0, interquartile

range = 5.75), F (2, 50) = 0.29, p = .75.

Partial correlations between each cognitive variable and the three measures of depressive,

anxiety, and stress symptoms were used to examine the magnitude of any relationship

between post-operative cognitive performance and current mood state whilst controlling for

demographic variables (hypothesis 5).

Under hypothesis 5 it was predicted that elevated depression, anxiety and stress scores

would be associated with poorer cognitive test performance. In partial support of this, the

on pump group, there was only one significant association between cognitive performance

at 12 months and psychological state. Specifically, stress was positively correlated with

response time on the Stroop Interference task, suggesting that elevated stress was

associated with slower performance on this task. As with the results at 1 and 3 months,

243

there were several associations between psychological variables and cognitive performance

in the off-pump group at this follow-up visit. Namely, both processing speed tasks

correlated significantly with levels of anxiety; with elevated anxiety associated with slower

performances on these tasks. In addition, higher-levels of depression and stress were also

associated with slower performance on one of these tasks (SDMT). Anxiety was also

negatively correlated with verbal working memory (KHMT) and was positively correlated

with performance on one of the executive tasks (Stroop Interference), while depression and

stress were positively correlated with verbal learning (RAVLT total) within this group. In

addition, both depression and stress were negatively correlated with the TMT ratio,

suggesting that an increase in psychological symptoms was associated with a reduction in

the ratio score (i.e. improved efficiency on this task).

244

Table 8.8.

Partial correlations between DASS scores and 12 month post-operative cognitive scores in the on-pump group

Variables

Mood Variables


r Cognitive


f FSIQ

g

Speed of

Processing SDMT

a (total written

score) -.07

(-.03)

-.10

(-.10)

-.09

(<.01) -.64** .17 .12 .54* -.09

TMTab

(seconds) .17

(-.05)

.29

(.10)

.21

(-.16) .45* .15 -.24 -.58** .14

Working

Memory KHMT

c (total

correct) -.36

(-.38)

.02

(-.11)

-.25

(-.30) -.39 .21 .08 .33 .25

Verbal

Learning

RAVLTd Total


5)

.15

(-.05)

-.06

(-.14)

.30

(-.01) -.36 .11 .51* .34 .39

Verbal

Delayed

Recall

RAVLTd delay

(total number of

words: delayed recall)

.06

(-.05)

.04

(<-.01)

.18

(.04) -.39 .19 .51* .50* .26

Executive

Function

Fluency COWAT

e (total

score)

-.47

(-.35)

-.20

(-.13)

-.26

(-.12) -.36 .12 .30 .54* .22


.42

(.28)

.37

(.27) .53*

(.30) .41 .05 -.25 -.35 .01

Cognitive

Flexibility TMT

bratio (Ratio

score) -.18

(.04)

-.19

(.05)

-.27

(.11) .17 -.29 .02 .07 -.22

Key; * denotes p < .05; ** denotes p < .01; ^ denotes a trend (p<.06); aSDMT, Symbol Digit Modalities Test (Smith, 1982);

bTMT

, Trail Making Test





gFSIQ,

Estimated Full Scale IQ. Zero-order correlations are presented in parentheses. Note n = 21

245

Table 8.9.

Partial correlations between DASS scores and 12 month post-operative cognitive scores in the off-pump group

Variable

Mood Variables


r Cognitive


f FSIQ

g

Speed of

Processing SDMT

a (total

written score) -.51*

(-.35) -.67**

(-.65)**

-.56*

(-.31) -.33 .49* -.01 .38 .44^

TMTab

(seconds) .36

(.40)

.48

(.51)*

.41

(.29) .45* -.34 .29 -.36 .22

Working

Memory KHMT

c (total

correct) -.42

(-.44)^ -.58*

(-.49)*

-.31

(-.18) -.06 .25 -.11 .44^ .12

Verbal

Learning

RAVLTd Total


1-5)

.45

(.47)*

.39

(.25) .63*

(.56)** -.33 .08 -.06 -.32 -.02

Verbal

Delayed

Recall

RAVLTd delay

(total number of

words: delayed

recall)

-.12

(-.10)

.31

(.18)

.27

(.19) -.33 -.18 -.09 -.21 -.31

Executive

Function Fluency

COWATe

(total

score)

.07

(-.05)

-.46

(-.43)^

-.33

(-.15) .14 .28 .28 .54* .45*


.62*

(.57)**

.50^

(.48)*

.42

(.31) -.03 -.33 .02 -.49* .41

Cognitive

Flexibility TMT

bratio

(Ratio score) -.57*

(-.43)

-.37

(-.34) -.67**

(-.59)** -.22 -.11 -.17 -.28 -.05

Key; * denotes p < .05; ** denotes p < .01; ^ denotes a trend (p<.06) aSDMT, Symbol Digit Modalities Test (Smith, 1982);

bTMT

, Trail Making Test





gFSIQ,

Estimated Full Scale IQ. Zero-order correlations are presented in parentheses. Note n = 20

246

Discussion

The current study sought to examine the chronic neuropsychological sequelae of CABG

surgery, and determine whether off-pump surgery carries any long-term cognitive benefits

over traditional on-pump CABG. This was done by examining the relative post-operative

cognitive performance between on- and off-pump CABG at 12 months after surgery.

It was expected that the previous differentiation of neuropsychological functions between

the two surgical techniques - in particular specific impairments following on-pump CABG

- would no longer be evident at the 12 month follow-up. Consistent with this, there were

no significant group differences for any of the cognitive scores, nor in the incidence of

impairment at this follow-up visit. That is, there was no evidence for significant,

demonstrable dysfunction one year after on-pump CABG, or any notable long-term

cognitive benefit of avoiding cardiopulmonary bypass and performance off-pump CABG.

However, the findings from this study should be interpreted with caution, given the

relatively small number of controls used to construct the regression equations. Specifically,

the attrition in the control group may have influenced the interpretation of the findings by

introducing an artefact into the regression predictions. Even though the predicted-obtained

statistics imply that impairment may have resolved, examination of the raw data and

change over time indicates fairly stable performances across these scores over time, with

significant improvements from three to five months noted in speed of processing and two

aspects of executive functioning (inhibition, cognitive flexibility). Moreover, as shown in

Table 8.5., these improvements did not differ significantly across groups (CABG, controls).

247

Several of the published randomised trials with follow-up times greater than 3 months have

also found comparable long-term cognitive outcomes after on- and off-pump CABG (Baker

et al., 2000; Hernandez et al., 2007; Jensen et al., 2006; Jensen, Rasmussen, & Steinbruchel,

2008; Motellebzadeh, 2007). Others have reported a modest benefit in cognitive outcome,

in the form of greater improvement in selected test scores, following the off-pump

compared to the on-pump procedure (Ernest et al., 2006; Lee et al., 2003; van Dijk et al.,

2002). In terms of the incidence of impairment, only Chernov et al. (2006) and Ernest et al.

(2006) have produced results that favour the off-pump method. Both Takagi et al. (2007,

2008) and Marasco et al. (2008) meta-analytic findings of a small number of studies at long

term follow-up showed no appreciable benefit of off-pump over traditional CPB. However,

in Marasco et al.’s analysis, off-pump patients showed significantly greater improvement

on one timed task (TMT part A) at both acute and long-term follow-up compared to the on-

pump group. In the current study, performance on this task by the entire CABG sample at

follow-up was significantly better than predicted (see table 8.4), and there was a non-

significant benefit of off-pump over on-pump CABG for this task. Inspection of the data

suggests that considerable variability in the discrepancy scores (predicted-obtained) for this

task may have precluded a significant finding.

Almost 25 percent of the participants allocated to receive off-pump in Ernest et al.’s (2006)

study were crossed over to on-pump during their surgery. Somewhat surprisingly, the

noted modest benefit of off-pump reported by these authors occurred only when the groups’

data were analysed under the ‘Intention to Treat’ principal (where data are analysed

according to initial randomisation) and not when analysed according to actual treatment

248

received. Given their relatively small sample size, this number of crossovers and analysis

based on intention to treat is likely to be problematic.

