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ORIGINAL ARTICLES |
Departments of Anesthesiology (B.P.B., J.M., W.D.W., M.F.N.), Psychiatry and Behavioral Sciences (B.P.B., J.A.B. K.W.-B.), Medicine (D.M.), and Surgery (K.L.), Duke University Medical Center, Durham, NC.
Address correspondence and reprint requests to Barbara Phillips Bute, PhD, Box 3094, DUMC, Duke University Medical Center, Durham, NC 27710. E-mail: phill016{at}mc.duke.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSINSTRUMENTSRESULTSDISCUSSIONAPPENDIX: NEUROLOGIC OUTCOME...ACKNOWLEDGMENTSREFERENCES |
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MATERIALS AND METHODS: Two hundred eighty patients (96 women and 184 men) underwent neurocognitive and QOL evaluation at baseline (preoperatively) and at 1 year after CABG. Multivariable linear regression was used to assess the relationship of gender to follow-up QOL and cognitive function. Measures used to evaluate QOL were IADL, DASI, work activities (SF-36), social activities, social support, general health perception (SF-36), CESD, STAI, and symptom limitations. Cognitive function was measured with a battery of performance-based neuropsychological tests, reduced to a four-cognitive domain scores with factor analysis, and a self-report measure of cognitive difficulties. Covariates in multiple regression models included age, years of education, marital status, Charlson Comorbidity Index, hypertension, diabetes, race, and baseline QOL/cognitive status.
RESULTS: Female patients showed significantly worse outcome than male patients at 1 year follow-up in several key areas of QOL. After adjusting for baseline differences, women are at greater risk for increased cognitive difficulties (p= 0.04) and anxiety (p= 0.03), as well as impaired DASI (p= 0.02), IADL (p= 0.03), and work activities (p= 0.02). Cognitive sequelae attributable to bypass surgery were similar between men and women.
CONCLUSIONS: Even after adjusting for known risk factors for compromised QOL and cognitive functioning, women do not show the same long-term quality benefits of CABG surgery that men do.
Key Words: quality of life, • cognitive function, • CABG surgery, • gender.
Abbreviations: CABG = coronary artery bypass grafting; QOL = quality of life;; WAIS-R = Wechsler Adult Intelligence Scale-Revised;; DASI = Duke Activity Status Index;; OARS-IADL = The Duke Older Americans Resources and Services Procedures-Instrumental Activities of Daily Living;; CES-D = Center for Epidemiological Studies Depression Scale;; CPB = cardiopulmonary bypass;; SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSINSTRUMENTSRESULTSDISCUSSIONAPPENDIX: NEUROLOGIC OUTCOME...ACKNOWLEDGMENTSREFERENCES |
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Improved quality of life (QOL) is one of the most important outcomes of cardiac surgery (4–8). Physical functioning (9,10), social functioning, and psychological well-being have all been shown to improve. However, not all patients experience these improvements after surgery (11). Important predictors of QOL outcomes have been shown to include age, education, comorbidities, social isolation, and, sometimes, gender (12).
Cognitive functioning after CABG surgery is also an area that has received a good deal of attention. Although many patients show an improvement in neuropsychological testing, a significant subgroup of patients exhibit cognitive impairment after cardiac surgery (13), in which as many as 50% or more of patients experience cognitive deficit immediately after cardiac surgery. Long-term follow-up has also shown that immediate postoperative deficits are predictive of deficits 5 years later, even after controlling for baseline cognitive function. In addition, Newman and colleagues (14) have found that a decrease in postoperative cognitive functioning is associated with diminished QOL.
There has been some disagreement in the literature as to whether women fare worse than men do after CABG surgery. Rankin (15) found that women were more likely to die during hospitalization, stay longer in intensive care units, and experience cardiac dysfunction. Other studies have reported that men experience improved outcomes compared with women (9,16,17). However, more recent studies have reported (18) that long-term outcomes for men and women are similar.
