Abstract

Research has shown conflicting results with regard to the influence of depression and anxiety on neuropsychological performance following coronary artery bypass graft (CABG) surgery. Notably, the independent effects of depression and anxiety have not been examined among CABG candidates in the longer term where it is has been suggested that these patients show marked cognitive deterioration. A neuropsychological test battery and measures of psychological distress were completed by 86 CABG patients and 50 nonsurgical control participants at baseline and 6 months, whereas 75 patients and 36 controls, respectively, completed a 5-year follow-up. In CABG patients, cognitive and affective depressive symptoms were independently associated with lower and worse performance on the Boston Naming Test, Purdue Peg Board, and Digit Symbol Coding 6 months after surgery, whereas at 5-year follow-up an effect for Digit Symbol persisted, and an association was also observed for the Trail Making Test (TMT). On average, CABG patients performed worse on TMT and Digit Symbol at 6 months, whereas at 5-year follow-up their performance was worse on short-term delayed verbal recall. The results among the CABG patients did not show a consistent pattern of association between psychological distress and those neuropsychological domains that were on average significantly lower than a nonsurgical control group. The results here also support the use of nonbiased statistical methodology to document dysfunction among heterogeneous cognitive domains after CABG surgery.

Introduction

Coronary artery bypass grafting (CABG) surgery is one of the most scrutinized surgical procedures and the neuropsychiatric sequelae have been exhaustively documented (Reichenberg, Dahlman, Mosovich, & Silverstein, 2007). Several studies have suggested that postoperative neuropsychological test performance is associated with cognitive deterioration 5 years after surgery (Newman, Kirchner et al., 2001; Selnes et al., 2001; Stygall et al., 2003). In contrast, other studies have suggested that this decline is modest (Müllges, Babin-Ebell, Reents, & Toyka, 2002; Nathan et al., 2007) and comparable to persons not undergoing CABG with similar cardiac risk factors (Selnes et al., 2008; van Dijk et al., 2008).

The pathophysiological mechanisms that underlie neuropsychological deterioration after CABG with cardiopulmonary bypass (CPB) are not universally agreed upon or well understood. However, the release of intraoperative gaseous and particulate microemboli, changes in the hemodynamic status of the patient, temperature management, and activation of the systemic inflammatory response have been implicated. Widespread reduction in cerebral perfusion following cardiac surgery with CPB has been observed in the frontal and parietal cortex of the right hemisphere (Chernov, Efimova, Efimova, Akhmedov, & Lishmanov, 2006) and also the left temporal lobe and occipital lobes and cerebellar hemispheres bilaterally (Lee et al., 2003). However, as recently reported, new postoperative lesions such as that identified by diffusion weighted magnetic resonance imaging may not necessarily translate to significant neuropsychological deterioration in the long term (Knipp et al., 2008).

In a similar vein to the mechanisms of cognitive decline, the statistical methodology to detect a neuropsychological change after cardiac surgery has been debated. Current review evidence has favored the adjusted reliable change index or a standardized regression-based (SRB) method over arbitrary and confounded group mean calculations such as a 20% decline in two or more tests (Raymond, Hinton-Bayre, Radel, Ray, & Marsh, 2006; Temkin, Heaton, Grant, & Dikmen, 1999). With these methodological advances established in the literature (Kneebone, Andrew, Baker, & Knight, 1998; Kneebone, Luszcz, Baker, & Knight, 2005), it is timely to consider alternative confounding factors when documenting long-term neuropsychological performance after cardiac surgery such as the high prevalence of emotional distress seen in patients with underlying cardiovascular pathology (Alexopoulos et al., 1997; Bankier, Januzzi, & Littman, 2004; Murkin, Newman, Stump, & Blumenthal, 1995; Stockton, Cohen-Mansfield, & Billig, 2000).

Clinicians will be cognizant that psychological distress can affect neuropsychological performance; however, this has not been sufficiently documented in CABG patients as a potential explanation for marked cognitive dysfunction in the longer term. The independent effect of depression and anxiety on long-term neuropsychological performance after CABG remains in question as previous studies have generally performed only correlation analyses (McKhann, Borowicz, Goldsborough, Enger, & Selnes, 1997; Newman, Grocott et al., 2001; Stroobant & Vingerhoets, 2008), analyzed a composite index of heterogeneous cognitive domains (Stygall et al., 2003), or examined early neuropsychological performance (Andrew, Baker, Kneebone, & Knight, 2000; Tsushima, Johnson, Lee, Matsukawa, & Fast, 2005). Also, previous research has not considered the substantial overlap between depression and anxiety. It is important to investigate the possibility that clinically meaningful cognitive deterioration after CABG is attributable to factors other than cardiac surgery per se as psychological distress symptoms (e.g., depression, anxiety) are potentially amenable to intervention. The implications of exploring the deleterious neuropsychological effects of cardiac surgery and the concomitant role of psychological distress in vascular diseases are vital as these impact patient quality of life, survival, and morbidity (Blumenthal et al., 2003; Mallik et al., 2005; Tully, Baker, & Knight, 2008), and the findings may help inform ongoing treatment options in these patients.

