Relationship between post-operative cognitive dysfunction and regional cerebral oxygen saturation and β-amyloid protein

Relationship between post-operative cognitive dysfunction and regional cerebral oxygen saturation and β-amyloid protein 术后认知功能障碍与脑氧饱和度及血浆β-淀粉样蛋白的关系 1 2 first-author †E-mail:13515397176@163.comwyldgf@163.com †E-mail:13515397176@163.comwyldgf@163.com 13515397176@163.com 3 4 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:13515397176@163.comwyldgf@163.com †E-mail:13515397176@163.comwyldgf@163.com 13515397176@163.com Department of Anesthesiology, Affiliated Qianfoshan Hospital of Shandong University, Jinan 250014, China Department of Anesthesiology, Affiliated Qianfoshan Hospital of Shandong University, Jinan 250014, China Department of Anesthesiology, Linyi City People's Hospital, Linyi 276000, China Department of Anesthesiology, Linyi City People's Hospital, Linyi 276000, China Department of Emergency Surgery, Linyi City People's Hospital, Linyi 276000, China Department of Emergency Surgery, Linyi City People's Hospital, Linyi 276000, China Department of Anesthesiology, Shandong Lunan Ophthalmologic Hospital, Linyi 276000, China Department of Anesthesiology, Shandong Lunan Ophthalmologic Hospital, Linyi 276000, China Objective: 2 To investigate the relationship between post-operative cognitive dysfunction (POCD) and regional cerebral oxygen saturation (rSO 2 ) and β-amyloid protein (Aβ) in patients undergoing laparoscopic pancreaticoduodenectomy. Methods: 2 Fifty patients undergoing elective laparoscopic pancreaticoduodenectomy received five groups of neuropsychological tests 1 d pre-operatively and 7 d post-operatively, with continuous monitoring of rSO 2 intra-operatively. Before anesthesia induction ( t 0 ), at the beginning of laparoscopy ( t 1 ), and at the time of pneumoperitoneum 120 min ( t 2 ), pneumoperitoneum 240 min ( t 3 ), pneumoperitoneum 480 min ( t 4 ), the end of pneumoperitoneum ( t 5 ), and 24 h after surgery, jugular venous blood was drawn respectively for the measurement of Aβ by enzyme-linked immunosorbent assay (ELISA). Results: 2 Twenty-one cases of the fifty patients suffered from POCD after operation. We found that the maximum percentage drop in rSO 2 (rSO 2, %max ) was significantly higher in the POCD group than in the non-POCD group. The rSO 2, %max value of over 10.2% might be a potential predictor of neurocognitive injury for those patients. In the POCD group, the plasma Aβ levels after 24 h were significantly higher than those of pre-operative values ( P < 0.01). After 24 h, levels of plasma Aβ in the POCD group were significantly higher than those in the non-POCD group ( P < 0.01). Conclusions: 2 The development of POCD in patients undergoing laparoscopic pancreaticoduodenectomy is associated with alterations of rSO 2 and Aβ. Monitoring of rSO 2 might be useful in the prediction of POCD, and Aβ might be used as a sensitive biochemical marker to predict the occurrence of POCD. 研究目的 2 探讨腹腔镜胰体尾切除术患者术后认知功能障碍（POCD）的发生与脑氧饱和度（rSO 2 ）及血浆β-淀粉样蛋白（Aβ）水平的相关性。 创新要点 2 POCD的发生机制与rSO 2 及Aβ有一定的相关性；rSO 2 较基础值下降的最大百分数（rSO 2, %max ） > 10.2%有可能发生POCD，因此，rSO 2 监测可能是预测POCD发生的有效工具；Aβ可能是发生POCD敏感的生化预警指标。 研究方法 2 择期行腹腔镜胰十二指肠切除术患者50例，于术前1天和术后7天分别行简明精神状态量表（MMSE）、数字广度、数字符号、循迹连线、词汇流畅性（VFT）和单词辨认神经心理测验。分别于麻醉诱导前（ t 0 ）、气腹开始前（ t 1 ）、气腹120min（ t 2 ）、气腹240min（ t 3 ）、气腹480min（ t 4 ）、气腹结束（ t 5 ）及术毕24h，抽取颈内静脉血3ml，采用酶联免疫法（ELISA）方法测定Aβ含量。术中利用近红外光谱技术（NIRS）连续监测rSO 2 ，并计算术中rSO 2 平均值、术中rSO 2 最小值（rSO 2, min ）和rSO 2, %max 。 重要结论 2 POCD的发生与rSO 2 及Aβ有关；危险因素可能有老年、低教育水平、较高基础体温、rSO 2 下降、CO 2 蓄积、血浆Aβ升高等；rSO 2 监测有可能是POCD的有效预测工具之一；Aβ有可能是发生POCD敏感的生化预警标志物之一。 