POD is among the most common postoperative complications in the elderly and is associated with increased mortality, morbidity, hospital costs, and discharge to long-term care facilities. Thus, understanding its predictors and sequelae has considerable significance.
In a prediction model of delirium in hospitalized medical patients, independent predictors included older age, severe illness, dehydration, and cognitive and visual impairment.33 This model was validated in patients undergoing elective orthopedic surgery.7 Age, type of procedure, physical status, glucose and electrolyte abnormalities, and diminished functional and cognitive status were independent predictors in a model for POD in noncardiac surgical patients.6 However, these studies used global measures of cognitive status such as the MMSE. Although sufficient for dementia screening, those instruments are not designed to detect subtle cognitive changes.
We hypothesized that lower scores on sensitive neurocognitive tests predict POD, a hypothesis supported by our results. By design, no patients included in this study had clinically apparent cognitive deficits. The neurocognitive test battery used in this study was sensitive enough to detect subtle differences in a variety of cognitive domains. Although clinically normal, patients who developed POD had decreased performance on the tests compared with those who did not, despite similar educational levels and verbal intelligence and MMSE scores. We can only speculate why lower scores on the neurocognitive tests predicted POD. Whether these patients are more likely to develop clinically significant cognitive deterioration is not known. The lower scores in the POD patients may be early signs of neurodegenerative diseases. Alternatively, they simply may be indicative of diminished baseline cognitive reserve.
Two recent studies found that tests of executive function and depressive symptoms were independent risk factors for POD in noncardiac surgical patients.9,10 Although we did not find depressive symptoms to be predictive of POD in this study, participants had low levels of these at baseline. However, history of psychiatric illness was an independent risk factor for POD, and depression was the most common psychiatric diagnosis. Together, this suggests that depression indeed has predictive value for POD.
In our study, we used the SWCT and COWAT to measure executive function and the AVLT to assess verbal learning and memory. Although lower scores on the SWCT, COWAT, and all 3 portions of the AVLT were univariate predictors of POD, only the AVLTPercent Retention was an independent predictor. The AVLTPercent Retention is a measure of short-term memory. Thus, we found that memory, not executive function, is an independent risk factor for POD. Although preoperative subjective memory complaints are predictive of POD in cardiac surgical patients,34 Rudolph et al.35 reported that lower scores on formal tests of memory are not predictive in that population. We are unaware of other studies demonstrating that memory is a predictor of POD. Greene et al.9 and Smith et al.10 found that executive function predicts POD, but neither reported scores for tests of memory. In both studies, patients were considerably younger than those in our study. In the Rudolph et al. study, patients were similar in age to our cohort, but they had cardiac surgery instead of elective lower extremity joint replacement surgery. Whether age has a role in determining which neurocognitive domains are most predictive of POD is not clear. More research is needed to determine which domains of cognitive function are most important in predicting POD and whether age or other factors alter which domains are most important.
Although the neurocognitive findings are interesting, routine preoperative formal neurocognitive testing is time consuming, expensive, and requires trained personnel. A more clinically useful predictor of POD would be helpful. In this study, the preoperative ADL score was an independent risk factor for POD. ADL scores are quickly obtained via questionnaire or allied health personnel interview, and add no cost to the preoperative examination. Thus, functional status assessment during the preoperative evaluation is feasible and could contribute to preoperative risk stratification.
Although not the goal of the project, the independent risk factors for POD found in this study (age, ADL and AVLTPercent Retention scores, and history of psychiatric illness) could form the basis of a clinical prediction rule to assess the likelihood of POD. Further study would be necessary to validate the strength of this model and its applicability to other surgical populations.
The other key finding in this study is that POD does not predict diminished cognitive or functional status 3 months postoperatively. In medical patients, delirium predicts long-term cognitive and functional decline.11 – 15 Similarly, POD predicts persistent cognitive impairment after hip fracture surgery.36 POD also predicts functional decline in hip fracture surgery patients. For example, POD is an independent predictor of declines in ADL scores and ambulation, and of an increased likelihood of death or nursing home placement.37 However, falls leading to hip fracture are often the result of concurrent medical illness and surgery is performed urgently, both of which may affect the pathogenesis of POD.
Cognitive decline temporally related to surgery is known as POCD. POCD is a research construct with definitions that vary by type of cognitive testing, degree of decline required for diagnosis, and time course.38 These variations in methodology make comparisons across studies of POCD difficult.