One factor that may explain this apparent discrepancy is that postoperative recovery differences may reflect the preoperative differences; ie, women appear to do worse because they were initially more compromised than men (10,19,20). In fact, Jacobs (21) reports that although raw incidence rates show worse outcomes for women than men, after accounting for preexisting differences, female gender is actually a predictor of improved 5-year survival after PTCA or CABG. Therefore, we examined QOL and cognitive outcomes after CABG surgery in men and women by carefully adjusting for baseline differences and known preoperative risk factors for these outcomes.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSINSTRUMENTSRESULTSDISCUSSIONAPPENDIX: NEUROLOGIC OUTCOME...ACKNOWLEDGMENTSREFERENCES |
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Procedures
Informed consent was obtained from all participants. Patients were administered a battery of QOL measures and neuropsychological measures the day before surgery (baseline) and at 1-year after surgery. Trained psychometricians administered instruments in a private hospital room. Questionnaires were completed individually; however, the instruments were read to patients if they were feeling ill, did not have their reading glasses with them, or if they had trouble reading.
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INSTRUMENTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSINSTRUMENTSRESULTSDISCUSSIONAPPENDIX: NEUROLOGIC OUTCOME...ACKNOWLEDGMENTSREFERENCES |
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A factor analysis with orthogonal rotation was performed for data reduction purposes and to appropriately weigh the neurocognitive test scores (13). Factor analysis on 10 baseline test scores suggests that four factors accounted for 85% of the variance present in our test battery at baseline. The four factors represent the cognitive domains of: (1) verbal memory and language comprehension—short-term and delayed; (2) figural memory—short-term and delayed; (3) attention and concentration; and (4) abstraction and psychomotor processing speed. The domains were defined at baseline and remained consistent at follow-up.
In addition to these objective measures, a subjective measure of cognitive difficulties was obtained. The Cognitive Difficulties Scale (25), a 39-item scale, was administered to patients for a self-report assessment of perceived problems in long- and short-term memory, concentration, attention, and psychomotor coordination. Sample items are "I forget errands I planned to do" and "I fail to recognize people I know". Scores range from 39 to 164, with higher scores indicating greater cognitive difficulty.
Measurement of QOL
QOL instruments were administered individually by a trained psychometrician who was blinded to the patient’s neurocognitive test results. Most of the questionnaires were self-administered; however, the measures were read to the patient if they were feeling ill or unable to read. The following QOL measures were used. Cronbach’s coefficient alphas are reported for as a measure of internal reliability, for this sample: (1) Duke Activity Status Index (DASI) (26). The DASI is a 12-item scale of functional capacity that has been found to correlate well with objective measures of maximal exercise capacity. Items reflect activities of personal care, ambulation, household tasks, sexual function, and recreational activities. Activities reported to be performed "with no difficulty" receive scores weighted higher for more taxing activities, which are summed for a quantitative measure of functional status. Scores range from 0 to 60; a higher weighted score is better. Cronbach’s coefficient alpha in the current sample is 0.86; (2) Duke Older Americans Resources and Services Procedures-Instrumental Activities of Daily Living (OARS-IADL) (27). This measure contains six items that assess the ability to perform important tasks for daily living (eg, "Could you prepare your own means?" "Could you drive a car?") Scores range from 6 to 24. Higher scores indicate increasing difficulty in engaging in daily activities. Cronbach’s coefficient alpha in the current sample is 0.91; (3) Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) (28). The SF-36 was designed to measure general health status. Two scales were used: work activities (4 items), and general health (1 item). A higher score on work activities indicates more health related problems. A high score in general health indicates better health