The present study had two aims, first to describe the proportion of neuropsychological deterioration, calculated with the SRB method, after cardiac surgery across heterogeneous cognitive domains (Kneebone et al., 2005). The second aim was to describe the association between psychological distress and neuropsychological functioning in cardiac surgery patients independent of the effects of cardiac risk factors and intraoperative variables. Clark and Watson (1991) have proposed that depression and anxiety share many symptoms such as concentration difficulties and irritability that are reflective of latent negative affect (NA). Therefore, it was hypothesized that general and nonspecific distress symptoms (i.e., NA) would account for neuropsychological deterioration rather than unique depression and anxiety symptoms, beyond the effects of cardiac and intraoperative variables. Second, it was hypothesized that emotional distress would be associated with neuropsychological tests tapping into executive function, verbal memory, visuomotor attention, and speed, showing little association to language and verbal fluency or manual dexterity.

Materials and Methods

Surgical Patients

Eligibility criteria for the follow-up study were ≥18 years and undergoing isolated CABG procedure with CPB at the study institution and the methods have been reported elsewhere (Andrew et al., 2001). Briefly, recruitment was between January 1996 and November 1998 and the following exclusion criteria was adopted; previous heart surgery, emergency surgery, renal disease, history of cerebrovascular disease, permanent or reversible neurological deficit, head injury resulting in loss of consciousness, English not first language, unable to complete neuropsychological assessment due to sight or hearing difficulties, history of substance abuse, residency outside South Australia for repeat assessment. Overt neuropsychiatric disease or current use of psychoactive medication was also an exclusion criteria assessed at interview and from medical records. Patients were recruited in the week preceding scheduled CABG. The CPB circuit and perfusion technique were consistent across the study period. This study received institutional ethics committee approval and all participants provided written informed consent.

Nonsurgical Control Group

The control sample was recruited from a community bowling club, a senior citizens group, and the study hospital volunteer service using the same exclusion criteria applied to surgical patients. The rationale was to provide a basis for estimating neuropsychological change in a cohort not undergoing cardiac surgery.

Patient Assessment

The neuropsychological tests administered were: California Verbal Learning Test-I (CVLT; Delis, Kramer, Kaplan, & Ober, 1987), Purdue Pegboard (PPB; Tiffin & Asher, 1948) right- and left-hand individually, Trail Making Test (TMT; Armitage, 1946), Wechsler Adult Intelligence Scale-Revised Digit Symbol Coding subtest (Wechsler, 1981), Boston Naming Test (BNT; Kaplan, Goodglass, & Weintraub, 1983), and the Controlled Oral Word Association Test (COWAT; Borkowski, Benton, & Spreen, 1967). All tests were the same throughout the study, and a parallel version of the CVLT (lists A and B) was administered on each alternative testing occasions to reduce learning effects.

The National Adult Reading Test-Revised (Crawford, 1992) was administered at baseline to provide an estimate of premorbid intellectual ability and prorated full-scale IQ (FSIQ). A short-term free recall (SDFR) memory retention score was calculated using the total words correctly free recalled after short delay divided by the number of words correctly free recalled on the last list learning trial of the CVLT. Selection of neuropsychological tests was principally to assess those domains endorsed by the Statement of Consensus of neurobehavioral outcomes after cardiac surgery (Murkin et al., 1995) and has been employed in previous research (Andrew et al., 2000; Kneebone et al., 1998; Tully, Baker, Kneebone, & Knight, 2008).

Patients and control subjects were assessed four times; baseline (preoperatively in surgical patients), at 6 days (prior to hospital discharge in surgical patients), 6 months, and 5 years. Here, only the longer term neuropsychological outcomes were analyzed given that within hospital cognitive performance is influenced by many transient perioperative factors such as pain, anesthesia, and the hospital environment (Murkin et al., 1995).

Psychological distress symptoms were assessed with the self-report Depression Anxiety and Stress Scales (DASS) and readers unfamiliar with this instrument are referred elsewhere for review (Lovibond & Lovibond, 1995a). Higher scores on this 42 item measure indicate higher distress over the course of the previous week. The three respective scales of the DASS have been shown to reflect three independent factors of cognitive and affective depressive symptoms (e.g., anhedonia, dysphoria) and autonomic anxiety and anxious affect (trembling, situational anxiety), with stress symptoms a marker of NA (e.g., irritability, relaxation difficulty), the symptoms of which are shared between depression and anxiety (Brown, Chorpita, Korotitsch, & Barlow, 1997; Clara, Cox, & Enns, 2001; Tully, Zajac, & Venning, 2009). Examples of depression scale items include “I couldn't seem to experience any positive feeling at all” and “I just couldn't seem to get going.” The anxiety scale contains such items as “I felt scared without any good reason” and “I felt I was close to panic.” The stress scale includes items such as “I tended to over react to situations” and “I found myself getting impatient when I was delayed in any way.” The DASS is a reliable and valid measure of distress that has been demonstrated to correlate moderately with the respective scales of the Hospital Anxiety Depression Scale, Beck Depression Inventory, and Beck Anxiety Inventory (Brown, Chorpita et al., 1997; Crawford & Henry, 2003; Lovibond & Lovibond, 1995a; Nieuwenhuijsen, de Boer, Verbeek, Blonk, & van Dijk, 2003). On all subscales, clinically relevant distress was documented according to mild level of symptoms determined from normative data (Lovibond & Lovibond, 1995b) as follows; depression ≥10, anxiety ≥8, stress ≥15.

Statistical Analyses

Statistical analyses were performed using SPSS® 15.0 statistical software package (SPSS Inc., Chicago, IL). Continuous data were analyzed with the general linear model, and categorical data were analyzed using the χ2 statistic with Fisher's exact test where appropriate.