The relationship between POCD and POD is unclear. The 2 entities may be a continuum of postoperative brain dysfunction wherein POD leads to POCD. Alternatively, they may be distinct and unrelated. Two studies using a z score definition of POCD have examined the relationship between POD and POCD.39,40 In both, POD was a predictor of POCD 1 week postoperatively, but not at 3 months.
In this study, changes in neurocognitive test scores 3 months postoperatively were not significantly different between patients experiencing POD and controls. This, and the studies noted above, suggest that after elective surgery, POD may not lead to POCD at 3 months postoperatively. In fact, mean neurocognitive test scores were improved 3 months postoperatively in both POD cases and controls. We cannot exclude that practice effects may have had some role in this. However, we attempted to minimize these effects by not retesting until 3 months postoperatively and, when available, using alternate test forms at follow-up. The improvement in test scores at 3 months may have also been influenced by the timing of preoperative testing. This was usually accomplished the day before surgery. It is possible that presurgical anxiety may have resulted in poorer performance at that time.41
In normal subjects, higher levels of educational attainment are protective against cognitive decline and dementia.42 However, higher levels of educational attainment may39 or may not43 be protective against POCD 3 months postoperatively. The participants in our study were relatively highly educated compared with those in other studies. We excluded the possibility that this had some role in our inability to find a difference in neurocognitive test scores between baseline and 3 months postoperatively in POD patients versus controls.
POD also did not affect functional status 3 months postoperatively. This, combined with the neurocognitive data, suggests that, unlike medical patients or those undergoing urgent procedures such as hip fracture repair, POD after elective surgery, once resolved, is not associated with functional decline 3 months postoperatively. Taken together, the follow-up neurocognitive and functional data suggest that, in elderly patients with good baseline functional and global cognitive status, anesthesia and elective surgery are not associated with cognitive or functional decline at 3 months.
This study has several limitations. First, it was conducted at a single institution on a homogeneous group of patients. It is unclear whether the results are generalizable to other patient populations, procedures, and institutions. However, the study design attempted to maximize the reliability of the neurocognitive and functional test results and limit confounders. One potential confounder is postoperative pain. We were not able to obtain pre- or postoperative pain scores. Pain can affect neurocognitive test scores44,45 and postoperative pain is associated with POD.46 Again, the study design attempted to account for this by including a homogeneous group of patients having similar operations. In addition, policy at our institution during the period of the study was for aggressive pain management with a goal numerical pain score of ≤3 of 10. We believe that these factors mitigated the effect of pain on the incidence of POD. Second, we developed the multivariate model using a stepwise algorithm. With this approach, there is the possibility of overfitting the observed data and suppression of some covariates. To account for this, we used bootstrap resampling to identify important patient or procedural characteristics predictive of POD. Third, patients' baseline neurocognitive and functional status were relatively high. POD may predict further cognitive decline only in patients with lower baseline cognitive and functional status. Similarly, although POD did not predict cognitive and functional decline 3 months postoperatively, only 37 patients with POD were available for follow-up testing and the SDs and CIs on the tests were large relative to the mean differences (Table 6). Thus, we cannot exclude a small effect on decline or that decline occurs later than 3 months. Finally, our study does not have adequate statistical power to compare groups using a dichotomous end point (POCD/no POCD). However, based on the distributions of the change scores observed in our study, we are not convinced that a dichotomous end point is the most appropriate way to evaluate changes in cognitive function. Thus, we treated these data in a continuous manner. This approach is consistent with the literature concerning cognitive decline in nonsurgical patients.47
In summary, diminished functional status and lower scores on sensitive neurocognitive tests predict POD in elderly patients undergoing elective total joint arthroplasty. Simple preoperative functional testing may help identify those patients at risk for POD. In this study, POD did not predict cognitive or functional decline at 3 months, suggesting that in this population, POD may not lead to adverse cognitive or functional sequelae and that POD and POCD may be clinically distinct entities. Further study is necessary to more clearly define this relationship.