state. Cronbach’s coefficient alpha for work activities in the current sample is 0.94; (4) Social activity. Eight items that indicate degree of social interaction. Sample items are "How often do you talk on the telephone with friends and relatives?" and "How often do you attend meetings of social groups, clubs, or civic organizations?" Scores range from 8 to 32. A lower score indicates more social activity. Cronbach’s coefficient alpha in the current sample is 0.67; (5) Symptom limitations (29). Patients were given a list of eight symptoms and asked to rate the degree to which the symptom limited daily activities. The symptoms were: angina, shortness of breath, arthritis, back trouble, leg pains, headaches, fatigue, and other. Scores range from 8 to 32, with higher scores indicating greater limitations. Cronbach’s coefficient alpha in the current sample is 0.75; (6) Center for Epidemiological Studies Depression Scale (CES-D) (30). The CES-D is a 20-item self-report measure designed to measure symptoms of depression. Subjects rate the degree to which they have experienced a range of symptoms of depression on items such as "I had crying spells" and "I felt lonely." Scores range from 0 to 60, with higher scores indicating greater depressive symptoms. Scores greater than 16 are typically considered indicative of clinically significant depression. Cronbach’s coefficient alpha in the current sample is 0.88; (7) Spielberger State and Trait Anxiety Inventory (STAI) (31). The STAI consists of two 20-item scales that measure state (current) and trait anxiety (chronic). Representative items include statements such as "I feel nervous" and "I feel worried." These items are rated on a 4-point scale of how well they describe the patient’s current or typical mood from "not at all" to "very much so." Scores range from 20 to 80, with higher scores indicating greater anxiety. Cronbach’s coefficient alpha in the current sample is 0.93; and (8) Perceived Social Support Scale (32). Twelve items include how strongly subjects agree there is "a special person who is around when I am in need" and "my family really tries to help me." Choices range from "very strongly disagree" to "very strongly agree." Items are summed for a range of 12 to 84, with a high score meaning more social support. Cronbach’s coefficient alpha in the current sample is 0.97.
Comorbidity Index
The NNE modified version of the Charlson comorbidity index (33) was used to assess the cumulative burden of medical comorbidity. The index takes into account the number and seriousness of 10 possible medical conditions, with the weighting coefficients derived from the approximate 1-year adjusted relative risk of mortality associated with that condition in a general medical population. Conditions included in the index are: peripheral vascular disease, COPD, peptic ulcer, diabetes, renal disease, liver disease, tumor/lymphoma/leukemia, metastatic cancer, dementia, and AIDS.
Surgical Management
Anesthetic management with midazolam, fentanyl, isoflurane, and vecuronium has been previously described (4). All patients underwent standard nonpulsatile hypothermic (30°C–34°C) cardiopulmonary bypass (CPB). The perfusion apparatus included a Cobe CML membrane oxygenator (COBE Chem Labs, Lakewood, CO), a Sarns 7000 MDX pump (Sarns, 3M, Ann Arbor, MI), and a Pall SP 3840 arterial line filter (Pall Biomedical Products, Glen Cove, NY). Nonpulsatile perfusion of 2 to 2.4 liters per minute per square meter was maintained throughout surgery. The pump was primed with crystalloid solution to achieve a hematocrit of 18% or more during extracorporeal circulation, with packed red blood cells added when necessary to achieve the desired hematocrit. All patients underwent CPB using an ascending aortic cannula and aortic cross-clamping to achieve cardioplegic arrest. Throughout CPB, arterial carbon dioxide tension was maintained at 35 to 40 mm Hg (uncorrected for temperature) and partial pressure of oxygen at 150 to 250 mm Hg.
Statistical Analysis
For descriptive purposes, baseline univariate comparisons were performed to identify gender-related differences for each QOL and cognitive outcome. Similar comparisons were performed for the 1-year follow-up time periods.
Statistical analysis was multivariate linear regression analyses for each measure. The outcome is 1 year functioning, controlling for baseline values. Assumptions of linearity were checked by examination of residuals. Assumptions of additivity were checked by examining selected interaction terms.