Neuropsychological Decline

The incidence of meaningful neuropsychological change at 6 months and 5 years independent of practice effects, measurement error, and regression to the mean was calculated using SRB methodology reported in the cardiac surgery field (Kneebone et al., 2005; Tully, Baker, Kneebone et al., 2008) and epilepsy surgery field (Sawrie, Chelune, Naugle, & Luders, 1996), and favored over arbitrary statistical methodology (Raymond et al., 2006). Briefly, the 6-month and 5-year retest scores of control participants were regressed in a stepwise manner against the baseline scores and demographic predictors (i.e., age, sex, education years, predicted FSIQ, and test–retest interval). Only covariates with p < .10 were retained. The regression equations were used to obtain predicted retest scores for CABG patients on each measure at follow-up and the difference between observed and predicted scores were transformed into standardized z-scores. Thus, any SRB change score exceeding ±1.64 (90% confidence interval) among the surgical group was taken to indicate significant improvement or decline, and comparatively by definition 5% improvement and 5% decline would be observed among the control group. Appropriate modifications were made to SRB calculations for timed tasks so that higher scores denoted improved performance.

Psychological Predictors of Neuropsychological Functioning

The influence of intraoperative, cardiac, and psychological factors on CABG patient neuropsychological performance over time was examined with a series of linear hierarchical regressions. The SRB z-score for each measure at 6 months and 5 years was the dependent variable and each of the DASS subscale scores at each respective assessment were independent predictors. The DASS score distribution necessitated square-root transformation. Several covariates were selected a priori for their reported influence on neuropsychological performance based on previous results and these were: minimum nasopharyngeal temperature during CPB (Bruggemans, Van de Vijver, & Huysmans, 1997; Nathan et al., 2007; Townes et al., 1989), total CPB time (Newman, Kirchner et al., 2001), maximum arterial outlet temperature during CPB (Nathan et al., 2007; Townes et al., 1989), hypertension (Chin et al., 2008; Gatto et al., 2008; Newman, Kirchner et al., 2001; Tzourio, 2007), diabetes mellitus (Newman, Kirchner et al., 2001; Ryan, 2005; Selnes et al., 1999), and peripheral vascular disease (PVD; Ryan, 2005). Covariates were entered in block fashion at the first step, followed by continuous DASS stress scores at the second step, and depression and anxiety scores at the third step. A negative β-value for DASS scales would suggest increased emotional distress is associated with lower and therefore worse SRB z-score. This analysis strategy was employed to determine the role of unique depression and anxiety symptoms on cognitive decline beyond the effects of NA whom these emotions share a large portion of variance. In all analyses, an alpha value p < .05 was considered significant and no adjustment was made for multiple comparisons (Rothman, 1990).

Surgical Technique

Additional surgical technique detail may be found in Ahmed, Tully, Baker, and Knight (2009). Briefly, all surgical patients underwent isolated CABG with CPB and received a moderate fentanyl-based anesthetic technique. The CPB circuit and perfusion technique were consistent across the study period, with bypass instituted following cannulation of the aorta and the right atrium utilizing a membrane oxygenator (Maxima® [Medtronic, Anaheim, CA] or a Capiox SX18 [Terumo Corporation, Japan]) PVC tubing and 40 µm arterial line filter. All bypass was performed utilizing an alpha stat blood gas management, nonpulsatile flow, aiming for cardiac index of 1.6–2.4 L·min−1·m−2, minimum hematocrit of 0.21, pCO2 35–45 mmHg, and pO2 of 100–300 mmHg. All patients received antegrade blood cardioplegia, and cardiotomy suction was not utilized.

Results

From 110 consecutive eligible surgical participants, there were 88 who consented at baseline, 86 tested at 6 months, and 75 participants completed the 5-year follow-up. From 65 approached control subjects, informed consent was obtained for 53 at baseline, 50 were tested at 6 months, and 36 completed the 5-year assessment. The surgical and control cohort were not found to be significantly different on demographic and neuropsychological factors at baseline as shown in Table 1, and the raw scores at follow-up are shown in Table 2.

Table 1.

Descriptive comparisons at baseline between the surgical and control groups on variables related to SRB calculation and distress

 Surgical group (n = 86)
 
Control group (n = 50)
 
forumla p-value 
 Range M (SD)a Range M (SD)a   
Demographic distress 
 Age 36–84 65.1 (9.9) 44–82 68.0 (7.9) .02 .08 
 Men, n (%)  63 (73.3)  34 (68.0)   
 Women, n (%)  23 (26.7)  16 (32.0)  .51 
 FSIQ 79–120 101.7 (9.1) 86–118 102.5 (9.3) <.01 .65 
 Years of education 6–18 10.2 (2.5) 7–16 10.2 (1.7) <.01 .92 
Neuropsychological distress 
 CVLT total 23–69 46.4 (10.7) 32–67 47.1 (9.8) .01 .72 
 CVLT SDFR 36–125 82.8 (16.5) 40–136 83.1 (25.7) <.01 .92 
 PPB right 8–17 11.8 (2.0) 5–16 12.1 (2.2) <.01 .45 
 PPB left 6–16 11.4 (1.9) 8–16 12.1 (1.9) .03 .08 
 COWAT 14–82 36.6 (12.3) 14–63 36.5 (11.5) <.01 .96 
 TMT A 19–96 39.9 12.4) 18–63 36.0 (10.0) .03 .16 
 TMT B 42–350 90 (72–112) 49–280 82 (68–95) .03 .10 
 Digit Symbol 17–62 39.2 (10.2) 26–65 42.4 (8.8) .03 .08 
 BNT 46–60 55.6 (3.2) 42–60 55.2 (4.2) <.01 .49 
Psychological distress 
 DASS depression ≥10, n (%) 0–28 6 (7.0) 0–25 5 (10.0)  .53 
 DASS anxiety ≥8, n (%) 0–29 16 (18.6) 0–26 6 (12.0)  .35 
 DASS stress ≥15, n (%) 0–35 12 (14.0) 0–24 8 (16.0)  .80 
 Surgical group (n = 86)
 