Laparoscopic pancreaticoduodenectomy Regional cerebral oxygen saturation β-Amyloid protein Post-operative cognitive dysfunction 术后认知功能障碍 局部脑氧饱和度 β-淀粉样蛋白 Introduction 1 The incidence of early post-operative cognitive dysfunction (POCD) can reach as high as 40%–50%, which adversely affects quality of life and rehabilitation of patients (Rohan et al., 2005 2005 ). The underlying pathophysiological mechanism of POCD remains unclear. Alzheimer’s disease (AD) is a chronic progressive neurologic degeneration. Recent studies have shown that prolonged POCD increases the incidence of dementia (Vanderweyde et al., 2010 2010 ; Bittner et al., 2011 2011 ). Fodale et al., ( 2010 2010 ) thought that the pathological mechanism of POCD is similar to that of AD. Also, the type of operation and anesthesia, differences in genes, central cholinergic system, β-amyloid protein (Aβ), cholinergic system, older age, and anesthetics may also have impact on the development of POCD. The possible risk factors contributing to the development of POCD include age, pre-operative cognitive function, operation time, hypoperfusion, embolism, post-operative pain, respiratory complications, and infections (Krenk et al., 2010 2010 ). The proposition of intervention includes cerebral oxygen saturation monitoring and the control of the depth of anesthesia. In non-cardiac surgery, monitoring of regional cerebral oxygen saturation (rSO 2 ) has been proven to be important for improving the results of intervention factors (Casati et al., 2005 2005 ; Farag et al., 2006 2006 ; Slater et al., 2009 2009 ). Transcranial near-infrared spectroscopy (NIRS) provides a non-invasive method to detect rSO 2 . Recent studies have shown that the development of POCD had a significant relationship with the levels of rSO 2 in patients undergoing coronary artery bypass graft (CABG) (Olsen et al., 1996 1996 ; Murkin et al., 2007 2007 ). The studies using NIRS have shown that there was a significant relationship between low rSO 2 and neurologic complications, cognitive function, and prolonged hospitalization for the patients undergoing abdominal operation or CABG surgery under anesthesia (Monk et al., 2002 2002 ; Goldman et al., 2004 2004 ; Yao et al., 2004 2004 ; Casati et al., 2005 2005 ). Laparoscopic pancreaticoduodenectomy has been widely used with reduced hospitalization time, fast recovery, and improved quality of life for patients. However, it also has some shortcomings; for example, compared with a conventional operation, its average operation time is up to 10 h, average blood loss 139 ml, post-operation hospitalization time up to 6.6 d (Jacobs and Kamyab, 2013 2013 ; Mesleh et al., 2013 2013 ), and the incidence of cognitive dysfunction is higher than that of other abdominal surgery. It might have a strong relationship with operation time and anesthesia management. In this study, we detected rSO 2 and compared it with changes of plasma Aβ levels to explore the relationship between post-operative cognitive function and rSO 2 and plasma Aβ for the patients undergoing laparoscopic pancreaticoduodenectomy. We hypothesize that the changes of Aβ levels and rSO 2 would be predictive factors for POCD in patients following this operation with general anesthesia. Materials and methods 1 Materials 2 This study was approved by the Ethics Committee of Linyi City People’s Hospital, China and obtained informed consent of all patients. Fifty patients, American Standards Association (ASA) classes II–III, were recruited from our hospital; they received laparoscopic pancreaticoduodenectomy from December 2010 to May 2013. There were 29 males and 21 females. The age range was 40 to 80 years old. Pre-operative imaging showed that there were 30 cases of pancreatic cancer affecting the body of the pancreas and 20 cases affecting the pancreatic tail. We abided by the following exclusion criteria: (1) pre-operative mini-mental state examination (MMSE) score less than 24; (2) a current or past history of psychiatric disorder or central nervous system disease; (3) a history of cardiovascular surgery or craniotomy; (4) drug or alcohol dependence; (5) hepatic failure; (6) renal failure; (7) inability to read or speak; and, (8) serious hearing or vision impairment (Lin et al., 2013 2013 ). Anesthetic management 2 All patients received a standardized anesthetic management. In the operating room, 5-ECG leads were attached, with leads II and V 5 continuously monitored. A 20-G radial artery catheter was inserted to measure arterial blood pressure and arterial blood gas. A 7-Fr vein catheter introducer was inserted into the right internal jugular for mixed venous oxygen saturation (SvO 2 ) monitoring (Hong et al., 2008 2008 ) and for blood sample collection to be used for Aβ assay. Three electrodes connected with Narcotrend® monitor (Narcotrend®-Compact, MT