Because of the importance of baseline gender differences, careful consideration was given to selection of covariates. Covariates were identified a priori and were included in all multivariable linear regression analyses. Based on previous research, we selected surgical age, Charlson comorbidity, years of education, marital status (as a marker for social isolation), and baseline function. Because of the baseline differences in our sample, we also included history of hypertension, diabetes, and race as covariates. Separate models were run for each outcome measure. In each model, the appropriate baseline measure is included; ie, in the model examining 1 year DASI, baseline DASI function is included in the model as a covariate.
Nonsignificant covariates were included in the models. Our sample size allows us the luxury of full-model fits, including all selected covariates, thus allowing us to interpret all p values as pre-specified and less subject to bias (34). All statistical analyses were performed with SAS statistical software version 8.02.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSINSTRUMENTSRESULTSDISCUSSIONAPPENDIX: NEUROLOGIC OUTCOME...ACKNOWLEDGMENTSREFERENCES |
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At 1 year
Unadjusted comparisons show that female patients score lower than male patients on cognitive domain 3 (attention and concentration); none of the other cognitive domains shows significant raw differences. Multivariate analyses show mixed results. After adjusting for baseline differences, men show less improvement than women on cognitive domain 2 (figural memory) (p= 0.02). In cognitive domain 3 (attention and concentration), while men show an improvement at 1 year, women show a decline (p= 0.05). Domains 1 and 4 show no significant gender differences. One-year scores are adjusted for age, Charlson comorbidity index, history of hypertension, diabetes, race, years of education, marital status, and baseline cognitive function.
QOL
Baseline
The preliminary repeated measures analysis showed significant gender effects in every QOL outcome measure.
At 1 year
In most measures of QOL, the sample as a whole had improved QOL 1 year after CABG compared with baseline. Depression and anxiety levels were both significantly lower, health perception was better, work activities were increased, and DASI scores were increased. In contrast, two measures showed a decline: patients experienced less social support and cognitive difficulties had increased. The IADL showed no significant change. Table 2 presents the means for all measures, for males and females, for each test period.
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After inclusion of covariates, results of the multivariate analysis show that gender related differences are evident in the following measures: IADL, DASI, work activities (SF-36), cognitive difficulties, and anxiety (STAI). Social support, CESD, and general health perception no longer show gender differences after adjusting for baseline differences. These multivariate results are shown in Table 3.
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show selected measures to graphically illustrate gender differences at baseline and at 1-year follow-up. Unadjusted and adjusted scores are depicted. DASI, cognitive difficulties, and STAI all demonstrate gender differences, with females scoring worse, which persist even after controlling for baseline measures. These findings indicate that these postoperative gender differences in QOL are not explained by pre-existing differences. Although the CESD figure illustrates that gender differences exist at each time point, with women showing more depression, the multivariable model predicting 1-year depression does not reflect a gender effect after controlling for baseline measures (p= 0.68). These results indicate that postoperative depression levels are attributable to preoperative depression levels and not to differential recovery after CABG surgery.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSINSTRUMENTSRESULTSDISCUSSIONAPPENDIX: NEUROLOGIC OUTCOME...ACKNOWLEDGMENTSREFERENCES |
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Guidelines jointly published by the American College of Cardiology and the American Heart Association suggest that improvements in QOL and not just survival should be accounted for when offering CABG surgery as an option to a patient (35). It is generally assumed that relief of physical symptoms, such as angina after surgery, should by itself lead to improvements in QOL, but it is clear that mental health status also significantly affects QOL. Newman and colleagues have shown that postoperative cognitive decline is associated with cognitive dysfunction 5 years after surgery (13), and this decline in turn is associated with lower general health and a less productive working status (14). Studies have also demonstrated that depressed patients with coronary disease are at increased risk for mortality (36). Even though depressive symptoms may not always worsen after cardiac surgery, the presence of depression at baseline significantly increases their risk for postoperative adverse cardiac events (37). The importance of assessing QOL in patients undergoing CABG surgery is further illustrated in a study by Rumsfeld (38), who found that preoperative health-related QOL, as measured in 2480 patients, is a predictor of mortality after surgery. According to Rumsfeld, scoring 10 points lower on the SF-36 Physical Component Summary score had an odds ratio of 1.39 for predicting mortality.