1. Anonymous. Profile of General Demographic Characteristics: 2000. US Census Bureau, 2000
2. Dyer CB, Ashton CM, Teasdale TA. Postoperative delirium: a review of 80 primary data-collection studies. Arch Intern Med 1995;155:461–5
3. Bitsch M, Foss N, Kristensen B, Kehlet H. Pathogenesis of and management strategies for postoperative delirium after hip fracture: a review. Acta Orthop Scand 2004;75:378–89
4. Franco K, Litaker D, Locala J, Bronson D. The cost of delirium in the surgical patient. Psychosomatics 2001;42:68–73
5. Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery: a systematic review. J Am Geriatr Soc 2006;54:1578–89
6. Marcantonio ER, Goldman L, Mangione CM, Ludwig LE, Muraca B, Haslauer CM, Donaldson MC, Whittemore AD, Sugarbaker DJ, Poss R, Haas S, Cook EF, Orav EJ, Lee TH. A clinical prediction rule for delirium after elective noncardiac surgery. JAMA 1994;271:134–9
7. Kalisvaart KJ, Vreeswijk R, de Jonghe JFM, van der Ploeg T, van Gool WA, Eikelenboom P. Risk factors and prediction of postoperative delirium in elderly hip-surgery patients: implementation and validation of a medical risk factor model. J Am Geriatr Soc 2006;54:817–22
8. Culley DJ, Monk TG, Crosby GJ. Postoperative central nervous system dysfunction. In: Silverstein JH, Rooke GA, Reves JG, McLeskey CH eds. Geriatric Anesthesiology. 2nd ed. New York: Springer, 2008:123–36
9. Greene NH, Attix DK, Weldon BC, Smith PJ, McDonagh DL, Monk TG. Measures of executive function and depression identify patients at risk for postoperative delirium. Anesthesiology 2009;110:788–95
10. Smith PJ, Attix DK, Weldon BC, Greene NH, Monk TG. Executive function and depression as independent risk factors for postoperative delirium. Anesthesiology 2009;110:781–7
11. Murray AM, Levkoff SE, Wetle TT, Beckett L, Cleary PD, Schor JD, Lipsitz LA, Rowe JW, Evans DA. Acute delirium and functional decline in the hospitalized elderly patient. J Gerontol 1993;48:M181–6
12. Inouye SK, Rushing JT, Foreman MD, Palmer RM, Pompei P. Does delirium contribute to poor hospital outcomes? A three-site epidemiologic study. J Gen Intern Med 1998;13:234–42
13. O'Keeffe S, Lavan J. The prognostic significance of delirium in older hospital patients. J Am Geriatr Soc 1997;45:174–8
14. Cole MG. Delirium in elderly patients. Am J Geriatr Psychiatry 2004;12:7–21
15. McCusker J, Cole M, Dendukuri N, Belzile E, Primeau F. Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study. CMAJ 2001;165:575–83
16. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98
17. Grober E, Sliwinski M. Development and validation of a model for estimating premorbid verbal intelligence in the elderly. J Clin Exp Neuropsychol 1991;13:933–49
18. Rey A. Psychological examination in cases of traumatic encephalopathy. Arch Psychol 1941;28:286–340
19. Harris ME, Ivnik RJ, Smith GE. Mayo's Older Americans Normative Studies: expanded AVLT Recognition Trial norms for ages 57 to 98. J Clin Exp Neuropsychol 2002;24:214–20
20. Steinberg BA, Bieliauskas LA, Smith GE, Ivnik RJ, Malec JF. Mayo's Older Americans Normative Studies: Age- and IQ-Adjusted Norms for the Auditory Verbal Learning Test and the Visual Spatial Learning Test. Clin Neuropsychol 2005;19:464–523
21. Benton AL. Development of a multilingual aphasia battery: progress and problems. J Neurol Sci 1969;9:39–48
22. Steinberg BA, Bieliauskas LA, Smith GE, Ivnik RJ. Mayo's Older Americans Normative Studies: Age- and IQ-Adjusted Norms for the Trail-Making Test, the Stroop Test, and MAE Controlled Oral Word Association Test. Clin Neuropsychol 2005;19:329–77
23. Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18:643–62
24. Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Measure 1977;1:385–401
25. Ewing JA. Detecting alcoholism: the CAGE questionnaire. JAMA 1984;252:1905–7
26. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: advantages of a new specific activity scale. Circulation 1981;64:1227–34
27. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged: the index of ADL—a standardized measure of biological and psychosocial function. JAMA 1963;185:914–9
28. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9:179–86
29. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method—a new method for detection of delirium. Ann Intern Med 1990;113:941–8