Importantly, the central method of analysis in the current study differs from those used

previously, as it attempts to account for important psychometric factors and practice effects

when assessing cognitive changes over time. Many previous studies have utilised

dichotomous outcomes, by classifying participants as either “impaired” or not (Ernest et al.,

2006), and have often employed arbitrary criteria to do so (Kneebone et al., 1998). These

methods fail to acknowledge, or account for, expected changes due to repeat test

administration.

The only previous study to employ a similar regression-based approach to that used in the

current study is Tully et al. (2008). These authors reported no significant differences

between on- and off-pump CABG in the incidence of cognitive impairment at 6 months, a

finding that as been essentially replicated in the current study at a slightly longer follow-up.

Theirs is the first published study to employ a regression-based approach to address the

complex issues of repeat neuropsychological assessment.

In terms of the overall CABG sample, persisting cognitive deficits (in the domains of

information processing speed, working memory, and memory) were expected. When data

was collapsed across the two surgical groups, deficits were identified for verbal learning

(RAVLT total score), verbal memory (RAVLT delayed recall), and one measure of

attention and speed of information processing (SDMT). That is, for the CABG samples

combined, their observed performances on these measures were poorer than were predicted

249

based on their presurgical performance, age, gender, estimated premorbid IQ, and fluid

reasoning ability. Similarly, Tully et al. (2008) report a high incidence of cognitive

impairment irrespective of CABG technique, with the greatest deficits occurring in speed of

processing, delayed verbal memory, and executive functioning. Thus, the current long-term

findings are in line with the only published study that has appropriately, and systematically,

addressed the methodological shortcomings within the previous randomised trials to date.

When each individual case was examined independently, the rate of impairment was

highest for measures of executive functioning (Stroop Interference) and verbal memory

(RAVLT delayed recall), with 26.83% and 17.07% of the overall CABG patients classified

as impaired on these tasks respectively. On a single-case level, there were no individual

cases who met the criteria for impairment in verbal learning, despite the fact that the group

average was significantly lower than expected on this task. Additionally, although just over

one quarter of participants demonstrated impaired inhibitory functioning (Stroop

Interference), the group average did not meet the criteria for impairment. These

discrepancies were likely a product of differential patterns of change across participants

over time. That is, some participants improved while others declined on each task. Given

the size of the sample in the current study, it was not possible to explore the factors, which

influenced on these divergent patterns of change further. Future larger trials could

investigate the individual trajectories of change, and contributing factors using structural

equation modelling techniques.

Many previous studies have identified a susceptibility for a weakness in learning and

memory following CABG surgery (Chernov et al., 2005; Jacobs et al., 1998; McKhann,

250

Goldsborough, et al., 1997; Stygall et al., 2003; Tully et al., 2008), although this was often

reported exclusively after either the on- (Lee et al., 2003; van Dijk et al., 2002) or the off-

pump (Baker et al., 2000) method.

As mentioned in chapter 2, and consistent with the findings in the acute follow-up period,

the presence of executive difficulties in a quarter of the CABG patients raises the

possibility of disruptions to frontostriatal networks (Bigler & Alfano, 1988; Cummings et

al., 1984; Petito, 1987). Additionally, although initial learning did not appear to be affected,

delayed recall was problematic for over 15% of the CABG patients at the 12 month follow-

up; implying potential hippocampal vulnerability. Given the circulatory inefficiency of the

hippocampal region of the mesial temporal cortex, such a finding would not be unexpected

following a period of suboptimal cerebral perfusion.

The finding of collective deficits in the combined CABG group would suggest that factors

associated with the general CABG procedure, irrespective of surgical method, could give

rise to persisting cognitive dysfunction. In the absence of a general, non-CABG surgical

control group, it is only possible to speculate on the cause of such effects. One possibility

is general anaesthesia.

Post-operative cognitive dysfunction is not limited to CABG surgery (Moller et al., 1998;

Vingerhoets, Van Nooten, Vermassen, et al., 1997). The International Study of Post-

operative Cognitive Dysfunction (Abildstrom et al., 2000; Moller et al.) provides evidence

that surgery can give rise to new impairments in the early post-operative period that

dissipate within the first few months after surgery. That is, even when anaesthetic agents

251

have been cleared from the body, cognitive effects are evident (Lewis et al., 2007).

Importantly, the incidence of impairment after 1-2 years following non-cardiac surgery is

comparable to age-similar peers (Abildstrom et al.), which suggests that impairments are

transient.

Within the broader literature there is mounting evidence that use of general anaesthetic

agents can cause a range of important persisting neuromodulatory effects, including

alteration of proteins (Futterer, Maurer, Schmitt, Feldmann, Kuschinsky, & Waschke,

2004), beta-amyloid oligomerization which may hasten deposition in the brain (Eckenhoff

et al, 2004), neurotoxicity (Eckenhoff et al.; Jevtovic-Todorovic, Wozniak, Benshoff, &

Olney, 2001), and apoptosis (Raina et al., 2003). Such changes, could plausibly give rise

to persisting neuropsychological deficits, or even the emergence of new impairments long

after the pharmacological of the drug action has ceased.

As demonstrated in chapter 5, and within the neuropsychological literature, many cognitive

measures are highly vulnerable to the effects of practice. As such, clinically important

information can be derived from the absence of improvement, rather than an observed

decline in performance (McCaffrey et al., 1993; McCaffrey et al., 1992). Importantly, the

current study attempted to account for improvements associated with repeat

neuropsychological assessment, and chose not to define impairment using the atheoretical

methods previously employed. It is therefore surprising that observed performance

exceeded predicted performance on measures of non-verbal memory, verbal working

memory, processing speed, and cognitive flexibility. The small sample size and possible

influence of selection and dropout biases may have contributed to these unusual results.

252

Alternatively, these improvements may reflect a recovery of function, due to the

improvement in health by 12 months post-operatively. The absence of significant

improvement from the 3 to 12 month follow-up, specifically within the CABG group, does

not support the interpretation of the current results as potential recovery.

Central to this thesis is the employment of a regression-based approach to the evaluation of

post-operative neuropsychological dysfunction; the predicted-obtained method. As a

comparison, the RCI method with a correction factor applied to account for practice effects

was also applied to the data. Given the literature on practice effects, and the likely

differential impact of individual factors (ability, age, education), it was anticipated that the

predicted-obtained method would classify significantly more patients as

neuropsychologically impaired than the RCI approach. At the 12 month follow-up there

was limited support for this hypothesis, with significantly more CABG patients classified

as impaired using the predicted-obtained approach than the RCI for two tasks (Stroop

Interference, RAVLT delayed recall). However, as was the case with the 1 and 3 month

findings, these approaches again performed fairly consistently when the surgical groups

were compared. That is, contrary to expectation, the predicted-obtained method did not

detect significantly more patients as impaired in the on-pump group when compared to the

RCI method, although there was a trend in this direction for one task at 12 months (TMTa).

While the impact of sample size must be considered, given the significant findings across

these methods in the overall group, there may only be a minor advantage of accounting for

additional individual variables when examining post-operative neuropsychological

functioning. Both approaches are simple to apply, and importantly, deal wit the most

critical factors in evaluating change: practice effects and imperfect test reliability.

253

The 12 month follow-up time employed in the current study allows for post-acute

assessment of cognitive change. A few previous studies have extended follow-up to

several years, with some (Lyketsos et al., 2006; Newman et al., 2001; Selnes et al., 2001;

Stygall et al., 2003) claiming a late cognitive deterioration following CABG surgery. It

would appear that patients who suffer from acute neurocognitive decline are also at greater

risk of chronic impairment that may only be evident after several years post CABG (Selnes

et al., 2005). Whether such decline reflects an accelerated aging, or occurs differentially

across on- and off-pump CABG requires further investigation with well-controlled, large

randomised trials that extend beyond 12 months, and control for important methodological

challenges such as practice effects, test reliability, as well as the impact of mood and

general age-related decline.