Monitor Technik GmbH und Co. KG, Germany) and an rSO 2 sensor connected with NIRS (INVOS 5100B, Somanetics, Troy, MI, USA) were placed on the skin of the forehead to separately record values of Narcotrend and rSO 2 at 30-s intervals during surgery (Lin et al., 2013 2013 ). After 5 min for equilibrium, Narcotrend and rSO 2 readings were regarded as the baseline values. Anesthesia was induced with midazolam 0.04–0.05 mg/kg, propofol 1.0–1.5 mg/kg, sufentanil 1.0–1.5 μg/kg, cis -atracurium 0.10–0.15 mg/kg. After intubation, all patients were administered with propofol 2–5 μg/(kg∙h), remifentanil 0.5–1.0 μg/(kg∙min), cis -atracurium 2–4 μg/(kg∙min), and inhalation of sevoflurane (1%–3%). The intra-operative blood pressure and heart rate were maintained to allow fluctuation less than 30% of the baseline values. The Narcotrend index was kept between D 1 and E 1 . All anesthesia-related data including dose of anesthetic agents, fluid input quantity, blood loss, the duration of operation and anesthesia, and recovery time were recorded routinely (Lin et al., 2013 2013 ). Physiologic variables 2 Physiologic variables including SvO 2 , arterial partial pressure of carbon dioxide (PaCO 2 ), arterial partial pressure of oxygen (PaO 2 ), glucose, and hematocrit were measured. The observation time points include: before induction of anesthesia ( t 0 ), before the start of pneumoperitoneum ( t 1 ), pneumoperitoneum 120 min ( t 2 ), pneumoperitoneum 240 min ( t 3 ), pneumoperitoneum 480 min ( t 4 ), pneumoperitoneum end ( t 5 ), and 24 h after surgery. A Radiometer ABL800 automatic blood gas analyzer was used for blood gas analysis. Monitoring rSO 2 2 The rSO 2 was detected by NIRS (Brawanski et al., 2002 2002 ) using a near-infrared light spectrum analyzer INVOS5100 (Somaneti, USA). The rSO 2 probe was placed on the right side of the forehead. The instrument can monitor continuously, record, and save the oxygen data automatically. The cerebral oxygen data were recorded twice per minute. These data were transferred to a computer for statistical processing after operation (Hong et al., 2008 2008 ). Surgeons and anesthesiologists were blinded to the patients’ group assignment and the measurement of rSO 2 so as to exclude subjective bias. Analysis of plasma Aβ 2 Plasma levels of the Aβ were analyzed as a biomarker of brain injury. Blood samples were taken from participants at baseline and 1 d post-operatively. Five-ml jugular vein blood was collected into a procoagulant polyvinyl chloride (PVC) tube and placed in the refrigerator for 2 h, and then centrifuged at 3000 r/min at 4 °C for 10 min to separate the serum. The supernatant was placed in a PVC tube and placed in cryogenic refrigerator at below −20 °C. The experimental specimens were set at room temperature before reconstitution and use. The Beta Amyloid 42 ELISA Kit was used (Covance Princeton, New Jersey, USA) and the assay was performed according to the instructions provided by the supplier to establish a standard curve; measured specimen OD values were calculated to obtain the protein content. Neurologic and neuropsychological assessments 2 All eligible patients underwent a battery of clinical quantitative neurologic and neuropsychological tests on the day before operation and 7 d after operation. The control group did the same tests on the same days. The battery primarily focused on memory, learning, attention, executive functions, and cognitive flexibility, and encompassed the following tests: MMSE, digit symbol substitutions test (DSST), trail making test (part A), verbal fluency test (VFT), and word recognition memory tests. The same physician carried out the evaluation of cognitive function among patients and controls according to the methods of Lin et al. ( 2013 2013 ). Learning effects were defined as mean variation of each test from baseline among control subjects. The tests were performed according to the International Study of Postoperative Cognitive Dysfunction (ISPOCD1 and ISPOCD2) (Moller et al., 1998 1998 ; Johnson et al., 2002 2002 ; Canet et al., 2003 2003 ). A Z score for each individual test was calculated by comparing with baseline scores and with test results one week after surgery, by subtracting the