30. Sauerbrei W, Schumacher M. A bootstrap resampling procedure for model building: application to the Cox regression model. Stat Med 1992;11:2093–109
31. Newman MF, Kirchner JL, Phillips-Bute B, Gaver V, Grocott H, Jones RH, Mark DB, Reves JG, Blumenthal JA. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 2001;344:395–402
32. Cohen J. Statistical Power Analysis for the Behavorial Sciences. Hillsdale, NJ: Erlbaum Associates, 1988
33. Inouye SK, Viscoli CM, Horwitz RI, Hurst LD, Tinetti ME. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 1993;119:474–81
34. Veliz-Reissmuller G, Aguero Torres H, van der Linden J, Lindblom D, Eriksdotter Jonhagen M. Pre-operative mild cognitive dysfunction predicts risk for post-operative delirium after elective cardiac surgery. Aging Clin Exp Res 2007;19:172–7
35. Rudolph JL, Jones RN, Grande LJ, Milberg WP, King EG, Lipsitz LA, Levkoff SE, Marcantonio ER. Impaired executive function is associated with delirium after coronary artery bypass graft surgery. J Am Geriatr Soc 2006;54:937–41
36. Gruber-Baldini AL, Zimmerman S, Morrison RS, Grattan LM, Hebel JR, Dolan MM, Hawkes W, Magaziner J. Cognitive impairment in hip fracture patients: timing of detection and longitudinal follow-up. J Am Geriatr Soc 2003;51:1227–36
37. Marcantonio ER, Flacker JM, Michaels M, Resnick NM. Delirium is independently associated with poor functional recovery after hip fracture. J Am Geriatr Soc 2000;48:618–24
38. Silverstein JH, Timberger M, Reich DL, Uysal S. Central nervous system dysfunction after noncardiac surgery and anesthesia in the elderly. Anesthesiology 2007;106:622–8
39. Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT, Heilman KM, Gravenstein JS. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008;108:18–30
40. Rudolph JL, Marcantonio ER, Culley DJ, Silverstein JH, Rasmussen LS, Crosby GJ, Inouye SK. Delirium is associated with early postoperative cognitive dysfunction. Anaesthesia 2008;63:941–7
41. Bierman EJ, Comijs HC, Jonker C, Beekman AT. Effects of anxiety versus depression on cognition in later life. Am J Geriatr Psychiatry 2005;13:686–93
42. Whalley LJ, Deary IJ, Appleton CL, Starr JM. Cognitive reserve and the neurobiology of cognitive aging. Ageing Res Rev 2004;3:369–82
43. Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Biedler A, van Beem H, Fraidakis O, Silverstein JH, Beneken JE, Gravenstein JS. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 1998;351:857–61
44. Hart RP, Martelli MF, Zasler ND. Chronic pain and neuropsychological functioning. Neuropsychol Rev 2000;10:131–49
45. Heyer EJ, Sharma R, Winfree CJ, Mocco J, McMahon DJ, McCormick PA, Quest DO, McMurtry JG III, Riedel CJ, Lazar RM, Stern Y, Connolly ES Jr. Severe pain confounds neuropsychological test performance. J Clin Exp Neuropsychol 2000;22:633–9
46. Lynch EP, Lazor MA, Gellis JE, Orav J, Goldman L, Marcantonio ER. The impact of postoperative pain on the development of postoperative delirium. Anesth Analg 1998;86:781–5
47. Hachinski V. Shifts in thinking about dementia. JAMA 2008;300:2172–3
APPENDIX: SUPPLEMENTAL ONLINE FIGURE LEGENDS
Figures 1–5 show the distributions of the changes between preoperative and 3-month postoperative neurocognitive test scores for patients with postoperative delirium (POD) and their matched controls. The dashed line represents a 1 SD decline from baseline. In all instances, the distributions are approximately normal and there is no difference in their means. Although for each scale there are some patients who decline by >1 SD, those patients do not appear to be outside the distribution. Given this, and literature suggesting that cognitive decline is best treated as a continuous variable,41 we believe that an analysis comparing the mean change between groups is more appropriate than one that defines postoperative cognitive decline as a dichotomous end point. AVLTLE = Learning Efficiency portion of the Auditory Verbal Learning Test; AVLT%R = Percent Retention portion of the Auditory Verbal Learning Test; AVLTDR = Delayed Recall portion of the Auditory Verbal Learning Test; COWAT = Controlled Word Association Test; SCWT = Stroop Color-Word Test.