Incidence and Risk Factors for Cognitive Dysfunction in Patients with Severe Systemic Disease

The Journal of International Medical Research 2012; 40: 612 620 Incidence and Risk Factors for Cognitive Dysfunction in Patients with Severe Systemic Disease FM RADTKE 1,a, M FRANCK 1,a, TS HERBIG 1, N PAPKALLA 1, R KLEINWAECHTER 1, F KORK 1, WR BROCKHAUS 1, K-D WERNECKE 1,2 AND CD SPIES 1 1 Department of Anaesthesia and Surgical Intensive Care, Charité University of Medicine Berlin, Berlin, Germany; 2 SoStAna GmbH, Berlin, Germany OBJECTIVE: To determine the relevance of surgery and other causative factors to the incidence of postoperative cognitive dysfunction (POCD) in patients with severe systemic disease. METHODS: This observational study included 107 noncardiac surgical patients and 26 nonsurgical control subjects, all of whom had an American Society of Anesthesiologists physical classification status of 3. Cognitive assessment was performed preoperatively and 7 days postoperatively, or with a 7-day interval for the control group. POCD was calculated as a combined Z-score. Mini Mental State Examination (MMSE) was used to exclude patients with pre-existing cognitive deficit (MMSE score 23). Surgical and other factors including duration of surgery/ anaesthesia and length of stay in the intensive care unit (ICU) were recorded. RESULTS: After 7 days, POCD was found in 40/107 (37.4%) surgical patients compared with 4/26 (15.4%) nonsurgical controls. Preoperative MMSE score, duration of surgery/anaesthesia, and length of stay in the ICU and hospital were associated with POCD. Logistic regression analysis revealed that preoperative MMSE score was an independent predictor of POCD. CONCLUSION: Lower baseline MMSE score was the only independent predictor for POCD in patients with severe systemic disease. KEY WORDS: SEVERE SYSTEMIC DISEASE; COGNITIVE DYSFUNCTION; POSTOPERATIVE; RISK FACTORS; AMERICAN SOCIETY OF ANESTHESIOLOGISTS (ASA) PHYSICAL STATUS Introduction Postoperative cognitive dysfunction (POCD) is a frequent complication after surgery, 1 3 characterized by impairment of memory and concentration detected by neuro - psychological testing. 4 6 It is associated with several complications including prolonged hospital stay, 7 increased risk of permanent a FM Radtke and M Franck contributed equally to this work. disability 2 and higher mortality in the year following surgery. 8 Studies have reported the incidence of POCD for noncardiac patients to range from 19% to 41%. 1,8 10 The aetiology of POCD is multi - factorial, 7,11 13 with known risk factors including increased age, lower educational level, duration of surgery, additional surgery, history of stroke and postoperative infection. 8,14,15 There is no standard 612

