Postoperative cognitive dysfunction (POCD) is defined by changes in neuropsychological tests administered before and after anesthesia and surgery, and has the potential to affect clinical outcomes up to 5 years postoperatively.1 Early studies focused on POCD after cardiac surgery. Shaw et al.2 identified rates of POCD of 79% at 7 days after surgery, with 38% showing significant symptoms of neuropsychological impairment.
The calculation of the incidence of POCD is dependent on many factors including the number and type of cognitive tests,3 the manner in which they were administered, and the definition of decline.4 The use of an appropriate control group from which to infer significant change in the test group also affects the calculated incidence of POCD.5 Without a control group, a decrease of 1 SD of the baseline mean for all patients has often been used to infer change (1 SD method), whereas if a control group is used, change in a test is inferred if an individual's z score is less than −1.96 (SD) for the relevant test (reliable change method).6 Control groups also correct for practice effects,6 normal age-related cognitive decline,7 and any other unknown confounders.
Subsequent studies have documented the incidence of POCD after cardiac surgery with widely ranging results.8 More recent data in cardiac surgery suggest a POCD incidence of 11% to 13% at 3 months and similar rates at 12 months (1 SD rule).9 The role of cardiopulmonary bypass (CPB) in contributing to POCD has been challenged by studies that have compared off-pump to on-pump cardiac surgery and found little difference in the incidence of POCD.10,11 The incidence of POCD in the elderly population (>60 years) undergoing noncardiac surgery has been cited as 9.9%12 and 12.7%13 after 3 months. These rates are not dissimilar to the rates at 3 months after cardiac surgery of 10.5% (1 SD method), 7.7% (reliable change method),5 and those of Silbert et al.9 (see above).
It is difficult, however, to draw meaningful conclusions by comparing data across varying procedures because of different clinical practice environments, differing neuropsychological batteries, and importantly, testing strategies.14 Furthermore, changes in clinical practice in recent years (anesthetic and procedural) may confound comparisons.
It is unclear what causes POCD, but the etiology is believed to be multifactorial.15 Although age is consistently correlated,16 the nature of the surgical or anesthetic procedures, perioperative stressors, and other patient factors may all be important. The testing and analytical methods among different study groups are seldom consistent, which is likely to lead to variability in reported incidences. Because direct comparisons among different studies may be misleading, there remains a need to clarify the effect of the procedure and its associated anesthetic as a whole, on POCD.
To address the question of the impact of procedure type and anesthetic, a single, consistent dataset is required. As a single research center, we have coordinated and conducted comprehensive pre- and postprocedural cognitive function testing in a large number of patients at a small number of institutions within the last decade. Furthermore, these assessments have been made by a consistent group of investigators trained under the supervision of a neuropsychologist (PM) and the patient population has a very high retention to follow-up.
The aim of this study was to determine the association of type of surgical procedure and associated anesthesia on the incidence of POCD after procedures involving light sedation, general anesthesia for noncardiac surgery, and general anesthesia for cardiac surgery involving CPB.
METHODS
Data for this investigation were prospectively collected and analyzed from 3 research projects investigating periprocedural cognitive dysfunction. The studies were conducted using the same personnel to screen, recruit, test, and follow-up each patient and control. All studies had institutional human research ethics committee approval, and written informed consent was obtained from all participants. Three procedure groups were included:
- Coronary angiography (CA) (percutaneous diagnostic procedure) under sedation (the CISCO study, ACTRN: 012607000051448).
- Noncardiac surgery: major noncardiac surgery (total hip joint replacement [THJR] surgery) under general anesthesia (the ACE study, ACTRN: 012607000049471).
- Cardiac surgery: coronary artery bypass graft (CABG) surgery under general anesthesia with CPB (the ANTIPODES trial,9 ACTRN: 012605000285651); previous publications have explored the cognitive results of these patients.
All patients were studied between 2001 and 2010. Only the results of the CABG surgery group have been published.9,17
Inclusion criteria included age >50 years for CA patients, age >55 years for THJR and CABG surgery patients, fluency with English, and geographical accessibility for baseline testing. Exclusion criteria included history of stroke or transient ischemic attack, treatment with sedatives, and clinical history of dementia or, for CA and noncardiac surgery patients, a Mini-Mental State Examination score of <26. Patients in the CA group who went on to have coronary artery surgery within 3 months were not included. Baseline demographic and medical data were collected for all patients.