Control group (n = 50)
 
forumla p-value 
 Range M (SD)a Range M (SD)a   
Demographic distress 
 Age 36–84 65.1 (9.9) 44–82 68.0 (7.9) .02 .08 
 Men, n (%)  63 (73.3)  34 (68.0)   
 Women, n (%)  23 (26.7)  16 (32.0)  .51 
 FSIQ 79–120 101.7 (9.1) 86–118 102.5 (9.3) <.01 .65 
 Years of education 6–18 10.2 (2.5) 7–16 10.2 (1.7) <.01 .92 
Neuropsychological distress 
 CVLT total 23–69 46.4 (10.7) 32–67 47.1 (9.8) .01 .72 
 CVLT SDFR 36–125 82.8 (16.5) 40–136 83.1 (25.7) <.01 .92 
 PPB right 8–17 11.8 (2.0) 5–16 12.1 (2.2) <.01 .45 
 PPB left 6–16 11.4 (1.9) 8–16 12.1 (1.9) .03 .08 
 COWAT 14–82 36.6 (12.3) 14–63 36.5 (11.5) <.01 .96 
 TMT A 19–96 39.9 12.4) 18–63 36.0 (10.0) .03 .16 
 TMT B 42–350 90 (72–112) 49–280 82 (68–95) .03 .10 
 Digit Symbol 17–62 39.2 (10.2) 26–65 42.4 (8.8) .03 .08 
 BNT 46–60 55.6 (3.2) 42–60 55.2 (4.2) <.01 .49 
Psychological distress 
 DASS depression ≥10, n (%) 0–28 6 (7.0) 0–25 5 (10.0)  .53 
 DASS anxiety ≥8, n (%) 0–29 16 (18.6) 0–26 6 (12.0)  .35 
 DASS stress ≥15, n (%) 0–35 12 (14.0) 0–24 8 (16.0)  .80 

Notes: BNT = Boston Naming Test; COWAT = Controlled Oral Word Association Test; CVLT = California Verbal Learning Test; DASS = Depression, Anxiety, and Stress Scales; FSIQ = full-scale IQ; PPB = Purdue Pegboard; SDFR = short delay free recall; SRB = standardized regression-based; TMT = Trail Making Test.

aMean and SD unless otherwise stated.

Table 2.

Neuropsychological performance and psychological distress at 6 months and 5 years for surgical and control participants

 Six monthsa
 
Five yearsb
 
 Surgical participants (n = 86)
 
Control participants (n = 50)
 
Surgical participants (n = 75)
 
Control participants (n = 36)
 
 Range M (SD)c Range M (SD)c Range M (SD)c Range M (SD)c 
CVLT total 23–80 50.9 (12.2) 28–71 51.6 (11.3) 20–69 43.6 (10.2) 25–72 47.2 (12.5) 
CVLT SDFR 37–127 84.5 (18.6) 45–157 91.0 (28.0) 25–160 76.0 (20.2) 25–167 91.2 (33.6) 
PPB right 7–20 12.2 (2.1) 8–16 12.6 (1.9) 5–17 10.8 (2.5) 4–19 11.7 (2.9) 
PPB left 7–15 11.5 (2.0) 8–17 12.3 (1.9) 5–16 11.1 (2.4) 7–16 11.3 (2.3) 
COWAT 13–76 38.1 (12.1) 18–64 38.4 (11.0) 13–71 33.9 (11.8) 11–61 33.9 (10.8) 
TMT A 20–74 38.8 (11.9) 19–45 32.0 (7.1) 17–144 43.9 (20.2) 18–68 38.2 (11.3) 
TMT B 30–280 99.2 (40.8) 38–151 76.6 (24.9) 47–558 123.9 (85.9) 39–259 102.5 (53.6) 
Digit Symbol 16–70 40.8 (11.6) 25–68 46.9 (9.6) 12–63 37.4 (10.2) 22–65 40.1 (10.4) 
BNT 47–60 56.1 (3.0) 45–60 56.4 (3.9) 26–60 54.0 (6.1) 32–60 54.1 (5.8) 
Psychological distressd 
 DASS depression ≥10, n (%) 0–41 6 (7.0) 0–18 4 (8.0) 0–24 12 (16.0) 0–17 2 (5.6) 
 DASS anxiety ≥8, n (%) 0–20 12 (14.0) 0–13 4 (8.0) 0–16 15 (20.0) 0–15 4 (11.1) 
 DASS stress ≥15, n (%) 0–39 9 (10.5) 0–23 4 (8.0) 0–30 7 (9.3) 0–19 2 (5.6) 
 Six monthsa
 
Five yearsb
 
 Surgical participants (n = 86)
 
Control participants (n = 50)
 
Surgical participants (n = 75)
 
Control participants (n = 36)
 