In summary, although the findings were somewhat contrary to expectation, they are

partially consistent with previous work. Given that cognitive deficits were not observed in

the on-pump group, the hypothesis that off-pump is neurologically and cognitively

protective in the long-term cannot be supported. The findings from this study should be

interpreted with caution, given the relatively small number of controls used to construct the

regression equations.

Further investigations, which attempt to examine the long-term cognitive changes

associated with on- and off-pump CABG will need to address the complicated issues

associated with serial neuropsychological assessment, and employ sensible statistical

criteria by which to define meaningful cognitive change.

254

CHAPTER 9 : GENERAL DISCUSSION

Outline

This final chapter serves five main purposes. First, revisit the rationale and central aims for

the thesis; second, review and summarise the key empirical findings; third, discuss the

strengths and limitations of the methodology used; and in the context of these, to fourthly

outline the implications of the main findings; and finally, offer suggestions for future

research directions.

Rationale and Aims

As discussed in the introductory chapter, CABG has been historically associated with

cognitive decline. In brief, surgeons traditionally utilise cardioplegia and cardiopulmonary

bypass to perform CABG on the motionless heart. Despite the technical advantage of a still

operative field, this method is known to introduce multiple microemboli into the brain and

decrease cerebral perfusion, which can induce ischemia and affect neurological integrity.

Using the alternative, off-pump method, surgeons graft vessels on the beating heart. This

method allows normal circulation to continue, thereby reducing both embolic load and

cerebral hypoperfusion. On this basis, it is argued that cerebral functioning, and therefore

neuropsychological function, is at greater risk of impairment with On-pump rather than off-

pump CABG (Mack, 2000). Whether such neurological insult arising from On-pump

CABG translates into meaningful, lasting, cognitive deficits remains controversial.

255

Chapter 2 concluded that the studies of post-operative cognitive dysfunction after CABG

have yielded inconsistent results. Single group studies of CABG appear to show a pattern

of acute performance decline followed by improvement, which is typically interpreted as

transient dysfunction and recovery. Within the controlled studies, early impairment is also

observed, however, there is conflicting evidence regarding subsequent recovery. Moreover,

performance declines are also observed in non-healthy controls (Selnes et al., 2003; Selnes

et al., 2006; Townes et al., 1989; Vingerhoets, Van Nooten, & Jannes, 1997), and post-

operatively following other procedures (Moller et al., 1998), which might indicate that

factors other than the pump are the cause of, or at least contribute to, post-operative

cognitive decline.

With respect to neuropsychological functioning, on-pump CABG is commonly associated

with increased incidence of cerebrovascular complications (including stroke), particularly

in elderly patients and those with concomitant atherosclerosis (Roach et al., 1996). Patients

who suffer from acute neurocognitive decline are also at greater risk of chronic impairment

(Newman et al., 2001; Selnes et al. 2001). While some authors report chronic disturbances

in cognitive performance following CABG, the effect appears to be most pronounced in the

acute phase and subtler over the long-term (Selnes et al., 1999).

To date, the precise cause mechanisms, temporal course, and cognitive domains affected

during CABG surgery remain uncertain. It was argued in chapters 1 and 2, that factors

such as different assessment times, cognitive domains assessed and test selection, use of

control samples, different and arbitrary criteria and definitions of impairment, as well as

256

failure to account for the influence of mood, practice effects, test-reliability and regression

to the mean have obscured the story.

The broad aims of this thesis were threefold; to test the idea that on-pump CABG surgery

causes cognitive impairment and that off-pump CABG results in better neuropsychological

outcome, to elucidate the nature of any deficits, and to determine whether they are transient

or persistent. In order to test whether some aspect of CABG surgery (namely

cardiopulmonary bypass technique) is the cause of cognitive decline, it was also important

to establish the cognitive status of cardiovascular diseased patients prior to surgery; as well

as examine the impact of serial neuropsychological assessments on cognitive test

performance over time.

More specifically, the thesis aimed to:

1) Evaluate the pattern of practice effects and psychometric properties of the selected

neuropsychological test battery.

2) Evaluate the pre-surgical cognitive status among candidates for CABG

3) Determine whether off-pump and on-pump CABG surgery result in different

neuropsychological sequelae, and specifically whether the off-pump technique

produces better post-operative outcomes compared with on-pump CABG.

4) Determine whether the neurocognitive effects of CABG are acute and resolvable, or

lead to chronic alterations in cognitive function.

5) Determine which cognitive processes/domains are at risk during CABG surgery.

More specifically, determine whether the performance decline is general, or is

specific to certain cognitive processes.

257

Summary of Findings

The following is a summary of the empirical findings that comprise this thesis.

Repeat neuropsychological assessment.

An improvement in test scores is an inevitable consequence of repeat neuropsychological

assessment. Consequently, it is possible that such practice effects could mask cognitive

deterioration and lead to the erroneous conclusion that cognition is unaffected, or even

improves following CABG surgery. Chapter 5 sought to examine the learning effects in

healthy, mature adult volunteers on a range of neuropsychological measures tapping a

number of cognitive domains. After an initial session the test battery was re-administered

to a sample of healthy volunteers five weeks, and thirteen weeks later. Large gains

(practice effects) were observed for tasks assessing verbal fluency, response inhibition,

psychomotor speed, and verbal working memory, but not visuospatial skill, cognitive

flexibility, or any aspect of learning and memory. The extent of practice effects varied

across assessment times and cognitive measures. Although not specifically evaluated,

practice effects were absent among learning and memory measures that employed alternate

forms (MCG figures, RAVLT, SDMT). In contrast, significant gains were observed on

tasks tapping executive function despite the use of alternate test versions at each assessment.

Without exception, significant gains were more readily detected in those tasks with better

reliability.

In summary, the findings from this initial study (chapter 5) showed that: 1) practice effects

occur differentially across cognitive domains; 2) these effects are not necessarily attenuated

through use of alternate forms (for tasks susceptible to test-specific improvement, or those

258

reliant on novelty); 3) improvements can extend beyond two test sessions; and 4) rates of

change may also be influenced by test reliability, with gains more easily detected in reliable

measures.

These results provide further evidence that there are complex issues associated with repeat

testing. Furthermore, it can be concluded that pre-baseline testing, use of alternate forms,

or a single correction factor across individuals or measures, do not adequately deal with

these issues, and more refined approaches for evaluating cognitive change are necessary.

Moreover, inclusion of a neurologically healthy control sample is vital when examining

neuropsychological changes over time and attempting to tease apart the effects of injury,

disease, or intervention from methodological factors associated with serial

neuropsychological assessment.

Presurgical cognitive sequelae in candidates for CABG surgery.

In order to establish whether on-pump CABG plays a causal role in the aetiology of

cognitive impairment, it was necessary to understand the cognitive status of patients before

surgery. Chapter 6 was specifically devoted to exploring the pre-surgical

neuropsychological functioning in cardiovascular diseased patients awaiting CABG surgery

while accounting for the likely effects of emotional state in the surgical group.

The principal finding in this study (chapter 6) was that cardiovascular diseased patients due

to undergo CABG surgery show specific impairments in verbal memory and cognitive

flexibility. Cardiovascular disease that is severe enough to warrant surgical intervention is

259

associated with important neuropsychological deficits and weaknesses. Importantly, these

impairments were shown to be independent of demographic or mood state factors. This

provides evidence that disease factors, rather than non-organic factors, contribute to

cognitive impairments. That is, observed impairments appear not be an artefact of pre-

surgical anxiety, stress, or depressed mood.

Post-operative cognitive sequelae: General CABG.

Chapters 7 and 8 sought to determine whether there is any cognitive benefit to avoiding the

use of cardiopulmonary bypass, and performing surgery on the beating heart. This was

done by examining the relative cognitive performance between patients who were

randomly assigned to on- or off-pump CABG at 1, 3, and 12 months after surgery.