methodology for the detection of POCD. Variation exists in the range of tests used, the interval between test sessions, endpoints, statistical methods and the definition of neuropsychological deficit and POCD. Specific sets of conventional neuropsychological tests have been recommended in order to introduce uniformity into the assessment and definition of postoperative cognitive decline. 4,9,16 Postoperative cognitive dysfunction is defined by a decrease of cognitive function from a preoperative base level; 4 thus, the screening for POCD depends on the assessment of both pre- and postoperative cognitive function. 16 The wide variability in normal human cognitive capacities associated with ageing makes baseline preoperative measurements a critical component of these evaluations. The ability of neuropsychological tests to detect postoperative cognitive decline depends heavily on their sensitivity. 16 The Stroop colour word test (SCWT) parts 1 3, and the visual verbal learning test (VVLT) with delayed recall have been shown to be highly sensitive and specific in POCD studies. 4,9,16 Comorbidities may trigger POCD, particularly if they coincide with major surgery of long duration. 1,7 Between 25% and 35% of surgical procedures in university hospitals are performed on patients with severe systemic disease. 17,18 The incidence of POCD is likely to increase due to the ageing population, with increasing morbidity and a higher rate of surgical procedures in elderly patients. In order to determine the relevance of surgery and other causative factors, the present study determined the incidence of cognitive dysfunction in patients with severe systemic disease who underwent surgery and in control subjects who did not undergo surgery. Patients and methods STUDY POPULATION Consecutive patients aged > 40 years who presented for planned admission for elective major noncardiac surgery under general anaesthesia at Charité University of Medicine Berlin, Berlin, Germany, between September 2006 and April 2008 were recruited to the study. Major surgery was defined as any operation with estimated duration > 120 min. The control group comprised ambulatory patients who had not undergone surgery, recruited from an office for internal medicine (Praxis Lichterfelde, Celsiusstrasse, Berlin, Germany) between December 2006 and February 2007. All patients and controls had severe systemic disease of American Society of Anesthesiologists (ASA) physical status classification 3 (http://www.asahq.org/ clinical/physicalstatus.htm). Exclusion criteria were: (i) central nervous system disease; (ii) Mini Mental State Examination (MMSE) 19 score 23 at the time of recruitment; (iii) history of drug or alcohol abuse; (iv) cardiac or neurosurgery; (v) unwillingness to comply with the study protocol or procedures; (vi) inability to understand the local language; (vii) severe visual or auditory disorders; (viii) illiteracy; (ix) participation in other studies. The study was approved by the Ethics Committee of Charité University of Medicine Berlin. All study participants provided written informed consent prior to enrolment. COGNITIVE TESTING The MMSE 19 was used to screen for patients with pre-existing cognitive deficit, as described above. The SCWT, parts 1 3 20, was used to examine attention, concentration and suggestibility of disturbing factors. The test included subtests for speed of reading and the ability to identify colours. The time taken 613

and number of errors were recorded for each part of the test. The VVLT with delayed recall based on Rey s auditory recall of words 21 was used to examine learning efficiency and memory. A list of 15 words was learned in three consecutive presentations at a fixed rate and patients were asked to recall as many words as possible. The number of errors and correctly recalled words were noted. 9 Participants were asked to work as fast and as accurately as possible. Two parallel versions of VVLT were given to the patients to reduce the learning effect. The SCWT was performed first, followed by the VVLT. Tests were carried out in a quiet room with only the patient and investigator present. The investigators were trained by a psychologist to administer the battery of tests. The first test session was administered to patients the evening before surgery. The postoperative SCWT and VVLT were performed after 7 days at around the same time in order to avoid changes in cognitive function caused by time of day. Patients who were too unwell to take the postoperative tests were tested as soon as possible thereafter. Subjects in the control group were tested with a 7-day interval. The extent of POCD was calculated using the combined Z-score, as previously described: 4,16 Z Patient Z Combined = SD(Z Control ) with Z Patient/Control = x Patient x Control SD(x Control ) Z-values were derived from the SCWT (time taken and number of errors) and the VVLT (correct and incorrect answers), from which combined Z-value were calculated. All values were recorded so that negative test results indicated deterioration. Patients were considered to show cognitive decline when either the combined Z-value was less than 1.96 or at least two tests had a Z-value of less than 1.96. DEMOGRAPHIC, CLINICAL AND SURGICAL PARAMETERS Data regarding patient age, gender, body mass index (BMI), the use of volatile and epidural anaesthesia, the duration of anaesthesia and surgery, prior surgical procedures and administration of packed red blood cells were collected from the anaesthesia record sheet. The Charlson comorbidity index 22 and length of stay in the intensive care unit (ICU) and the hospital were obtained from the hospital information system. STATISTICAL ANALYSES Data were analysed using the SPSS software package, version 15 (SPSS Inc., Chicago, IL, USA) for Windows and were reported as median (interquartile range) or odds ratios (95% confidence intervals). Between-group comparisons were performed using Fisher s exact test for categorical variables, and the Mann Whitney U-test for continuous variables. After univariate analysis of differences between patients with or without POCD, logistic regression analysis with POCD as the response variable and multiple linear regression analysis with postoperative hospital stay as the dependent variable were conducted in order to confirm the results and to investigate the impact of further influencing factors. A two-tailed P-value < 0.05 was considered to be statistically significant. Results A flow chart indicating the patient recruitment process and study design is shown in Fig. 1. The study recruited 145 614