In the current study, despite finding no consistent gender-related differences in our cognitive domains, we do find that women report more cognitive symptoms than men do on the Cognitive Difficulties scale. This association is consistent with our finding that women show a greater decline on cognitive domain 3 (attention and concentration). The Cognitive Difficulties scale is correlated with three of our four cognitive domains: verbal memory (p= 0.0002), attention and concentration (p= 0.0009), and abstraction and psychomotor processing speed (p= 0.04), but not with figural memory (p= 0.28). Figural memory, the domain in which women improve significantly more than men, is the domain in which women have the lowest baseline scores, and in which there is the largest initial discrepancy between men’s and women’s scores.
Perception of cognitive functioning has also been shown to be related to the presence of anxiety and depression (41). The prevalence of depression before or after CABG surgery is generally reported to be approximately 20% (37). In our study, unadjusted CESD scores show more depression in women both at baseline and at 1 year after surgery, but multivariate analysis indicates that the postsurgical depression experienced by women is attributable primarily to already existing depression. In contrast, anxiety, which is also a greater problem for women than men both before and after surgery, appears to be related to differential recovery from CABG, exaggerating a difference that already existed. In terms of daily activities and work activities, as measured by the IADL, DASI, and work activities scale (SF-36), we see that although both men and women have surpassed baseline levels, women do not experience the same degree of improvement as men.
The observation that women do not show the same QOL benefit from CABG surgery as men do cannot be explained by preoperative differences, as we have measured them. We offer two possible explanations why women have poorer QOL profiles than men. First, women do not experience the same degree of surgical benefit that men do, and therefore the change in QOL is not as great. Allen et al. (18) speculate that this difference can be partly explained by the size of the coronary arteries and less favorable cardiovascular profiles. Even after adjusting for preoperative risk differences, women are more likely than men to die in hospital after CABG surgery (42). In addition, the long-term bypass graft patency rate in women has been reported to be poorer than for men (43). Thus, women continue to have multiple coronary risk factors after CABG, experience less relief of angina and dyspnea, experience poorer levels of health, have more bedridden and restricted activity days, and are more likely to be using cardiac medications than men, putting them at high risk for future coronary heart disease events (18). The impaired QOL that we find in our analysis may therefore be related to the generally poorer prognosis for women after CABG surgery.
A second possible explanation for the diminished QOL benefit from surgery is that women’s compromised QOL is less related to cardiac health than is men’s QOL, and therefore less responsive to cardiac intervention. If the causes of lower preoperative QOL are more environmental and/or personality-related for women than for men, this could account for the observed differences in improvement. In this case, other interventions besides CABG surgery would be required for women to achieve the same improvements as men, even if women experienced equivalent cardiac benefits from the surgery.
Our results differ from previous studies, such as that by Hunt (6) who reported no significant gender differences on any SF-36 subscale at 1-year follow-up. However, that study was smaller (total N= 123, women = 22), and did not include baseline data. Examination of the actual means also indicates that some differences (as much as 9 points on individual scales) did exist, and may have been found significant in a study of sufficient power. Similarly, King (10) concluded from her study of 120 patients that gender does not play a consistent role in predicting biopsychosocial recovery, and found that women fare as well as men in the post operative period. However, it is possible that on longer-term follow-up, gender differences may have emerged, as we see in our larger study. Finally, Sjoland (44) reported lower QOL in women than in men (total N= 2121, women = 401) at each follow-up time period, but no gender-related differences in change in QOL. Unfortunately, the reported analysis did not statistically adjust for any preoperative differences between men and women except for age.