 Range M (SD)c Range M (SD)c Range M (SD)c Range M (SD)c 
CVLT total 23–80 50.9 (12.2) 28–71 51.6 (11.3) 20–69 43.6 (10.2) 25–72 47.2 (12.5) 
CVLT SDFR 37–127 84.5 (18.6) 45–157 91.0 (28.0) 25–160 76.0 (20.2) 25–167 91.2 (33.6) 
PPB right 7–20 12.2 (2.1) 8–16 12.6 (1.9) 5–17 10.8 (2.5) 4–19 11.7 (2.9) 
PPB left 7–15 11.5 (2.0) 8–17 12.3 (1.9) 5–16 11.1 (2.4) 7–16 11.3 (2.3) 
COWAT 13–76 38.1 (12.1) 18–64 38.4 (11.0) 13–71 33.9 (11.8) 11–61 33.9 (10.8) 
TMT A 20–74 38.8 (11.9) 19–45 32.0 (7.1) 17–144 43.9 (20.2) 18–68 38.2 (11.3) 
TMT B 30–280 99.2 (40.8) 38–151 76.6 (24.9) 47–558 123.9 (85.9) 39–259 102.5 (53.6) 
Digit Symbol 16–70 40.8 (11.6) 25–68 46.9 (9.6) 12–63 37.4 (10.2) 22–65 40.1 (10.4) 
BNT 47–60 56.1 (3.0) 45–60 56.4 (3.9) 26–60 54.0 (6.1) 32–60 54.1 (5.8) 
Psychological distressd 
 DASS depression ≥10, n (%) 0–41 6 (7.0) 0–18 4 (8.0) 0–24 12 (16.0) 0–17 2 (5.6) 
 DASS anxiety ≥8, n (%) 0–20 12 (14.0) 0–13 4 (8.0) 0–16 15 (20.0) 0–15 4 (11.1) 
 DASS stress ≥15, n (%) 0–39 9 (10.5) 0–23 4 (8.0) 0–30 7 (9.3) 0–19 2 (5.6) 

Notes: BNT = Boston Naming Test; COWAT = Controlled Oral Word Association Test; CVLT = California Verbal Learning Test; DASS = Depression, Anxiety, and Stress Scales; PPB = Purdue Pegboard; SDFR = short delay free recall; TMT = Trail Making Test.

aRefer to Table 3 for a statistical comparison of surgical and control group neuropsychological performance at 6 months.

bRefer to Table 3 for a statistical comparison of surgical and control group neuropsychological performance at 5 years.

cMean and SD for neuropsychological measures, n and % for psychological distress measures.

dNo significant differences between surgical and control groups on the proportion of mild distress at 6 months and 5 years.

Neuropsychological Change

Six months

The average 6-month follow-up assessment was performed 27.8 weeks (SD = 2.8) after baseline. The 6-month SRB calculations showed that baseline neuropsychological performance contributed significantly to all equations, and the total variance explained was between 34% (CVLT) and 73% variance (BNT, Digit Symbol). The CVLT was influenced by age and sex with these demographics contributing 4% of variance each to CVLT SRB z-scores, with women and younger participants performing better. Sex also explained 6% of variance in TMT part B SRB z-scores and women performed worse on this measure. The proportion of neuropsychological change among CABG patients at 6 months is shown in Table 3 where a comparison is also made based on SRB z-scores. The surgical group had significantly lower SRB z-scores on TMT parts A and B, and Digit Symbol. Improvement in 12% of patients on the CVLT was possibly biased by selective drop out of patients or controls with poorer verbal memory.

Table 3.

Mean SRB z-scores and percentage of surgical patients showing decline, no change and improvement in neuropsychologic performance at 6 months and 5 years after surgery

  Six-month SRB z-score (n = 86)a
 
Five-year SRB z-score (n = 75)b
 
  M (SD Declined (≤−1.64)  No change (≥−1.63 ≤ 1.63)  Improved (≥1.64)  forumla   p-value  M (SD Declined (≤−1.64)  No change (≥−1.63 ≤ 1.63)  Improved (≥1.64)  forumla   p-value 
CVLT total  .14 (1.25)  10.5  77.9  11.6  .01  .47  −.21 (.92)  5.3  93.3  1.3  .01  .28 
CVLT SDFR  −.33 (1.13)  4.0  92.0  4.0  .02  .09  −.73 (1.11)  13.3  82.7  4.0  .09  <.001 
PPB right  −.18 (1.15)  10.5  84.9  4.7  .01  .38  −.29 (.95)  12.3  86.3  1.4  .02  .14 
PPB left  −.23 (1.11)  9.3  86.0  4.7  .01  .22  .33 (1.08)  2.7  86.5  10.8  .02  .12 
COWAT  −.08 (1.08)  9.3  86.0  4.7  .01  .70  −.18 (1.24)  9.3  81.3  9.3  .01  .46 
TMT A  −.89 (1.77)  29.1  67.4  3.5  .07  <.001  −.31 (1.77)  12.0  84.0  4.0  .01  .34 
TMT B  −.78 (1.62)  23.3  73.3  3.5  .07  <.001  −.20 (1.52)  6.8  90.5  2.7  .01  .49 
Digit Symbol  −.62 (1.21)  12.8  83.7  3.5  .07  <.01  .13 (1.24)  12.0  81.3  6.7  .01  .59 
BNT  −.32 (.90)  5.0  93.0  1.8  .03  .06  −.18 (2.13)  12.0  81.3  6.7  .01  .65 
  Six-month SRB z-score (n = 86)a
 