Recruited 171 patients 145 undergoing surgery 26 nonsurgical control patients Exclusions MMSE score 23 Refusal Testing not possible due to illness Other n = 38 n = 2 n = 23 n = 8 n = 5 Exclusions n = 0 Tests completed successfully Tests completed successfully n = 26 n = 107 POCD No POCD n = 40 n = 67 POCD No POCD n = 4 n = 22 FIGURE 1: Flowchart of the patient recruitment process and study design. POCD, postoperative cognitive dysfunction; MMSE, Mini Mental State Examination 19 noncardiac surgical patients, of whom 38 (26.2%) did not complete the postoperative assessment. Patients who were lost to followup did not differ significantly from those who continued in terms of gender, age, time between tests, baseline MMSE score, Charlson comorbidity index or BMI. The final analysis included 107 noncardiac surgical patients and 26 controls. Patients were significantly younger (P < 0.001) and there were significantly more males (P < 0.001) than among the control subjects (Table 1). There were no other significant between-group differences in baseline characteristics. At 7 days postoperatively, 40 of 107 patients (37.4%) and four of 26 controls (15.4%) were affected by POCD (P = 0.034). There was a significant relationship between POCD and duration of surgery (P = 0.013), duration of anaesthesia (P = 0.01), length of hospital stay (P = 0.019), length of stay in the ICU (P = 0.013) and preoperative MMSE score (P = 0.004; Tables 2 and 3). There was no significant relationship between POCD and age, number of prior surgical procedures, use of volatile or epidural anaesthesia, administration of packed red blood cells, Charlson comorbidity index or BMI (Table 2). There was a significant relationship between the development of POCD and SCWT findings (increase in the time taken and number of errors; P < 0.001) and VVLT results (decrease in number of correct answers and increase in the number of errors; P 0.001; Table 3). 615

TABLE 1: Demographic and clinical and surgical characteristics of patients with American Society of Anesthesiologists physical classification status 3 who underwent major elective noncardiac surgery and nonsurgical control subjects Patients Control group Statistical Characteristic n = 107 n = 26 significance a Male 75 9 P = 0.001 Female 32 17 P = 0.001 Age, years 67.0 (59.0 73.0) 76.0 (68.0 81.5) P < 0.001 Time between tests, days 7.0 (6.0 9.0) 7.0 (6.0 7.0) NS MMSE score at screening 29.0 (28.0 30.0) 29.0 (28.0 30.0) NS Charlson comorbidity index 22 3.0 (2.0 6.0) 3.0 (2.0 5.0) NS Body mass index, kg/m 2 27.3 (23.0 29.4) 29.0 (23.3 32.3) NS Data presented as number (n) of subjects or median (interquartile range). a Fisher s exact test. NS, not statistically significant (P 0.05); MMSE, Mini Mental State Examination. 19 Logistic regression analysis revealed that preoperative MMSE score was independently associated with POCD (P = 0.048; Fig. 2). Linear multiple regression analysis found that duration of surgery and preoperative Charlson comorbidity index were associated with duration of hospital stay (P = 0.001 and P = 0.007, respectively). There were no other significant findings from the linear multiple regression analysis. Discussion This present study demonstrated that 37.4% of patients with severe systemic disease were affected by POCD 7 days after surgery. This incidence is in the upper range of previous studies that did not focus only on high risk patients (6.8% 41%) 1,5,9,10,23 and confirms that increased comorbidity is a risk factor for POCD. 7,15 Some studies have found a significant relationship between ASA physical status and incidence of POCD, 1,7 whereas another found no correlation. 9 The high incidence of cognitive dysfunction in the present study suggests that patients with ASA physical status 3 are at increased risk of developing POCD after surgery. In the present study, 15.4% of subjects in the matched control group fulfilled the criteria for POCD. To our knowledge, this is the first study to include such a matched control group. Other studies with more heterogeneous control groups have found an incidence of POCD of 3 4% in controls. 1,9 Patients with severe systemic disease are more likely to require medical treatment that may then result in impairment of cognitive function. 24 In contrast to the findings of others, 15 the present study showed that patients with POCD had a significantly longer postoperative length of stay in the ICU. The increased duration of hospital stay in POCD patients is in accordance with previous findings, 8 although one study found no relationship between POCD and length of hospital stay. 25 The duration of surgery and anaesthesia have been shown to influence the development of POCD in some studies 4,7,9,15 but not in others. 1,23 The finding that patients with cognitive dysfunction had a significantly lower MMSE score is in accordance with the findings of Price et al. 26 Low preoperative MMSE score was an important indicator for POCD. A lower functional reserve is a major factor in 616