Our conclusion is that women do not show the same benefit from CABG surgery that men do in a number of important QOL measures, and that these differences cannot be attributed to preoperative differences. In every measure of QOL, baseline QOL is the single best predictor of 1-year QOL. By adjusting for baseline measures in our multivariate models, we controlled for the many intangible and unmeasured factors that cause women to appear more compromised at baseline. While absolute levels of QOL and cognition are worse for women at 1-year follow-up, it is striking how many of these differences persist even after adjustment for risk factors. In many domains, women start worse than men, finish worse than men, and have worse recovery profiles than men.
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APPENDIX: NEUROLOGIC OUTCOME RESEARCH GROUP OF THE DUKE HEART CENTER |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSINSTRUMENTSRESULTSDISCUSSIONAPPENDIX: NEUROLOGIC OUTCOME...ACKNOWLEDGMENTSREFERENCES |
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Anesthesiology:
John V. Booth, MD, Hilary P. Grocott, MD, Steven E. Hill, MD, Joseph P. Mathew, MD, Mark F. Newman, MD, J.G. Reves, MD, Debra A. Schwinn, MD, Mark Stafford-Smith, MD, David Warner, MD, Madan Kwatra, PhD, Bonita L. Funk, RN, ED Derilus, BS, Jason Hawkins, RN, BSN, I. Lee McClurkin, BA, RN, Terri Moore, BA, Chonna Campbell, BS, Amanda Cheek, AS, Roger L. Hall, AAS., Tanya Kagarise, BS, Jerry L. Kirchner, BS, Satarah Latiker, BS, Erich Lauff, BA, Charles R. Peters, MA, Meredith Prince, Joe Russell, RN, Debra L. Whiteheart, BS, Regina DeLacy, BA, William Hansley, BS, Yvonne M. Connelly, MA, MPH, Barbara Phillips-Bute, PhD, and William D. White, MPH
Behavioral Medicine:
Michael A. Babyak, PhD, James A. Blumenthal, PhD
Cardiology:
Daniel B. Mark, MD, MPH and Michael H. Sketch Jr, MD
Neurology:
Carmelo Graffagnino, MD, Daniel T. Laskowitz, MD, John R. Lynch, MD, Ann M. Saunders, PhD, Warren J. Strittmatter, MD, and Kathleen A. Welsh-Bohmer, PhD
Pathology:
Ellen R. Bennett, PhD
Perfusion Services:
Greg Smigla, BS, CCP and Ian Shearer, BS, CCP
Surgery:
Robert W. Anderson, MD, Thomas A. D’Amico, MD, R. Duane Davis, MD, Donald D. Glower, MD, R. David Harpole, MD, James Jaggers, MD, Robert H. Jones, MD, Kevin Landolfo, MD, James E. Lowe, MD, Robert H. Messier, MD, Carmelo Milano, MD, Peter K. Smith, MD, Eric M. Toloza, MD, PhD, and Walter G. Wolfe, MD
Cardiothoracic Anesthesia Research Endeavors (C.A.R.E.) Director:
Mark Stafford-Smith, MD
Co-Director:
Joseph P. Mathew, MD
Anesthesiology:
Mark J. Bennett, MD, John V. Booth, MD, Fiona M. Clements, MD, Norbert de Bruijn, MD, Katherine Grichnik, MD, Hilary P. Grocott, MD, Steven E. Hill, MD, Joseph P. Mathew, MD, Mark F. Newman, MD, Mihai V. Podgoreanu, MD, Debra A. Schwinn, MD, Mark Stafford-Smith, MD, Madhav Swaminathan, MD, and Ian J. Welsby, MD
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSINSTRUMENTSRESULTSDISCUSSIONAPPENDIX: NEUROLOGIC OUTCOME...ACKNOWLEDGMENTSREFERENCES |
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The authors thank Yvonne M. Connelly MA, MPH, for her editorial contributions.
Received for publication September 23, 2002.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSINSTRUMENTSRESULTSDISCUSSIONAPPENDIX: NEUROLOGIC OUTCOME...ACKNOWLEDGMENTSREFERENCES |
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