Five-year SRB z-score (n = 75)b
 
  M (SD Declined (≤−1.64)  No change (≥−1.63 ≤ 1.63)  Improved (≥1.64)  forumla   p-value  M (SD Declined (≤−1.64)  No change (≥−1.63 ≤ 1.63)  Improved (≥1.64)  forumla   p-value 
CVLT total  .14 (1.25)  10.5  77.9  11.6  .01  .47  −.21 (.92)  5.3  93.3  1.3  .01  .28 
CVLT SDFR  −.33 (1.13)  4.0  92.0  4.0  .02  .09  −.73 (1.11)  13.3  82.7  4.0  .09  <.001 
PPB right  −.18 (1.15)  10.5  84.9  4.7  .01  .38  −.29 (.95)  12.3  86.3  1.4  .02  .14 
PPB left  −.23 (1.11)  9.3  86.0  4.7  .01  .22  .33 (1.08)  2.7  86.5  10.8  .02  .12 
COWAT  −.08 (1.08)  9.3  86.0  4.7  .01  .70  −.18 (1.24)  9.3  81.3  9.3  .01  .46 
TMT A  −.89 (1.77)  29.1  67.4  3.5  .07  <.001  −.31 (1.77)  12.0  84.0  4.0  .01  .34 
TMT B  −.78 (1.62)  23.3  73.3  3.5  .07  <.001  −.20 (1.52)  6.8  90.5  2.7  .01  .49 
Digit Symbol  −.62 (1.21)  12.8  83.7  3.5  .07  <.01  .13 (1.24)  12.0  81.3  6.7  .01  .59 
BNT  −.32 (.90)  5.0  93.0  1.8  .03  .06  −.18 (2.13)  12.0  81.3  6.7  .01  .65 

Notes: BNT = Boston Naming Test; COWAT = Controlled Oral Word Association Test; CVLT = California Verbal Learning Test; PPB = Purdue Pegboard; SDFR = short delay free recall; SRB = standardized regression based methodology; TMT = Trail Making Test.

aSurgical group SRB z-score compared with the control group (M = 0, SD = 1) at 6-month follow-up.

bSurgical group SRB z-score compared with the control group (M = 0, SD = 1) at 5-year follow-up.

Five years

The average 5-year follow-up was performed 64 months (SD = 4.9) after baseline. The 5-year follow-up SRB calculations showed that baseline performance was a significant predictor on all measures, and the variance accounted for in each SRB equation ranged from 20% (CVLT) to 85% (BNT). Women were found to predict better performance in Digit Symbol, PPB left, and CVLT accounting for 10.4%, 7.6%, and 9.6% variance, respectively. It was further shown that higher predicted FSIQ was associated with worse performance on TMT B, and this variable accounted for 7.2% variance. CABG patients had significantly lower SRB z-scores for the CVLT short delay retention measure (Table 3).

Predictors of Neuropsychological Performance

Six months

The hierarchical regression results for neuropsychological functioning 6 months after CABG surgery are shown in Table 4. These data showed that at the time of testing, depression scores were significantly associated with 6-month neuropsychological functioning and explained approximately 5% of variance in the calculated SRB scores for PPB right (β = −.35, p = .04), BNT (β = −.34, p = .05), and Digit Symbol (β = −.37, p = .03). Anxiety was associated with 6-month COWAT performance and explained around 4% of the variance in the calculated SRB scores (β = −.30, p = .03). Among the covariates, longer length of time spent on CPB was significantly associated with PPB right, PPB left, and TMT part A. Stress was not associated with any neuropsychological measure in the final models. A significant effect at the second step was only evident for TMT part B (β = −.23, p = .03) that was not maintained when depression and anxiety scores were entered in this model at the final step. Thus, no support was found for the hypothesis of an effect for NA on neuropsychological function 6 months after CABG.

Table 4.

Hierarchical regression equations predicting 6-month neuropsychological functioning

Measure Step 2
 
Step 3
 
 R2 R2 change R2 R2 change Covariatesa
 
     Intraoperative and medicalb Stress (β) Depression (β) Anxiety (β) 
CVLT .11 .01 .14 .03 — −.05 −.13 −.14 
CVLT SDFR .05 .01 .11 .06 — −.01 −.19 −.14 
PPB right .11 .01 .16 .05 CPB time* −.27 −.35* −.03 
PPB left .11 .03 .16 .05 CPB time* −.22 −.07 −.09 
COWAT .03 .01 .07 .04 — −.08 −.15 −.30* 
TMT A .19 .01 .22 .03 CPB time* −.23 −.26 −.11 
TMT B .28 .06 .31 .03 Hypertension*** PVD** −.18 −.17 −.26 
Digit Symbol .07 .01 .13 .06 — −.01 −.37* −.23 
BNT .08 .03 .13 .05 — −.37 −.34* −.11 
Measure Step 2
 
Step 3
 
 R2 R2 change R2 R2 change Covariatesa
 
     Intraoperative and medicalb Stress (β) Depression (β) Anxiety (β) 
CVLT .11 .01 .14 .03 — −.05 −.13 −.14 
CVLT SDFR .05 .01 .11 .06 — −.01 −.19 −.14 
PPB right .11 .01 .16 .05 CPB time* −.27 −.35* −.03 
PPB left .11 .03 .16 .05 CPB time* −.22 −.07 −.09 
COWAT .03 .01 .07 .04 — −.08 −.15 −.30* 
TMT A .19 .01 .22 .03 CPB time* −.23 −.26 −.11 
TMT B .28 .06 .31 .03 Hypertension*** PVD** −.18 −.17 −.26 
Digit Symbol .07 .01 .13 .06 — −.01 −.37* −.23 
BNT .08 .03 .13 .05 — −.37 −.34* −.11 

Notes: BNT = Boston Naming Test; COWAT = Controlled Oral Word Association Test; CPB = cardiopulmonary bypass; CVLT = California Verbal Learning Test; PPB = Purdue Pegboard; PVD = peripheral vascular disease; SDFR = short delay free recall; TMT = Trail Making Test.

aAt third step when all psychological predictors entered.

bSignificant covariates listed.