TABLE 2: Relationship between the presence or absence of postoperative cognitive dysfunction (POCD) a and perioperative risk factors in patients with American Society of Anesthesiologists physical classification status 3 who underwent major elective noncardiac surgery (n = 107) With POCD Without POCD Statistical Missing data with Risk factor n = 40 n = 67 significance b POCD/without POCD Duration of surgery, min 267.5 (180.0 317.3) 160.0 (91.0 259.0) P = 0.013 Duration of anaesthesia, min 352.5 (222.5 435.0) 240.0 (153.8 352.5) P = 0.01 n = 0/n = 1 Hospital stay, days 19.50 (13.25 26.75) 14.00 (9.00 21.00) P = 0.019 n = 0/n = 2 Intensive care unit stay, days 1.00 (0.00 2.75) 0.00 (0.00 1.00) P = 0.013 n = 0/n = 2 Age, years 69.00 (61.25 73.75) 66.00 (57.00 72.00) NS Number of prior surgical procedures 2.00 (1.00 3.00) 2.00 (1.00 3.00) NS n = 1/n = 1 Volatile anaesthetic use 1.00 (1.00 1.00) 1.00 (0.00 1.00) NS n = 0/n = 1 Epidural anaesthesia with catheter use 0.00 (0.00 1.00) 0.00 (0.00 1.00) NS Packed red blood cell use 0.00 (0.00 0.00) 0.00 (0.00 0.00) NS n = 1/n = 0 Charlson comorbidity index 22 3.00 (2.00 8.00) 3.00 (2.00 4.00) NS Body mass index, kg/m 2 26.86 (22.67 29.12) 27.64 (23.67 29.65) NS Data presented as median (interquartile range). a POCD was assessed 7 days postoperatively. b Fisher s exact test. NS, not statistically significant (P 0.05). 617

TABLE 3: Relationship between the presence or absence of postoperative cognitive dysfunction (POCD) a and psychometric test results in patients with American Society of Anesthesiologists physical classification status 3 who underwent major elective noncardiac surgery (n = 107) With POCD Without POCD Statistical Cognitive test n = 40 n = 67 significance b SCWT 20 Time taken, s Preoperative 56.83 (47.64 69.06) 53.98 (45.65 65.53) NS Postoperative 69.38 (54.49 89.86) 50.97 (41.56 62.78) P < 0.001 Change c 13.36 ( 22.67 4.78) 1.65 ( 3.96 5.91) P < 0.001 Number of errors Preoperative 0.00 (0.00 1.00) 0.00 (0.00 1.00) NS Postoperative 3.00 (0.00 6.75) 0.00 (0.00 0.00) P < 0.001 Change c 2.50 ( 5.00 0.00) 0.00 (0.00 0.00) P < 0.001 VVLT 21 Correct answers Preoperative 8.00 (5.00 10.00) 8.00 (6.00 9.00) NS Postoperative 5.50 (4.00 8.00) 8.00 (6.00 10.00) P = 0.001 Change c 1.00 ( 2.75 0.00) 1.00 ( 1.00 2.00) P < 0.001 Number of errors Preoperative 0.00 (0.00 0.00) 0.00 (0.00 1.00) NS Postoperative 1.00 (0.00 2.00) 0.00 (0.00 1.00) P < 0.001 Change c 1.00 ( 2.00 0.00) 0.00 (0.00 0.00) P < 0.001 Preoperative MMSE 19 score 29.00 (28.00 29.75) 30.00 (29.00 30.00) P = 0.004 Data presented as median (interquartile range). a POCD was assessed 7 days postoperatively. b Fisher s exact test. NS, not statistically significant (P 0.05); SCWT, Stroop colour word test; VVLT, visual verbal learning test; MMSE, Mini Mental State Examination. c Change represents the difference preoperative postoperative for every patient. explaining differences in the onset of clinical symptoms or impaired test performance. 27 MMSE provides an indication of which patients might have a higher likelihood of postoperative cognitive decline. There were limitations to the present study including the small sample size and the absence of long term follow-up testing. Thus, the study conclusions can be used to refer only to the development POCD 1 week after surgery. In conclusion, the incidence of POCD in ASA physical status 3 patients was not solely influenced by perioperative precipitating factors (such as epidural anaesthesia, volatile anaesthesia, duration of surgery and length of stay in the ICU). A lower baseline cognitive score, as assessed by MMSE, was shown to be an independent predictor for the development of cognitive dysfunction in patients with severe systemic disease. Acknowledgement This work was supported by grants from Charité University of Medicine Berlin, Berlin, Germany. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. 618