Irrespective of surgical technique, patients who underwent CABG showed significantly

poorer than expected cognitive performance across multiple cognitive measures (chapters 7

& 8). Impairments seemed to reflect a fairly global reduction of cognitive functioning,

with verbal learning, verbal memory, speed of information processing, and verbal fluency

affected in the acute post-operative phase (1 and 3 months). Results of the long-term

follow-up study (chapter 8) indicate that many of these impairments persist (verbal learning,

verbal memory, and speed of processing), and remain evident even 12 months after surgery.

Collectively, these results suggest that heart surgery or surgery in general seems to reduce

several aspects of cognitive functioning, and that patients continue to demonstrate objective

weaknesses in test performance many months after undergoing CABG surgery.

260

Contrary to prediction, CABG patients also showed stronger than predicted performance on

some measures of executive function, at both 1 and 3 months post-operatively.

Improvements in executive function, therefore, exceeded the rates of change observed in

healthy participants. This apparent enhancement in cognitive performance may have

occurred due to the regression equations having been built using physically healthy and

slightly less anxious individuals who did not undergo any intervention. This may reflect

recovery of functioning associated with the alleviation of symptoms of heart disease and

possible improvement in blood flow. Given the absence of a negative practice effect

(chapter 5) on these tasks within the healthy control group, it is unlikely that observed

improvements on some executive tasks arose because of such phenomena. Moreover, it is

unlikely that resolution of preoperative anxiety can account for these improved

performances, given that anxiety did not contribute substantially to preoperative cognitive

impairments.

Post-operative cognitive sequelae: on- vs. off-pump CABG.

The results of chapter 7 revealed acute and differential patterns of cognitive performance

among patients who received either on-pump, or off-pump CABG. The on-pump method

was associated with deficits in executive functioning and psychomotor processing speed 1

month after surgery (chapter 7). In terms of incidence, impairment occurred more

frequently following on-pump than off-pump CABG in verbal working memory. These

group differences did not entirely resolve by 3 months, and the on-pump group showed

poorer mean performance (predicted-obtained discrepancy) than the off-pump group, on

measures of psychomotor speed and inhibition. However, only the speed of processing

261

measure met the criteria for impairment (obtained performance significantly lower than

predicted performance) at 3 months (chapter 7). By 12 months, there were no significant

group differences for any of the cognitive scores (chapter 8).

Collectively, the findings across chapters 7 and 8 produced evidence for significant,

demonstrable dysfunction specifically after on-pump CABG in the early post-operative

phase (1 and 3 months), which became undetectable 12 months after surgery. Thus, while

there appeared to be an acute cognitive benefit of avoiding cardiopulmonary bypass, the

current findings did not demonstrate any notable long-term advantage of off-pump CABG.

Comparison of the methods of identifying neuropsychological impairment.

When rates of impairment were examined, the domains most sensitive to impairment

appeared broadly consistent with the pattern of findings in the average group means as a

whole. Specifically, the domains most affected were verbal learning and memory, and

verbal fluency. There were some differences in the rate of impairment across the two

criteria employed (predicted-obtained versus adjusted RCI), with the results slightly

favouring the predicted-obtained method. That is, at each follow-up, impairment occurred

more frequently when the predicted-obtained approach was used compared with the RCI

method. This is reassuring with regard to the rationale behind the use of the regression-

based approach – and the additional factors that it is believed to account for in detecting

cognitive change over time. However, there was only one instance where this approach

outperformed the RCI method when the individual surgical groups were examined; with

significantly more on-pump than off-pump patients demonstrating impairment on one

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measure (KHMT) according to the predicted-obtained method but not the RCI method at

one month. There was also a similar trend at 12 months, whereby speed of processing

impairment was more likely to be detected in the on-pump group using the predicted-

obtained method over the RCI approach, χ2 = 3.59, p = .06.

Taken together these findings suggest that these approaches performed fairly consistently in

their ability to detecting cognitive impairment. However, there was some support for the

additional sensitivity afforded by the predicted-obtained approach over the RCI method,

suggesting that there may be an advantage in accounting for individual differences and

other factors when examining post-operative neuropsychological functioning. Overall,

both approaches are simple to apply, and appear to deal with the most critical issues in

evaluating cognitive changes - practice effects and test reliability.

Methodological Strengths and Limitations

In order to put the results and their potential implications in context, it is necessary to

review the common methodological flaws avoided in the design of the present research

project but at the same time acknowledge the limitations of this study.

Study design plays a critical role in informing us of the strengths and weaknesses within

each study, in terms of being able to address the questions of interest. Across the literature

reviewed, the methodology has varied in important ways. The interpretation of the findings

within many of these studies has often been clouded by methodological shortfalls including

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non-random allocation to treatment groups and absence of control samples, variable and

limited testing times, failure to adequately account for important factors such as differential

practice effects, the influence of mood state, and test-reliability. Furthermore, the widely

criticized diverse criteria, used to define cognitive impairment within the CABG literature,

have undoubtedly contributed to the discrepant findings (Mahanna et al., 1996; Roach et al.,

1996). Collectively, the methodological limitations have limited conclusions that could be

drawn from the existing research in this field. Each of these issues is now discussed in the

context of the research presented in chapters 5, 6, 7, and 8.

Sample biases and randomization.

Chapter 3 raised the important issue of randomisation in study design. Potential critical

confounds can be introduced to the data when individuals are not randomly allocated to

treatment groups (i.e. the independent variable of interest). When such confounds exist,

any changes in the outcome of interest cannot validly be attributed to manipulation of the

independent variable. Such threats to internal validity within CABG research might

include systematic differences between patients who receive on-pump compared to off-

pump CABG.

In support of this, it is well documented that characteristics such as pre-surgical cognitive

ability, disease severity, existence of co-morbid illness, or mood disturbance, modulate

post-operative changes in cognition (Browne et al., 2003; Malherios et al., 1995; Stroobant

et al., 2002; Taggart et al., 1999). If these potential confounds are not acknowledged in

study design, it is difficult to give causal credit to the effect of interest.

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By holding nuisance variables constant across samples or conditions within the study their

effect can be easily neutralised. Although this can be done a number of ways (e.g.

statistically covarying for influence, matching samples on some characteristic of interest),

one of the soundest ways of doing this is through random allocation to treatment groups.

For this reason, in the present series of studies, patients who were deemed eligible for

CABG surgery (either on- or off-pump) were randomly assigned to treatment group. By

randomly assigning patients to the two surgical methods, we can be assured that no

systematic differences are built in to each group, and that the groups are equivalent in all

other ways.

Across chapters 7 and 8, it can be seen that random allocation resulted in largely equivalent

groups (see Table 7.3., p. 180, Table 7.8., p. 189, & Table 8.1., p. 230). With the exception

of one measure of fluid reasoning (Raven’s Standard Progressive Matrices), those

participants randomly allocated to on- or off-pump CABG, who remained in the study at 1

and 3 months, did not differ in terms of demographics or estimated premorbid. Specifically,

the off-pump participants who remained in the study at 3 months demonstrated better

performance on Raven’s Standard Progressive Matrices, than those who had been allocated

to the on-pump group. Unfortunately, by the 12 month follow-up, the demographic

characteristics of the randomised groups were no longer equivalent. Of those assessed at

this final follow-up, participants who had been randomly assigned to the off-pump

procedure had higher estimated premorbid functioning, and higher pre-surgical fluid

reasoning scores than those who had received the on-pump method. Given that

performance on these measures was built into the analysis as predictors of post-operative

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cognitive performance, it is unlikely that it has exerted any significant influence on the

findings.

Issues associated with repeated neuropsychological assessment.

The most common and reliable way to measure impairment following a procedure such as

CABG is using a repeated measures, longitudinal design to evaluate changes in cognitive

test performance from baseline (Lewis, Maruff, & Silbert, 2004; Murkin et al., 1997).