Surgery and Anesthesia
The CA patients underwent nonurgent first-time CA via a percutaneous femoral approach using local anesthetic at the puncture site. Oral temazepam (10 mg) and promethazine (25 mg) administered 30 minutes before the procedure were used for premedication and sedation. No other sedatives were given. Paracetamol was used for postprocedural analgesia.
The noncardiac surgery patients underwent elective first-time THJR surgery. Anesthesia comprised temazepam premedication, spinal anesthesia with midazolam sedation up to 5 mg, and then a light general anesthetic using propofol and/or a volatile anesthetic with the aim of maintaining a bispectral index <60 (BIS Monitor; Aspect Medical Systems, Norwood, MA). After surgery, analgesia was provided by morphine patient-controlled analgesia for 48 hours, then oxycodone.
Cardiac surgery patients underwent elective, first-time CABG surgery on CPB. Premedication was oral temazepam 10 to 20 mg 60 minutes preoperatively. Anesthesia comprised an induction opioid dose of fentanyl 10 to 50 μg/kg, supplemental propofol as clinically indicated for induction, midazolam up to 5 mg, and rocuronium. No volatile anesthetic was used. The details are described elsewhere.9 The original trial was a comparison of low- and high-dose fentanyl on cognitive outcomes. Because no influence from anesthesia type was identified, the data from both groups have been combined, including patients who were excluded from the original trial analysis because of anesthesia protocol violations.
Neuropsychological Testing
Neuropsychological tests were administered by research personnel who were trained under the supervision of a neuropsychologist. The majority of testing was conducted by the same core group of research staff. The neuropsychological tests used in this study were selected on the basis of their sensitivity to impairment in a range of cognitive domains in older people and were based on those recommended by the consensus statement.18 The test battery administered to both study and control subjects consisted of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Auditory Verbal Learning Test, Digit Symbol Substitution Test, Trail Making Test parts A and B, Controlled Oral Word Association Test, Consortium to Establish a Registry for Alzheimer's Disease verbal fluency—animals (CERAD fluency), and the Grooved Pegboard Test Dominant and Nondominant Hands. All of these tests have been described elsewhere.9 The results are given as the number of correct answers or the time taken to complete the test.
Parallel forms were administered where available, and all the tests were administered in the same order. Intelligent quotient (IQ) was derived from the results of the National Adult Reading Test (NART), which was administered at the baseline assessment.19
All patients underwent baseline testing within 1 week before their procedure. Postprocedural testing was done at 7 days after the procedure for the THJR and CABG surgery patients and at 3 months for all groups. The protocol for the CA patients did not include a 7-day testing because it was thought that this group would be unlikely to show cognitive change at this time because of the minor nature of the procedure. The majority of this testing was done at the patient's home to provide a more relaxed and stress-free environment. Noisy and unfamiliar testing environments, such as hospitals, have been shown to negatively affect test results.18
A control group was recruited from the community as part of the ACE study. These subjects were aged >55 years, had large joint osteoarthritis, and had no surgery planned for the next 12 months. Otherwise, they met the inclusion and exclusion criteria cited above. These participants underwent neuropsychological testing with the same battery of tests, and at the same time intervals, as the study patients. Control subjects who underwent unexpected surgery between baseline testing and 3 months were excluded (3 subjects).
Test scores were analyzed to identify POCD using the reliable change index (RCI). The RCI rule was calculated following the procedure outlined by Rasmussen et al.6 RCIs were determined by subtracting the preoperative score (X1) from the postoperative score (X2), giving ΔX for each individual participant for a given task. The mean expected change for the controls, ΔXc, calculated in the same way, was then subtracted from this, removing any practice effect. This score was then divided by the standard deviation for the change in test results of the control group, SD(ΔXc), controlling for the expected variability. These scores were then used to create a combined test score (Zcombined) using the sum of z scores for each test (ΣZa,b,c,d,etc.) divided by the standard deviation of this summation in the control group (SD[ΣZcontrol]). POCD was defined in an individual when their RCI score was less than −1.96 on ≥2 tests and/or their combined z score was less than −1.96. This classifies POCD on the basis of a substantial failure on ≥2 tests, or a more pervasive subtle decline across the neuropsychological test battery.
