Post on 13-Jun-2020
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
v
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
Mood State and its Relationship to Cognitive Performance .................195
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
Mood State and its Relationship to Cognitive Performance .................240
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
Comparison of adjusted RCI method and Predicted-obtained method for
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
Partial correlations between DASS scores and 1 month post-operative cognitive
scores in the off-pump group. ...........................................................................201
TABLE 7.14..................................................................................................................202
x
Partial correlations between DASS scores and 3 month post-operative cognitive
scores in the on-pump group. ............................................................................202
TABLE 7.15..................................................................................................................203
Partial correlations between DASS scores and 3 month post-operative cognitive
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
Comparison of adjusted RCI method and Predicted-obtained method for
classifying patients as impaired at 12 months...................................................239
TABLE 8.8. ...................................................................................................................244
Partial correlations between DASS scores and 12 month post-operative cognitive
scores in the on-pump group.............................................................................244
TABLE 8.9. ...................................................................................................................245
Partial correlations between DASS scores and 12 month post-operative cognitive
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
xi
Test-retest reliability, Reliable change Cut-off, correction for practice effect, and
corrected RCI across measures at 3m. ..............................................................318
TABLE A.3. ..................................................................................................................319
Test-retest reliability, Reliable change Cut-off, correction for practice effect, and
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.
Specifically, it is predicted that;
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
71
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;
Specifically, it is predicted that;
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)
- failed to attend (n = 2)
- 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)
- failed to attend (n = 2)
- distance too great to attend (n = 2)
- uncontactable (n = 6)
- 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.
77
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
83
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.
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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,
117
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.
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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
Executive functioning
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)
Median (Interquartile
range)
173.50
(44.00)
165.50
(56.00)
156.50
(54.00)
.02 a
.17 .23
Cognitive flexibility TMT
c (Ratio score)
Median (Interquartile
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).
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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.
132
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**
Executive functioning
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.
Participants enrolled into the
study
(N =108)
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)
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
Median (Interquartile
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.
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)
- failed to attend (n = 2)
- 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)
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
Inhibition Stroop Task (seconds)
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);
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);
177
Table 7.2.
Results of the regression analyses of controls at 3 months.
Cognitive
Domain
B (SE) R2 R
2 change
Dependents Intercept
Baseline Gender Age Education NART RSPM 1 2 F p
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
Inhibition Stroop Task (seconds)
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
ǂ Chi Squared analyses; FSIQ = Estimated Full Scale Intelligence Quotient.
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);
cKHMT (Kaufman & Kaufman, 1983);
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
number of words: delayed
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
number of words: delayed
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
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 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)
Inhibition Stroop Task (seconds)
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);
cKHMT (Kaufman & Kaufman, 1983);
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
(total words, trials
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
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 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
ǂ Chi Squared analyses; FSIQ = Estimated Full Scale Intelligence Quotient.
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.
Combined surgical group: incidence of neuropsychological impairment.
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
Delayed Recall RAVLTd delay (total
number of words: delayed
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
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 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)
Inhibition Stroop Task (seconds)
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)
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 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
(total words, trials
1-5)
4 (16.67)
1 (4.17)
1.56
3 (12.50)
2 (8.33)
0.22
0.48
.49
Delayed Recall RAVLTd delay
(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
Inhibition Stroop Task (seconds)
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
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 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.
On- versus off-pump: incidence of neuropsychological impairment.
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).
Mood State and its Relationship to Cognitive Performance
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.
Mean DASS scores and partial correlations with cognitive test performance at 3
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
pr (r) Control 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
(total words, trials 1-
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
Inhibition Stroop Task (seconds)
.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
Note n = 24; * 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.
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
(total words, trials
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*
Inhibition Stroop Task (seconds)
-.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
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.
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
pr (r) Control 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
(total words, trials
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
Inhibition Stroop Task (seconds)
-.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
Note n = 24; * 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.
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
(total words, trials
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**
Inhibition Stroop Task (seconds)
-.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
(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.
204
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
208
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
210
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
223
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.
Participants enrolled into the
study
(N =108)
Randomised to On-pump
(n = 32)
Randomised to Off-pump
(n = 30)
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)
- failed to attend (n = 2)
- distance too great to attend (n = 2)
- uncontactable (n = 6)
- 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
Baseline Gender Age Education NART RSPM 1 2 F p
Speed of
Processing SDMT
a (total
written score) 24.26
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
(total words, trials
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
Inhibition Stroop Task (seconds)
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
written score) 40.34
(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)
Inhibition Stroop Task (seconds)
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)
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 Test (Benton et al., 1994);
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
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 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
Working Memory KHMTc
(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
number of words: delayed
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.
Combined surgical group: incidence of neuropsychological impairment.
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
Inhibition Stroop Task (seconds)
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);
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); 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
Delayed Recall RAVLTd delay (total
number of words: delayed
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);
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); 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
(total words, trials
1-5)
0 (0)
0 (0)
-
0 (0)
0 (0)
-
-
1.00
Delayed Recall RAVLTd delay
(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
Inhibition Stroop Task (seconds)
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
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 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.
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.
On- versus off-pump: incidence of neuropsychological impairment.
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).
Mood State and its Relationship to Cognitive Performance
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
Mean DASS scores and partial correlations with cognitive test performance at 12
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
pr (r) Control Variables
r Cognitive
Domain Depression Anxiety Stress Age Education Gender RSPM
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
(total words, trials 1-
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
Inhibition Stroop Task (seconds)
.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
(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 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
pr (r) Control Variables
r Cognitive
Domain Depression Anxiety Stress Age Education Gender RSPM
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
(total words, trials
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*
Inhibition Stroop Task (seconds)
.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
(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 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
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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.
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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
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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
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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.
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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
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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.
278
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
279
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.
280
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.
281
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
282
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
Delayed Recall RAVLTd delay
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
Key: aSDMT, Symbol Digit Modalities Test (Smith, 1982);
bTMT
, Trail Making Test
(R. Reitan, M, 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);
318
Table A.2.
Test-retest reliability, Reliable change Cut-off, correction for practice effect, and corrected RCI across measures at 3m.
Variable Test-retest
(BL to 1m)
p or r
Reliable
Change
(90%cut-off)
Correction for
Practice
Corrected RCI interval
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
Learning RAVLTd Total 0.67 ±12.36 +2.77 -9.59 15.13
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
Cognitive Flexibility TMTb
ratio 0.25 ±2.05 -0.12 -2.17 1.93
Key: aSDMT, Symbol Digit Modalities Test (Smith, 1982);
bTMT
, Trail Making Test
(R. Reitan, M, 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);
319
Table A.3.
Test-retest reliability, Reliable change Cut-off, correction for practice effect, and corrected RCI across measures at 12m.
Variable Test-retest
(BL to 1m)
p or r
Reliable Change
(90%cut-off)
Correction for
Practice
Corrected RCI interval
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
Working Memory KHMTc
0.61 ±6.61 +1.00 -5.61 7.61
Verbal Memory
Learning RAVLTd Total 0.65 ±17.30 +2.50 -14.80 19.80
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
Cognitive Flexibility TMTb
ratio 0.52 ±1.78 -0.37 -2.15 1.41
Key: aSDMT, Symbol Digit Modalities Test (Smith, 1982);
bTMT
, Trail Making Test
(R. Reitan, M, 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);