While cross sectional comparisons at post-test can explore the relative performances

between groups (e.g. on- vs. off-pump, or CABG vs. controls), measuring change in test

scores over time adds valuable and relevant information about the effect of the intervention

and the extent of cognitive change. To highlight, a post-operative difference between

CABG patients and controls tells us little about the cause of this difference, unless we can

demonstrate that this difference was not evident prior to surgery. To do this requires a

longitudinal approach and both pre- and post-test assessments. As demonstrated in chapter

6, candidates for CABG surgery perform differently on cognitive assessment to age-

matched healthy controls. That is, even before surgery, differences can exist (Ernest,

Murphy, et al., 2006; Keith et al., 2002; Rankin et al., 2003; Selnes et al., 2009). Thus,

previous studies that have focused predominantly on the incidence of impairment post-

operatively to conclude that CABG surgery is associated with cognitive impairment may be

misleading. Moreover, as reviewed in chapter 5, individual differences in ability and other

factors (such as age) can interact with other test factors and influence the patterns of change

over time. Investigations of changes over time (longitudinally), must therefore account for

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any such differences that might be apparent at baseline before a valid interpretation of

changes in test scores, or post-test performance, can be made.

While longitudinal design allows for both intra-and inter individual comparisons, there are

some potential problems inherent in investigations of long-term changes in cognition that

rely on serial neuropsychological assessment. In brief, cognitive scores may vary in the

absence of true change, purely as a consequence of both imperfect test-rest reliability

(Barnett et al., 2005; Raymond et al., 2005), and practice effects (Beglinger et al., 2005;

Benedict & Zgaljardic, 1998; Chelune et al., 1993; Collie et al., 2003; McCaffrey et al.,

1992; Rabbitt et al., 2001).

As discussed in chapter 3, distinguishing real change from artefactual change is extremely

challenging when examining subtle differences in cognitive test results. Scores can vary

due to regression to the mean (where more extreme scores become less extreme at re-test),

and as a result of practice effects. Therefore an appropriate definition of decline, that

determines whether change is greater than normal variability or improvement (given

individual differences), is essential. This will be dealt with in greater detail in a later

section of this discussion.

One sensible way of determining the impact of factors such as practice effects, test

reliability and associated regression to the mean is to examine these changes in an

appropriate control sample (Browne et al., 1999; Venes & Ore, 2002). Forming the basis

for chapter 3, a sample of adults age-matched with the CABG candidates from the

subsequent chapters, were assessed with the same test battery, at equivalent retest intervals

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to those in the CABG study (chapters 6-8). From this investigation, normative data could

be derived, which was used to evaluate the existence of cognitive impairment following

CABG surgery.

To capitalise on the benefits of a repeated measures design, and interpret the changes in test

scores, it is necessary to ensure that these influences are acknowledged and accounted for

in clever design and appropriate analysis (Murkin et al., 1995; Murkin et al., 1997). The

Statement of Consensus on Defining Dysfunction Following Cardiac Surgery (J.M. Murkin

et al., 1997) recommends the use of change scores and highlights the need to consider

practice effects in the analysis of change scores. In order to establish a threshold for such

change that represents meaningful dysfunction, some estimate of variability within the

population is required (Collie et al., 2002; Murkin et al., 1997).

Despite this recommendation, many studies to date have failed to account for such

influences (Chernov et al., 2005; Diegler et al., 2000; Jensen et al., 2006; Lee et al., 2003;

Lloyd et al., 2000; Lund et al., 2003; Stroobant et al., 2002; Van Dijk et al., 2002), while

others have used single correction factors in an attempt to address these issues (Baker et al.,

2000; Kneebone et al., 1998; Lewis et al., 2006).

One aspect of the current research project specifically evaluated the nature of cognitive

changes and test reliability in a sample of healthy older adults (chapter 5). In addition,

these data were later used to derive ‘continuous norms’, from which CABG patients’

changes in cognitive test performance were evaluated.

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It is acknowledged, however, that the control sample used in the current project reported

higher-levels of education, and scored higher on estimates of premorbid IQ and current

fluid reasoning. The use of regression equations to predict post-operative scores should

account for, and essentially partial out the impact of any such group differences in post-

operative cognitive performances. The significant attrition within the control sample by 12

months unfortunately limits the conclusions that can be drawn from the absence of effects

at 12 months. However, that there was no significant improvement in test performances

following the acute decline (i.e. from 3 to 12 months) within the CABG group provides

some evidence against ‘recovery’ of function at this time.

Timing of post-operative assessments.

From review of the literature in chapter 1, it would also seem that the reported existence or

extent of cognitive dysfunction reported is also dependent on the timing of post-operative

assessments. Several researchers have suggested that the incidence of impairment is most

pronounced within the acute stages of recovery from CABG. In accordance with this, the

Statement of Consensus on Assessment of Neurobehavioral Outcomes After Cardiac

Surgery (Murkin et al., 1995), suggests that at least one assessment should occur after 3

months.

Of the studies reviewed throughout this thesis, many have limited their assessments to the

acute (Jacobs et al., 1998; Rasmussen et al., 1999; Taggart et al., 1999), or very early acute

post-operative period (Bendszus et al., 2002; Kneebone et al., 1998; Müllges et al., 2000).

Additionally, early post-operative changes were not explored in some studies (McKhann,

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Goldsborough, et al., 1997; McKhann et al., 2005; Selnes, Goldsborough, Borowicz, Enger,

et al., 1999; Selnes et al., 2001), and few extended their assessments beyond 6-12 months

(Newman et al., 2001; Selnes et al., 2001). Given this variability across studies, it is

difficult to draw sensible conclusions about the true temporal nature of changes.

Marked declines were typically limited to studies that examined only early changes in post-

operative cognitive functioning (Bendszus et al., 2002; Hammon et al., 1997; Kneebone et

al., 1998; Müllges et al., 2000), whereas less dysfunction or improved cognition was more

typical in studies that did not investigate early post-operative changes (McKhann,

Goldsborough, et al., 1997; McKhann et al., 2005; Selnes, Goldsborough, Borowicz, Enger,

et al., 1999; Selnes et al., 2001). It would seem that the timing of post-operative

assessments plays an important role in determining the extent of post-operative cognitive

decline.

The current study employed both early, late acute, and longer-term follow-up times after

initial baseline testing, to examine the temporal changes in cognitive function. It was not

feasible to evaluate cognitive function in the present project beyond 12 months due to

practical time-constraints.

Definition of decline & statistical criteria for evaluating cognitive changes.

As discussed above, and earlier in chapter 3, distinguishing real change from random

variability and change that is due to repeat exposure to test materials is extremely

challenging when examining subtle differences in cognitive test results. Scores can vary

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due to regression to the mean (where more extreme scores become less extreme at follow-

up) and due to practice alone. Therefore, appropriate definition of decline that determines

whether changes exceed normal rates of improvement and ordinary variability is essential.

Within the literature, there is no agreement on how best to capture decline associated with

CABG surgery. An assortment of methods have been presented, with the prevalence of

decline varying considerably across these criteria (Blumenthal et al., 1995; Kneebone et al.,

1998; Mahanna et al., 1996). The magnitude of change that would be required to infer

cognitive dysfunction following CABG is yet to be conclusively demonstrated.

The three most commonly employed criteria are as follows;

1. The 20% method

2. Standardization cut-off method (1 SD, and Z score cut-offs)

3. Reliable Change Indices

To recap, according to the “20% decline” method, cognitive dysfunction would have

occurred if a patient’s post-operative test score had declined by at least 20% of the group

mean preoperative score. The 20% method is complicated by the fact that larger declines

would be necessary for individuals who performed more strongly at baseline than those

with relatively poorer baseline performance. For example, a drop of 2 points would not

meet the criteria for impairment for an individual with a baseline score of 20, but would in

a person who scored only 10 at baseline.

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Similarly, the “1 SD” method necessitates a drop of at least one standard deviation unit

from group mean baseline performance to define impairment. This method is anchored to

the reference sample and therefore not generalisable, and is particularly problematic when

baseline scores are low to begin with (Mahanna et al., 1996). Up to one third of Mahanna

et al.’s sample scored beyond one standard deviation below the mean prior to surgery, and

was therefore potentially misclassified at follow-up.

An extension of this, the Z score approach, also standardizes scores by dividing

performance by either the standard deviation of baseline performance or of a control

sample. When an individual’s Z score (mean-score/standard deviation) exceeds a

predetermined cut-off (i.e. 1.96 to reflect the lowest 2.5% of the sample), then impairment

is inferred.