Statistical Analysis
Group comparisons were made using unpaired t tests for continuous variables, the Spearman ranked correlation coefficient or Kruskal-Wallis test for ranked data, and χ2 or Fisher exact test for dichotomous variables. The type I error rate was controlled using the Holm-Bonferroni step-down procedure for multiple comparisons.20
Associations were determined using univariable analysis and multivariable logistic regression with a probability value of <0.2 set for entry into the multivariable regression models.
Tests were performed using STATA (version 11.0; Stata Corp., College Station, TX). A probability value of <0.05 was taken to indicate statistical significance.
RESULTS
There were 644 patients in the patient groups and 34 in the control group. The basic demographics, including cardiovascular risk factors, are summarized in Table 1. The procedural populations were slightly younger (mean difference, 4.3 years) and with a higher proportion of males, a higher proportion using β-blockers, and lower estimated IQ, than in the control group. After adjusting for the effect of multiple comparisons, there were no differences in the measured cardiovascular risk factors apart from body mass index.
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Table 1: Patient and Control Demographics and Medical History
The mean age of the CA and CABG surgery patients was younger compared with control subjects, and the proportion of males was higher, reflecting the age threshold for enrollment in these study groups and the demographics of patients having cardiac procedures (Table 2). There were no significant differences among the patient groups for baseline neuropsychological tests apart from the NART (used for estimated IQ), Controlled Oral Word Association Test, and the Word Learning Test. Associations between cardiovascular risk factors and POCD for each procedure group are shown in Appendix A (see Supplemental Digital Content 1, https://links.lww.com/AA/A254), and for age and POCD in Appendix B (see Supplemental Digital Content 2, https://links.lww.com/AA/A255).
Table 2: Test Score Results at Baseline for Control, Coronary Angiography, Total Hip Joint Replacement Surgery, and Coronary Artery Bypass Graft Surgery Groups
The median testing time at 7 days was 6 days (interquartile range, 6–8) and at 3 months was 97 days (interquartile range, 89–106). Data were available for POCD at day 7 for the THJR surgery and CABG surgery patients (for day 7, n = 162 and 281, respectively).The incidence of POCD was 17% for the THJR surgery patients and 43% for the CABG surgery patients (Table 3) (adjusted odds ratio = 0.2, 95% confidence interval [CI]: 0.1, 0.4; P < 0.01). The proportion of controls that deteriorated at this time compared with baseline (qualifying for classification of POCD) was 2 of 34 (6%), which was significantly lower than both patient groups.
Table 3: Incidence of Postoperative Cognitive Dysfunction for Control, Coronary Angiography, Total Hip Joint Replacement Surgery, and Coronary Artery Bypass Graft Surgery Groups
At 3 months, the incidence of POCD over all groups combined (n = 636) was 17% as detailed in Table 3. Two control subjects were not tested at this time, one because of overseas travel and one was on vacation. Within the study groups, 3-month testing was not recorded for 1 patient in the CA group (patient was unwell), and 7 patients in the THJR group (2 on vacation, 3 unwell, 2 missed for logistic reasons). There were no significant differences between any of the patient groups (adjusted odds ratio = 1.21, 95% CI: 0.94, 1.55; P = 0.13). The mean (95% CI) for the difference in proportions of POCD among groups was 0.00 (−0.07, 0.07) (P = 0.91) for CABG versus THJR; −0.05 (−0.12, 0.03) (P = 0.21) for CABG versus CA; and −0.05 (−0.13, 0.03) (P = 0.24) for THJR versus CA (Table 4). The incidence of POCD was significantly higher in all groups compared with the incidence in controls (χ2 = 6.698, P = 0.01). Of the 32 control subjects tested at 3 months, none qualified for classification of POCD (Table 3).