*p < .05.

**p < .01.

***p < .001.

Five years

The regression results for 5-year neuropsychological functioning are shown in Table 5. Depressive symptoms were associated with worse performance on the Digit Symbol task (β = −.46, p = .03) and explained 7.2% of the variance. For the timed executive tasks of TMT part A lower SRB score and thus worse performance was associated with stress symptoms (β = −.38, p = .05) and this variable explained 6.8% of variance. Stress symptoms were also associated with TMT part B (β = −.44, p = .03) as were depression symptoms (β = −.31, p = .05), and these variables explained 5.7% and 3.9% of variance, respectively. Stress was thus associated with only the TMT measures and was not significantly associated with other measures at the second step of the regression equations, thus showing little support for the hypothesis of an effect of NA on neuropsychological function 5 years after CABG.

Table 5.

Hierarchical regression equations predicting 5-year neuropsychological functioning

Measure Step 2
 
Step 3
 
 R2 R2 change R2 R2 change Covariatesa
 
     Intraoperative and medicalb Stress (β) Depression (β) Anxiety (β) 
CVLT .17 .00 .23 .06 Hypertension* .08 −.18 −.08 
CVLT SDFR .14 .02 .16 .02 Diabetes* −.13 −.11 −.23 
PPB right .12 .01 .15 .03 Diabetes* −.22 .01 −.23 
PPB left .14 .01 .15 .02 — −.31 −.17 −.05 
BNT .18 .01 .20 .03 Diabetes* CPB time* −.25 −.10 −10 
Digit Symbol .12 .01 .23 .11 — −.27 −.46* .03 
COWAT .08 .05 .09 .01 — −.11 −.11 −.21 
TMT A .18 .01 .25 .07 PVD −.38* −.23 .11 
TMT B .14 .00 .22 .08 Hypertension** min CPB temp* −.44* −.31* .14 
Measure Step 2
 
Step 3
 
 R2 R2 change R2 R2 change Covariatesa
 
     Intraoperative and medicalb Stress (β) Depression (β) Anxiety (β) 
CVLT .17 .00 .23 .06 Hypertension* .08 −.18 −.08 
CVLT SDFR .14 .02 .16 .02 Diabetes* −.13 −.11 −.23 
PPB right .12 .01 .15 .03 Diabetes* −.22 .01 −.23 
PPB left .14 .01 .15 .02 — −.31 −.17 −.05 
BNT .18 .01 .20 .03 Diabetes* CPB time* −.25 −.10 −10 
Digit Symbol .12 .01 .23 .11 — −.27 −.46* .03 
COWAT .08 .05 .09 .01 — −.11 −.11 −.21 
TMT A .18 .01 .25 .07 PVD −.38* −.23 .11 
TMT B .14 .00 .22 .08 Hypertension** min CPB temp* −.44* −.31* .14 

Notes: BNT = Boston Naming Test; COWAT = Controlled Oral Word Association Test; CPB = cardiopulmonary bypass; CVLT = California Verbal Learning Test; PPB = Purdue Pegboard; PVD = peripheral vascular disease; SDFR = short delay free recall; TMT = Trail Making Test.

aAt third step when all psychological predictors entered.

bSignificant covariates listed.

*p < .05.

**p < .01.

***p < .001.

Discussion

In regard to the first aim, neuropsychological function 5 years after cardiac surgery was, on average, not significantly below that observed among a nonsurgical control group apart for short-term memory retention. Also, the timed and executive functioning tasks of TMT and Digit Symbol were worse than predicted in CABG patients 6 months after surgery. These findings support earlier studies (Müllges et al., 2002; Nathan, Wells, Munson, & Wozny, 2001) including those utilizing a comparative control group (Selnes et al., 2008; van Dijk et al., 2008) that suggest that CABG surgery is not associated with cognitive dysfunction in the magnitude of 42% of all patients as has been reported with an arbitrary calculation of deficit (Newman, Kirchner et al., 2001). With regard to the second aim concerning the impact of psychological distress on neuropsychological function, these data suggested that distress had minimal effects on cognitive function after CABG when a nonbiased estimate of neuropsychological function was adopted and adjustment was made for medical and surgical covariates. The results also showed no support for the hypothesis that NA will account for neuropsychological decline more than depression or anxiety after cardiac surgery.

Cognitive and affective depressive symptoms explained no more than 7.2% of variance at any follow-up in each of the neuropsychological domains tapping into attention and visuomotor speed (Digit Symbol), abstraction and executive function (TMT part B), language (BNT), and manual dexterity (PPB right). Other long-term follow-up studies of CABG patients reported correlations between depressive symptoms and visuoconstruction and visual memory (McKhann et al., 1997) and motor performance on the Grooved Pegboard Test (Stroobant & Vingerhoets, 2008). It is, however, difficult to reconcile the largely discrepant associations reported between post-CABG cognitive function and distress (Andrew et al., 2000; Kneebone et al., 2005; McKhann et al., 1997; Rothenhausler et al., 2005; Stroobant, van Nooten, De Bacquer, Van Belleghem, & Vingerhoets, 2008; Tsushima et al., 2005), together with the inconsistent pattern of association across the two follow-up assessments here. Moreover, in these data, there was little overlap between the neuropsychological tests exhibiting substantial decline with those exhibiting an association to psychological distress. In other words, psychological distress did not readily translate to cognitive dysfunction in any follow-up period and this calls into question the results of previous studies that employed an arbitrary definition of dysfunction or performed only correlations between raw scores of neuropsychological performance and distress (McKhann et al., 1997; Stroobant et al., 2008). Nevertheless, as noted elsewhere, it is possible that depression affects post-CABG neuropsychological function in ways that are not captured by the current assessment battery (Freedland et al., 2009).