While simple to apply, these methods produce arbitrary cut-offs that do not account for the

influences of random error, measurement error and regression to the mean, or practice

effects. Moreover, there is very little consensus on how to apply these methods across

studies: Some have required a drop in only one measure (Shaw et al.1986), whereas others

have limited the definition to deteriorations of on two or more tests, a composite score

(Abildstrom et al., 2000; Lowe & Rabbitt, 1998; Moller et al., 1998; Rasmussen et al.,

2001), or 20% of tests (Mahanna et al., 1996). There are also differences in whether scores

were standardized against baseline performance, post-operative performance, or change

scores.

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When multiple neuropsychological measures are used, it is common for researchers to

report incidence of impairment according to some combined dichotomous outcome

measure (i.e. composite Z score). This is despite the fact that the tests employed usually

span a range of cognitive domains. From a neuropsychological standpoint, this unitary

measure makes little sense because it suggests cognitive dysfunction is one-dimensional.

Dichotomising patients as impaired or not using these arbitrary methods fails to

acknowledge, or account for, expected changes due to repeat test administration (Ernest et

al., 2006; Kneebone et al., 1998). On the other hand, examining mean change scores over

time (and comparing these between groups or between retest intervals) can produce

misleading information because deterioration in one individual may be offset by

improvement in another. It is therefore essential to somehow account for the test-retest

issues (random error, regression to the mean, practice effects) at an individual level when

determining whether impairment has occurred.

One approach, which has attempted to overcome the problems inherent in using arbitrary

cut-offs, is a Reliable change index which was first applied to the CABG literature by

Kneebone and colleagues (Kneebone, Andrew, Baker, & Knight, 1998). An RCI is

essentially a confidence interval within which scores would reasonably be expected to vary

due to measurement error. These intervals can be further adjusted for a set amount of

practice, thereby capturing the variability within scores that should occur due to retest

effects even in the absence of true change. Patients are classified as impaired when their

change scores (post-operative minus preoperative difference) fall outside of this interval.

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Unlike the previous and more commonly applied methods, this approach is well grounded,

and takes considered steps towards addressing the issues of measurement error, regression

to the mean and practice. However, this method controls for practice using a set, single

correction factor, which doesn’t allow for the complexities in rates of change that we know

occur with different levels of baseline function, intelligence, and age (Rabbitt et al., 2004;

Rabbitt et al., 2001; Rabbitt & Lowe, 2000). As yet, the approaches used to define

cognitive impairment in CABG patients have not fully accounted for the complex issues

associated with repeat assessment, and reliance on the more arbitrary approaches continues

(Hernandez et al., 2007; Jensen et al., 2008; Knipp et al., 2008).

Predicted Versus Obtained Test Performances: A Novel Approach to Post-CABG

Cognitive Dysfunction

The statistical approach and design within the studies forming this thesis expected, and

specifically accounted for, the influence of these factors at follow-up. In particular, this

approach simultaneously dealt with measurement error, regression to mean, and differential

practice effects. Specifically, test-retest data from the control sample were used to develop

regression equations that were employed to predict CABG patients’ post-operative test

performance based on each individuals pre-surgical cognitive performance, demographics,

and estimated premorbid IQ. Predicted performance was then contrasted with patients’

obtained test scores to determine whether post-operative cognition was significantly lower

than would be expected (i.e. reflecting impairment). This method simultaneously accounts

for differences in pre-surgical ability, regression to the mean and test reliability, and

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practice effects and the effect of individual differences on the trajectory of change over

time (including practice effects). Thus, it provides a more ‘pure’ representation of change

that is not limited by arbitrary boundaries that are present in those methods that

dichotomise cognitive dysfunction. This is the first study to employ such an approach in

the evaluation of cognitive changes following CABG surgery.

Although this has been done on an individual case-study level (Crawford & Howell, 1998;

Crawford & Garthwaite, 2006) a current formulation of how to do this at the group level

was limited. One of the central questions in the current project was whether CABG

surgery results in meaningful cognitive impairment. As such, based on the principle of

evaluating predicted-obtained differences promoted by Crawford and colleagues (Crawford

& Garthwaite, 2006; Crawford & Howell, 1998b), the mean predicted-obtained discrepancy

of the CABG sample was compared with an expected discrepancy of zero. When we want

to make an inference about whether the discrepancy between predicted and obtained scores

within our group, as a whole, represent a meaningful difference and not just the result of

random variation, the independent samples t-test is appropriate. We can be confident, that

the observed discrepancies within the current CABG sample are unlikely to have occurred

by chance.

Tully and colleagues (2008) are the first published study to employ this approach within the

CABG literature, and specifically the neuropsychological outcomes following on- versus

off-pump CABG. While their landmark trial makes significant gains in overcoming the

methodological shortfalls within the literature, their approach did not appear to account for

additional error that arises from using regression data from a control sample to estimate

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population regression coefficients and predict outcome in a separate sample (Crawford &

Howell, 1998b). Particularly within smaller samples, such as those reported in Tully et al.’s

paper and those in the current thesis, this may result in narrower confidence limits, and a

less stringent criterion. The current approach attempts to account for this by adjusting the

standard error when evaluating members from a group other than the regression sample

(Crawford & Howell, 1998; Crawford & Garthwaite, 2006).

One potential limitation within the present series of studies was the gender distribution

between the CABG patients and controls. In general, females were underrepresented in the

cardiovascular diseased CABG surgery patients whereas males and females were equally

represented in the control sample. To what extent this is likely to influence

neuropsychological test performance is controversial (Hobson, 1961; Jackson, 2006;

Lachance, 2006; Rizk-Jackson, 2006). The existence of gender differences across a range

of cognitive domains in older adults (de Frias et al., 2006) was cause enough for concern.

Therefore, gender was included as a predictor variable in the regression analyses for

chapters 5 and 6, in an attempt to minimise any gender bias. On this basis, it is unlikely

that the observed differences between our samples can be attributed to gender effects.

Mood and its Influence on Neuropsychological Test Performance

Undergoing major surgery, such as CABG, is undoubtedly a significant life event for most

individuals. It is not uncommon for candidates for CABG surgery to report higher than

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normal symptoms of mood disturbance (Andrew et al., 2000; Keith et al., 2002; Tsushima

et al., 2005).

Given that elevated anxiety and depression are known to influence neuropsychological test

performance, particularly in older adults (Deptula, Singh, & Pomara, 1993), mood changes

in CABG patients would be expected exert some influence on test scores and therefore on

the likelihood of impairment after surgery (Blumenthal et al., 1995 White, Croughwell, &

Newman, 1995). Despite this, many studies have not acknowledged this possibility, and

therefore have not measured changes in mood in their investigations of post-CABG

cognitive dysfunction (Baker et al., 2001; Diegler et al., 2000; Mahanna et al., 1996;

Rankin, et al., 2003; Stroobant, et al., 2002; Zamvar et al., 2002). In studies that have

specifically examined the relationship between mood status and changes in cognitive

functioning associated with CABG surgery, the findings have been unclear. Specifically,

an association between measures of mood and cognitive test performance has been reported

by some (Andrew et al., 2000) and not others (Tsushima et al., 2005). The current study,

therefore sought to include measures of current depression, anxiety and stress, and examine

the relationship between these variables and cognitive test performance.

In the current series of studies there were important relationships between elevated

symptoms of anxiety, stress and depression and cognitive test performance. In general,

elevated depressive symptomatology was associated with slower speed of processing (e.g.

TMT, SDMT) and some evidence of stronger performances on measures of verbal learning

and recall. Higher-levels of stress seemed to correlate with enhanced performance on some

speeded and executive function measures, whereas higher-levels of anxiety were correlated

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with poorer executive functions and working memory and some instances of faster speed of

processing. Given that these correlations were not observed in the control group, it is

possible that the observed cognitive impairments in the CABG sample were related to

changes in mood. These relationships are important to consider when examining the

overall changes in cognitive performance within the CABG group as a whole.