Table 4: Incidence and Difference in Proportion of Postoperative Cognitive Dysfunction for Coronary Angiography, Total Hip Joint Replacement Surgery, and Coronary Artery Bypass Graft Surgery Groups
When comparing POCD outcomes for impairment (i.e., z score less than −1.96 below controls for that test) on individual tests (Table 5), the highest frequencies were Grooved Pegboard Nondominant Test and CERAD fluency test. This demonstrates that deficits occurred across the range of tests and that attribution of POCD was therefore the result of those patients exhibiting deficits in multiple tests.
Table 5: Impaired Performance at 3 Months in Neuropsychological Tests
The combined patient data at 7 days and at 3 months were analyzed by univariable and multivariable analysis to identify associations among surgery/anesthetic type (procedure group: CA, THJR surgery, and CABG surgery), patient factors, and POCD (Table 6). All demographic variables (Table 1) and medical risk factors were included in the univariable analysis, including education level (estimated IQ based on the NART includes level of education). Previous stroke was an exclusion for all studies. At 7 days, a number of factors were identified as associated on univariable analysis, but only age and procedure group (THJR surgery or CABG surgery) remained significant on multivariable analysis. At 3 months, although the procedure group (CA, THJR surgery, or CABG surgery) was not significantly associated in the univariable analysis, it was included in the multivariable analysis because it was the primary outcome of the study. Increasing age was the only significant predictor for POCD using multivariable analysis at 3 months. Hosmer-Lemeshow goodness-of-fit statistics are shown in Table 6, and reveal that the logistic regression multivariable models implemented are a reasonable fit to the data. Graphs of regression residuals are shown in Appendix C (see Supplemental Digital Content 3, https://links.lww.com/AA/A256).
Table 6: Univariable and Multivariable Analyses
DISCUSSION
In this study, we compared the incidence of POCD across a range of procedure groups (CA, THJR surgery, and CABG surgery) from a single study center, and conclude that type of surgery and anesthesia are not associated with the incidence of POCD at 3 months after surgery for these interventions. At 7 days postprocedure, the patient group undergoing CABG surgery had a significantly higher incidence of POCD (43%) than the general anesthesia THJR surgery patients (17%). However, by 3 months, the incidence of POCD was 21%, 16%, and 16% for procedures involving CA with local anesthesia and sedation, THJR surgery under general anesthesia, and CABG surgery under general anesthesia with CPB, respectively. There was no statistically significant difference between the incidence of POCD in each of the procedure groups. The 95% CIs for the difference in proportions between procedural groups are shown in Table 4. This demonstrates that the risk of a type II error (declaring there is no difference between groups when there is a difference) having occurred at 3 months is unlikely. The upper limit of the CIs indicates that the difference in the incidence of POCD among patients undergoing CA, THJR surgery, or CABG surgery is unlikely to be >5% to 7%.
These findings support previous studies that have identified a high incidence of POCD in the short term (1 week) after both major surgery13 and cardiac surgery.8 However, the type of surgical procedure or anesthetic is not associated with POCD, suggesting that nonspecific factors such as procedural stress or patient susceptibility may be important factors. It is possible that residual pharmacological effects from both the period of anesthesia and also postoperative analgesia have contributed to the effects at day 7. In analyzing POCD incidence at 7 days for noncardiac surgical patients who received general anesthesia or regional anesthesia with sedation, Rasmussen et al.21 found an incidence of 21.2% versus 12.7% (P = 0.04), respectively. Because the surgical operations in that investigation were similar, this suggests that the effects may be pharmacological. Finally, in our studies at day 7, CABG surgery patients were tested while they were still in hospital whereas the THJR surgery patients were tested at home, and this may have contributed to impaired performance in the CABG surgery patients. Testing in hospital has been associated with an increased incidence of POCD.22
The finding that the incidence of POCD after surgery with sedation or anesthesia was not different at 3 months among CA, THJR surgery, and CABG surgery challenges many current concepts regarding the pathogenesis and reversibility of POCD. If the magnitude of the operation or the dose and complexity of the anesthetic were significant factors for this intermediate-term POCD, then differences in incidence would be expected. Support for this thesis is provided by Canet et al.22 who demonstrated 6.6% incidence of POCD after minor surgery, which was not statistically different from a previous study in which they found a 9.9% incidence after major noncardiac surgery in the elderly.