Indeed, the present results support recent studies that have indicated late cognitive dysfunction is minimal (Müllges et al., 2002; Nathan et al., 2007) or comparable to patients not undergoing CABG (Selnes et al., 2008; van Dijk et al., 2008). Previous work has shown that prior to CABG, neuropsychological deficits, as defined by z-scores ≤−1.70, are prominent in 48.8% of patients on verbal memory tasks and 51.2% of patients on tasks of psychomotor speed (Rankin, Kochamba, Boone, Petitti, & Buckwalter, 2003), and a patient’s cognitive reserve may increase the threshold for neuropsychological deterioration after CABG (Ropacki, Bert, Ropacki, Rogers, & Stern, 2007).

Other authors have concluded that late neuropsychological performance after CABG is influenced by advancing age and progression of vascular disease (Hammon & Stump, 2007). Here, the covariates hypertension, diabetes, and less commonly PVD were associated with lower SRB z-scores on six neuropsychological measures at 5-year follow-up contrasting to previous CABG studies (Newman, Kirchner et al., 2001; Selnes et al., 2001) though supporting other research among non-coronary artery disease populations (Gatto et al., 2008; Phillips & Mate-Kole, 1997; Ryan, 2005). It has been suggested elsewhere that observed late cognitive decline is attributable to the advancement of vascular pathology and this potentially exacerbates cerebral damage sustained intraoperatively (Brown, Moody, Tytell, Ghazi-Birry, & Challa, 1997). The current study also showed that the length of time spent on CPB was associated with worse neuropsychological performance, thus generally supporting other work (Sotaniemi, Mononen, & Hokkanen, 1986). The CPB circuit is hypothesized to expose patients to microemboli and hypoperfusion (Brown, Moody et al., 1997), and it has been shown that mild hypothermia may have an early neuroprotective effect (Nathan et al., 2001) that is reportedly not maintained at 5-year follow-up (Nathan et al., 2007).

The discrepancy in our results compared with other CABG studies is perhaps a result of the methodology to explore individual neuropsychological subtests rather than statistically determined cognitive domains (Newman, Kirchner et al., 2001; Phillips-Bute et al., 2006) as the latter may conceal heterogeneity of cognitive dysfunction and thus obscure potential mechanisms of brain injury (Kneebone et al., 2005). Indeed, subtle nuances in neuropsychological measures and statistical methodology will inevitably yield varying estimates of cognitive deterioration following cardiothoracic procedures (Raymond et al., 2006); however, there appears to be little consensus in this extensive research field to guide researchers. The present results highlight the difficulties with applying a group mean change to neuropsychological deterioration, even if to SRB estimates. Indeed, a group mean comparison of SRB z-scores may conceal or even overestimate meaningful clinical differences. Readers should bear in mind that estimation of neuropsychological deficit with SRB would anticipate 5% decline among the control group by definition. Thus, at 5-year follow-up for example, the discrepancy in impairment between groups did not exceed 8% on any individual neuropsychological measure, considering the SDFR measure exhibited the greatest decline (i.e., 13.3% subtract 5% decline among controls).

These results are presented with several limitations to bear in mind such as the small size of the control group tested at 5 years and attrition of study participants that has reduced statistical power (Bezeau & Graves, 2001). Baseline discrepancies between surgical and control groups may also impact on SRB estimates (Van der Elst, Van Boxtel, Van Breukelen, & Jolles, 2008). Another limitation concerns the level of distress observed among the surgical and control groups, and it was possible that a selection bias was evident with nonconsenting patients possibly more distressed, whereas overt psychiatric disorder or treatment was an exclusion criteria. Cardiac covariates were not documented for control group SRB calculations and this may confound the predicted estimates, whereas a repeat evaluation of medical covariates was not performed for surgical patients. Only cognitive and affective depressive symptoms tapping into hopelessness, anhedonia, and self-deprecation were measured (Lovibond & Lovibond, 1995b), and it is assumed that many patients would also have experienced somatic and vegetative symptoms of inertia, psychomotor agitation, sleep and concentration difficulties, and fatigability with the latter also common in coronary artery disease. Lastly, it is possible that vascular disease, psychological distress, and cognitive dysfunction are reciprocally reinforcing, thus contrasting to the prevailing hypothesis here that emotional distress portends worse performance on neuropsychological functioning. Supporting this, Gallo, Malek, Gilbertson, and Moore (2005) showed that subjective perception of early-cognitive difficulties was associated with a negative course of emotional symptoms after CABG, though early emotional distress did not predict poor cognitive function to 5 months follow-up.

In conclusion, 6-month and 5-year follow-up of CABG surgery patients suggested that psychological distress does not significantly affect the neuropsychological domains that were on average significantly lower than a nonsurgical control group. The results here also show support for the use of nonbiased statistical methodology to document dysfunction among heterogeneous cognitive domains after CABG surgery.

Funding

PJT was supported by an Australian Postgraduate Award and a Sir Robert Menzies Memorial Scholarship in the Allied Health Sciences.

Conflict of Interest

None declared.

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