Despite persistently higher ratings of anxiety symptoms at 1 and 3 months in the CABG

sample compared to healthy controls, mood scores appeared to exert minimal influence on

differences between the two surgical groups. Explicitly, differences between the on- and

off-pump groups remained after scores on the Depression, Anxiety and Stress Scale (DASS,

Lovibond & Lovibond, 1995) were statistically controlled for. That is, with the exception

of delayed recall on the RAVLT, the findings essentially remained unchanged when

depression, anxiety and stress were controlled for. Moreover, visual inspection of the

DASS scores plotted against cognitive test results at each follow-up did not suggest the

presence of any clear non-linear relationships. Thus, we can be confident that the observed

differences between on- and off-pump were not an artefact of mood disturbance.

The possibility was raised by Andrew et al. (2000), however, that somatic symptoms (i.e.

dryness of mouth, faintness) on the same self-report measure used in the present project

were endorsed for reasons other than anxiety, stress or depression. Conversely, they may

reflect symptoms that are associated with cardiovascular disease itself, or the side effects of

pharmacotherapies.

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Implications and Future Directions for Research

In line with the stated aims, the present series of studies have implications for CABG

research, as well as neuropsychological research in general.

It would appear, from the findings outlined above, that severe cardiovascular disease

warranting surgical revascularisation is associated with significant neuropsychological

deficits (chapter 6). Essentially, objective dysfunction can arise from either structural

and/or functional deficits. That is, deficits indicate that 1) neural tissue is potentially

compromised with cardiovascular disease, either because of concomitant carotid artery or

cerebrovascular stenosis, or directly by some mechanism of reduced blood flow, or 2) there

has been some change in the processes that enable performance on a given task. While

symptoms of depression, anxiety and stress were associated with reduced performances on

some tasks, cognitive impairments could not be fully accounted for by mood disturbance

within the CABG candidates. This would indicate that disease related factors, are

responsible for the objective deficits in patients who are awaiting CABG surgery.

Given the profile of impairments, the locus of any structural damage is highly likely to

include metabolically vulnerable medial temporal structures such as the hippocampus

(Yonelinas, 2004), in addition to more diffuse white matter changes that may disrupt

fronto-subcortical networks (Cummings, 1995).

New ischemic lesions are commonly reported in over half of patients who have undergone

CABG surgery (Barber et al., 2008; Knipp et al., 2008; Kohn, 2002), though the

relationship between MRI findings and cognitive impairment remains somewhat

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controversial. For example, a number of studies (Barber et al., 2008; Restrepo et al., 2002 ),

report associations between lesion burden and new cognitive impairment in the acute post-

operative period. However, others have found no association between the presence of new

lesions and fairly high rates of cognitive impairment at much later follow-ups (Cook et al.,

2007; Knipp et al., 2004; Knipp et al., 2008).

The results outlined in the study described in chapter 6 highlight the importance of

examining, and incorporating, pre-surgical measures of functioning in any study that aims

to examine post-surgical changes in neuropsychological function.

One of the most concerning limitations to previous research within the CABG field has

been the arbitrariness of the approach to defining meaningful cognitive dysfunction. In

particular, despite clear recommendations from the Statement of Consensus on Defining

Dysfunction following cardiac surgery (Murkin et al., 1997), most have failed to

acknowledge the issues of repeat neuropsychological testing in their statistical criteria of

decline. One promising approach, which has been more theoretically grounded, was the

use of Reliable Change Indices (see Kneebone et al., 1998). This approach takes error

variance into consideration when making judgements about whether a change in test

performance from baseline to post-operative follow-up is true or artefactual. Kneebone et

al. (1998) extended this idea one step further, by also correcting for mean practice effects

derived from a control sample. While this surpasses the previous, atheoretical and arbitrary

cut-offs uses to define dysfunction, it does not fully account for the complex nature of

practice effects.

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The current project attempted to deal with the differential trajectories in practice by using a

regression-based method to predict each individuals post-operative test performance. A

comparison with predicted and obtained test scores could then be made to determine

whether the group, as a whole, had performed as expected. When the discrepancy between

predicted and obtained scores was significantly greater than anticipated, impairment could

be confidently inferred.

Using this novel approach, the most salient finding from the randomised controlled study

described in chapters 7 and 8 indicate that the on-pump method can induce selective, yet

meaningful neuropsychological change. Given that cognitive deficits were not observed in

the on-pump group at 12 months, the hypothesis that off-pump is neurologically and

cognitively protective in the long-term cannot be supported. These findings partially

support the hypothesis that CABG surgery, particularly when performed using

cardiopulmonary bypass can affect the integrity of neurological tissue, and thereby disrupt

neuropsychological function. That is, the use of the pump exerts a specific, albeit mild,

injurious effect on cognitive functioning. This effect also exceeds the detrimental apparent

general effect of undergoing a cardiac procedure, although it appears to be only evident

within the first few months after surgery. It is acknowledged, however, that the

interpretation of the long-term follow-up study (chapter 5) is restricted due to a small

control sample relative to the surgical groups. Further investigations that attempt to

address the long-term cognitive changes associated with on- and off-pump CABG are

indeed necessary to characterise the effects of CABG surgery. These will need to address

the complicated issues associated with serial neuropsychological assessment, and employ

sensible statistical criteria by which to define meaningful cognitive change.

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Contrary to predictions, the findings also suggest that the off-pump procedure can be

associated with cognitive decline. The finding of a relative weakness in delayed verbal

memory, specific to the off-pump group, once the impact of mood was statistically

controlled is not without precedent (Baker, Andrew, Ross & Knight, 2000). A specific

deficit following off-pump CABG raises the possibility that neurological function may be

compromised by some different mechanism when this surgical approach is used (Stroobant

et al., 2002; Taggart & Westaby, 2001). Hemodynamic instability, associated with the off-

pump procedure, is one possibility (Watters et al., 2001). Studies incorporating baseline

and post-operative functional neuroimaging may provide some insights into this.

The current results also provide partial support for the use of the predicted-obtained

regression-based approach, over the RCI method in detecting post-operative

neuropsychological impairment. While the adjusted RCI approach has been effectively

employed in the CABG literature to deal with issues of re-testing, current findings suggest

there may be an added benefit in accounting for the likely differential impact of other

individual variables (such as individual differences) in longitudinal studies of cognitive

change. This requires replication within both the CABG, and broader neuropsychological

literature. If the findings are replicated, there are important future implications for

stratifying patients’ risk of post-operative impairment, and there may be scope to

investigate the application of theories regarding neural and cognitive reserve (Stern, 2007)

in this setting.

Cognitive reserve refers to the notion that individuals with a larger neural capacity may

have additional resources that could provide for better compensatory skills and therefore

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mask or delay features of impairment following brain insult. The relationship between

markers of reserve (e.g. estimated pre-morbid IQ, together with educational and

occupational attainment) and post-CABG cognitive change could easily be explored using

regression analyses. Additionally, with a sufficient sample, moderating factors such as

microembolic load, intra- and post-operative perfusion and length of anaesthesia could be

incorporated as moderator variables to examine their relative influence.

One unfortunate limitation within the current project was the apparent difference in years of

education and estimated premorbid IQ in controls relative to the CABG groups. This may

have affected the predictions made for the CABG group post-operatively that formed the

basis for evaluating whether cognitive deterioration had occurred. Technically, predictions

based on regression equations built from a sample are only applicable to that sample, unless

an appropriate adjustment is made for the prediction intervals around the regression slope

(see Crawford & Howell, 1998b). This is likely to have been particularly problematic for

the 12 month follow-up, given the very small sample used to derive the regression

equations. Future work should extend the present work, by employing a larger control

group, and ensure they are more adequately matched to experimental samples.

The choice of neuropsychological measures was largely based on the Statement of

Consensus criteria (Murkin et al., 1997) and the published literature within the field to date.