Interestingly, the presence of cardiac history, cardiovascular risk factors, or treatment for cardiovascular disease was not associated with POCD. Previous assumptions in relation to cardiac surgery or cardiac interventions were that the high incidence of POCD was a consequence of cardiovascular disease.23 For example, Wahrborg et al.24 in the “Stent or Surgery” trial examined 77 patients after percutaneous coronary intervention and compared group neurocognitive outcomes with 68 patients having coronary artery surgery. There was no significant difference in group mean scores at 6 or 12 months after the intervention. A history of cardiovascular disease has been reported to be associated with decreased cognitive function in population studies,25 which would suggest that similar associations would pertain to subjects undergoing surgical procedures. Our results show that POCD arises independently of cardiovascular risk factors.
The implications of these findings are important. They indicate that some old and elderly patients experience POCD at 3 months totally independent of the surgical procedure or even the anesthetic. These results shift the focus from a procedural cause to a patient susceptibility and beckon us to identify why some patients exhibit POCD even after simple CA with sedation and no general anesthesia.
A strength of this investigation is the testing methodology. One difficulty with comparing POCD incidence across procedural groups is the possibility of heterogeneity with testing and analytic methods, not assessing patients contemporaneously, and using different control groups. We have sought to minimize these confounders by using patients from 3 primary investigations conducted at our center where the tests are identical and are being administered by consistent staff members who have been trained and supervised by the same people across the patient groups. Testing conditions for these patients were designed to minimize stress, and when they were tested as outpatients, it was usually in their own homes. The ability to undertake home testing also contributes to our high subject retention rate (>90% at 3 months).
A limitation of this study is not having day 7 testing for the CA patients, which was a logistic issue related to study design. Another limitation is that the RCI method relies on an appropriate control group, and although the controls we have used have differing baseline means for 2 (of 8) neuropsychological tests, the calculation of POCD relies on change from baseline rather than raw test results; as such, the baseline raw score does not affect attribution of POCD except as a factor of change. It is unlikely, therefore, that the difference between controls and study groups for these 2 tests would have had an impact on the incidence of POCD, because the effect was consistent across all study groups. The control group is part of the THJR surgery–based ACE study, from which the THJR surgery sample is drawn. Thus, patients tended to be older, more often female, larger (higher body mass indexes), and less likely to be taking β-blockers than the CA or CABG surgery patients. How these factors might affect the analysis of RCI is uncertain, although as increasing age is the only consistent risk factor for POCD, the older age in the control population would tend to make the attribution of POCD more rigorous because it would likely decrease the incidence. Of interest, the incidence of POCD is higher than that reported by Moller et al.12 at 9.9% and Monk et al.13 at 12.7% at 3 months postoperatively. This could be explained by the small variability in our control group, resulting in a small standard deviation associated with expected change in the control group. Importantly, the incidence for all 3 subgroups would be influenced equally and thus not interfere with comparisons among groups.
In conclusion, we have demonstrated that the incidence of POCD in old and elderly patients 3 months after CA, THJR surgery, or CABG surgery is independent of the nature of the type of procedure or anesthetic for these interventions. However, there does seem to be a larger effect for CABG surgical procedures at 1 week. Cardiovascular risk factors were not predictive of POCD in any of the procedure groups studied. The only factor associated with POCD at both day 7 and 3 months was increasing age. Future studies should focus on the influence of patient-related factors on POCD.
DISCLOSURES
Name: Lisbeth Evered, BSc, MBiostat.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Lisbeth Evered has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: David A. Scott, MB, BS, PhD, FANZCA.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: David A. Scott has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Brendan Silbert, MB, BS, FANZCA.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Brendan Silbert has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Paul Maruff, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Paul Maruff has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
ACKNOWLEDGMENTS
The authors thank Sarah Maher, BSc, Candice Johnson, BSc, and Sally Pritchard, BSc, clinical research assistants, Department of Anaesthesia, St. Vincent's Hospital, Melbourne, Australia, for their tireless assistance.
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