Gender 1.205 (0.467, 3.107) MMSE score 0.713 (0.509, 0.997) Thoracic epidural 1.298 (0.445, 3.781) Volatile anaesthetic 0.423 (0.139, 1.289) Age 1.008 (0.961, 1.058) Length of ICU stay 1.077 (0.896, 1.296) Surgery duration 1.002 (0.998, 1.007) 0.1 1 10 Odds ratio FIGURE 2: Multiple logistic regression analysis of risk factors for postoperative cognitive dysfunction (POCD) in American Society of Anesthesiologists physical classification status 3 patients who underwent major elective noncardiac surgery (n = 107). POCD was assessed 7 days postoperatively. Data presented as odds ratios with 95% confidence intervals. Gender, female versus male; MMSE, Mini Mental State Examination; 19 volatile anaesthetic, total intravenous anaesthesia versus volatile anaesthetic Received for publication 18 October 2011 Accepted subject to revision 2 November 2011 Revised accepted 14 December 2011 Copyright 2012 Field House Publishing LLP References 1 Johnson T, Monk T, Rasmussen LS, et al: Postoperative cognitive dysfunction in middleaged patients. Anesthesiology 2002; 96: 1351 1357. 2 Steinmetz J, Christensen KB, Lund T, et al: Longterm consequences of postoperative cognitive dysfunction. Anesthesiology 2009; 110: 548 555. 3 Deiner S, Silverstein JH: Postoperative delirium and cognitive dysfunction. Br J Anaesth 2009; 103(suppl 1): i41 i46. 4 Abildstrom H, Rasmussen LS, Rentowl P, et al: Cognitive dysfunction 1 2 years after noncardiac surgery in the elderly. ISPOCD group. International Study of Post-Operative Cognitive Dysfunction. Acta Anaesthesiol Scand 2000; 44: 1246 1251. 5 Newman S, Stygall J, Hirani S, et al: Postoperative cognitive dysfunction after noncardiac surgery: a systematic review. Anesthesiology 2007; 106: 572 590. 6 Krenk L, Rasmussen LS: Postoperative delirium and postoperative cognitive dysfunction in the elderly what are the differences? Minerva Anestesiol 2011; 77: 742 749. 7 Müller SV, Krause N, Schmidt M, et al: Cognitive dysfunction after abdominal surgery in elderly patients. Z Gerontol Geriatr 2004; 37: 475 485 [in German, English abstract]. 8 Monk TG, Weldon BC, Garvan CW, et al: Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008; 108: 18 30. 9 Moller JT, Cluitmans P, Rasmussen LS, et al: Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post- Operative Cognitive Dysfunction. Lancet 1998; 351: 857 861. 10 Rasmussen LS, Johnson T, Kuipers HM, et al: Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiol Scand 2003; 47: 260 266. 11 Monk TG, Price CC: Postoperative cognitive disorders. Curr Opin Crit Care 2011; 17: 376 619

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