Given the apparent vulnerability of memory, processing speed and executive functions

within the current sample, there is scope to further refine the assessment battery. In

attempting to provide a measure of visuospatial skill and visuospatial memory with

sufficient control of ‘item-specific’ practice effects, the current study selected the Medical

283

College of Georgia Complex figures. However, based on the findings reported in chapter 5

the data from this component of the assessment were not considered reliable. This resulted

in omission of potentially important neuropsychological information relating to two distinct

cognitive domains.

The finding of collective deficits in the combined CABG group would suggest that factors

associated with the general CABG procedure, irrespective of surgical method, could give

rise to persisting cognitive dysfunction. In the absence of a general, non-CABG surgical

control group, it is only possible to speculate on the cause of such effects. One possibility

is general anaesthesia (Abildstrom, Rasmussen, Rentowl, Hanning, Rasmussen, Kristensen,

Moller, 2000). Indeed, long term postoperative cognitive dysfunction has been well

documented in older persons who have undergone non-cardiac procedures (Abildstrom et

al., 2000; Moller et al., 1998; Rasmussen et al., 1999; Rasmussen et al., 2003; Rasmussen

et al., 2001). However, a systematic review (Bryson & Wyand, 2006) reported no

compelling evidence for differences in cognitive outcome following randomisation to

regional or general anaesthetic regimens, suggesting that general anaesthesia may not be

primarily responsible for impairment. Bryson and Wyand (2006) hypothesise that age, and

extent of physiological stress (associated with the type of procedure), or pre-operative

medication use might moderate the degree of post-operative impairment. Further

investigations that specifically examine the potential influence of pre-operative medications,

known to modify cholinergic and dopaminergic activity (Agostini, Leo-Summers, &

Inouye, 2001; Trzepacz, 2000), on cognition following both cardiac and non-cardiac

surgery may improve our understanding of the mechanisms behind the phenomenon of

Post-operative Cognitive Dysfunction (POCD; Abildstrom et al., 2000).

284

Alternatively, patients who undergo CABG are likely to have broader chronic ischemic

vascular disease including cerebrovascular illness. As time progresses, so does the

cognitive impact of this. In support of this view, Selnes et al. (2009) reported generally

equivalent rates of cognitive change among cardiovascular diseased patients treated non-

surgically compared with both on- and off-pump CABG over a 72 month follow-up.

Compared to healthy controls, cardiac patients (irrespective of treatment used) showed a

biphasic cognitive decline, with deterioration occurring more rapidly from 12 to 72 months

compared with the change from baseline to 12 months.

Future research could also compare objective cognitive assessment with subjective ratings

of post-operative cognitive change by patients and their loved ones. Within the broader

neuropsychological literature, there is evidence for poorer test performance among those

who complain of cognitive difficulties compared to those who do not (Chamelian &

Feinstein, 2006; Marrie, Chelune, Miller, & Cohen, 2005). Some authors argue that

subjective complaints are almost solely attributable to significant mood disturbance

(Chamelian & Feinstein, 2006; Maor, Olmer, & Mozes, 2001), whilst others have shown

impairments persist even after controlling for mood (Kinsinger, Lattie, & Mohr, 2010;

Marrie et al., 2005).

With regard to serial assessment, the finding of differential patterns of change over time,

within a neurologically healthy sample of older adults, has implications for broader

neuropsychological research and clinical practice. Better understanding the nature of

changes across measures, cognitive domains, and individuals will guide us to consider

expected changes when we endeavour to assess cognitive changes over time.

285

Acknowledgement of the magnitude and duration of such improvements and the

interactions of ability, age, test reliability, and efficacy of alternate forms warrants more

detailed investigation. The current project has attempted to apply the intuitively useful and

simple method of regression in order to account for statistical artefacts related to test

reliability, and differential rates of practice across individuals. Crawford and colleagues

(Crawford & Howell, 1998; Crawford & Garthwaite, 2006) have been strong advocates of

this approach at a single case-study level. Moreover, they have developed a computerised

program (regdisclv.exe, available http://www.abdn.ac.uk/~psy086/dept/psychom.htm) that

analyses the discrepancy between scores predicted using regression equations from scores

obtained on testing.

Conclusions

In conclusion, this series of studies set out to investigate the neuropsychological sequelae

associated with two methods of CABG surgery (on-pump and off-pump). Highlighting one

of the major limitations within the previous CABG literature, it was first shown that

repeated assessment of individuals yields changes as a result of statistical artefacts (related

to test reliability) or because of prior exposure to test items or task demands (practice

effects). Independent of the effects of elevated anxiety, stress or depression, specific verbal

memory impairment was demonstrated among candidates for CABG surgery prior to

admission. Follow-up studies from a randomised trial of two CABG procedures (on-pump

and off-pump) produced marginally favourable results for the off-pump method over the

“gold standard” or traditional on-pump technique.

286

Previous controversy has existed as to whether the apparent physiological advantages of the

off-pump method (including less embolisation and better cerebral perfusion) would

translate into tangible neuropsychological benefits that could justify revision of

standardised operating procedures in Australian hospitals. The current findings offer some

support that off-pump CABG is offers some protection against neurological insult, and that

there are neuropsychological costs associated with on-pump CABG. Fortunately, the

deficits associated with on-pump CABG are largely resolved by 3 months, although CABG

procedures were associated with a global dampening that lasted across both 1 and 3 months.

287

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Appendix A

Table A.1.

Test-retest reliability, Reliable change Cut-off, correction for practice effect, and corrected RCI across measures at 1m.

Cognitive Domain Variable Test-retest

(BL to 1m)

p or r

Reliable Change

(90%cut-off)

Correction for

Practice

Corrected RCI interval

SDMTa 0.76 ±10.33 +2.00 -8.33 12.33 Speed of

Processing TMTba 0.50 ±18.86 +4.02 -14.84 22.88

Working Memory KHMTc 0.82 ±3.34 +1.24 -2.10 4.58

Verbal Memory

Learning RAVLTd Total 0.62 ±13.87 +1.89 -11.98 15.76


0.52 ±4.52 +0.33 -4.19 4.85

Executive Function

Fluency COWATe 0.67 ±12.79 +4.68 -8.11 17.47

Inhibition Stroop Task 0.75 ±50.86 +10.09 -40.77 60.95

Cognitive Flexibility TMTb

ratio 0.32 ±1.49 -0.16 -1.65 1.33


bTMT

, Trail Making Test

(R. Reitan, M, 1958);



eCOWAT, Controlled Oral Word Association Test

(Benton et al., 1994);

318

Table A.2.


Variable Test-retest

(BL to 1m)

p or r

Reliable

Change

(90%cut-off)

Correction for

Practice


Speed of

Processing SDMT

a 0.66 ±8.80 +1.50 -7.30 10.30

TMTba

0.38 ±17.83 -2.37 -20.20 15.46

Working Memory KHMTc 0.69 ±4.26 +1.73 -2.53 6.00

Verbal Memory


Delayed Recall RAVLTd delay 0.58 ±4.53 +0.60 -3.93 5.13

Executive Function

Fluency COWATe 0.74 ±11.99 +3.73 -8.25 15.72

Inhibition Stroop Task 0.73 ±43.84 -19.27 -63.11 24.58


ratio 0.25 ±2.05 -0.12 -2.17 1.93


bTMT

, Trail Making Test

(R. Reitan, M, 1958);





319

Table A.3.


Variable Test-retest

(BL to 1m)

p or r

Reliable Change

(90%cut-off)

Correction for

Practice


Speed of

Processing SDMT

a 0.97 ±4.82 +0.17 -4.66 4.99

TMTba 0.53 ±27.86 -1.50 -29.36 26.36


0.61 ±6.61 +1.00 -5.61 7.61

Verbal Memory


Delayed Recall RAVLTd delay 0.66 ±5.23 +0.08 -5.14 5.31

Executive Function

Fluency COWATe 0.81 ±9.75 +3.00 -6.75 12.75

Inhibition Stroop Task 0.90 ±36.50 -9.25 -45.75 27.25


ratio 0.52 ±1.78 -0.37 -2.15 1.41


bTMT

, Trail Making Test

(R. Reitan, M, 1958);





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