average learning effect from these changes, and being divided by the standard deviation (SD) of the control group. POCD was defined as Z scores equal to or greater than 1.96 on at least two tests (Moller et al., 1998 1998 ; Johnson et al., 2002 2002 ; Canet et al., 2003 2003 ; Lin et al., 2013 2013 ). Statistical analysis 2 Statistical analysis was performed using SPSS 19.0 (IBM, Armonk, NY, USA). Continuous variables were expressed as mean±SD and processed with Student’s t -test. Categorical variables were expressed as numbers (percentages) and processed with chi-square test or Fisher exact tests. Multivariate analysis of predictors for POCD was assessed with logistic regression. A P value less than 0.05 was considered statistically significant. Results 1 Incidence of POCD 2 The clinical and demographic characteristics of the 50 patients and the comparison between POCD and non-POCD are presented in Table 1 1 . Only 46 patients of the 50 performed the early cognitive post-test (2 patients did not participate the neurologic or neuropsychological tests, 2 patients were transferred to open pancreaticoduodenectomy). Of these 46 patients, 21 (45.7%) showed early POCD because of the Z score ≥1.96. Advanced age and lower education level were significant pre-operative predictors for POCD (Hong et al., 2008 2008 ). Basal body temperature was significantly higher in the POCD patients than in normal patients. Data are presented as mean±SD or the percentage of all patients. ASA: American Society of Anesthesiologists; T a : axillary temperature Variable Non-POCD ( n =25) POCD ( n =21) P Age (year) 65±5 73±3 0.010 Male/female 8/17 6/15 0.529 Height (cm) 164±4 161±5 0.135 Weight (kg) 62±6 61±5 0.611 Body mass index 23.1±2.5 23.4±1.3 0.674 Education level (year) 11±2.55 8±2.65 0.030 ASA physical status  II (%) 48 47.6 0.607  III (%) 52 52.4 2 Pre-operative complication  Hypertension (%) 44 28.6 0.363  Diabetes (%) 24 19.0 0.735  Smoking history (%) 32 23.8 0.744  Surgical history (%) 48 47.6 0.493 Duration of anesthesia (min) 562±30 553±21 0.230 Duration of surgery (min) 530±30 524±22 0.493 Fluid replacement (ml) 4480±157 4524±162 0.189 Blood loss (ml) 141±18 149±21 0.198 Recovery time (min) 32±5.2 35±5.1 0.079 Propofol (mg) 2117.2±7.9 2112.4±8.3 0.051 Remifentanil (mg) 6.51±0.13 6.60±0.19 0.062 cis -Atracurium (mg) 27.5±2.66 28.9±2.59 0.082 T a (°C) 36.5±0.27 36.9±0.3 <0.001 Neurologic and neuropsychological tests 2 Peri-operative congnitive function test scores are shown in Table 2 2 . In the POCD group, post-operative scores of MMSE, DSST, and VFT were significantly lower than those at baseline ( P < 0.05). Patients with POCD showed significant deterioration in learning and memory abilities and performance functional disorder, and were more anxious and depressed than non-POCD patients. The test results (scores, except time (s) for trail making test A) are presented as mean±SD. Pod#7: post-operative Day 7; MMSE: mini-mental state examination; DSST: digit symbol substitutions test; VFT: verbal fluency test P < 0.05, vs. non-POCD group P < 0.05, vs. baseline in either group 2 Test 2 Score or time (s) 2 P Non-POCD ( n =25) POCD ( n =21) MMSE  Pre-operative 29.00±0.67 29.30±0.34 0.054  Pod#7 28.83±0.68 27.10±0.41 * * , ** ** <0.001 DSST  Pre-operative 32.32±4.75 31.00±4.23 0.329  Pod#7 29.96±4.86 26.14±3.13 * * , ** ** 0.003 2 Trail making test A (s)  Pre-operative 17.60±5.68 19.40±5.62 0.289  Pod#7 17.84±6.06 20.50±5.86 0.140 VFT  Pre-operative 16.70±1.77 16.01±1.58 0.180  Pod#7 16.35±1.85 14.51±1.71 * * , ** ** <0.001 2 Word recognition memory test  Pre-operative 1.20±0.44 1.30±0.48 0.689  Pod#7 1.40±0.43 1.90±0.42 0.965 Physiologic variables 2 PaCO 2 was significantly higher at t 3 and t 4 in the POCD patients than in normal patients. PaO 2 was significantly higher at t 1 to t 4 than at t 0 in all patients. Remaining variables including SvO 2 , glucose, and hematocrit did not significantly differ between groups (Table 3 3 ). Data are presented as mean±SD; SvO 2 : mixed venous oxygen saturation; PaCO 2 : arterial partial pressure of carbon dioxide; PaO 2 : arterial partial pressure of oxygen P < 0.05, vs. non-POCD group 2 Time 2 SvO 2 (%) 2 PaCO 2 (mmHg) 2 PaO 2 (mmHg) 2 Glucose (mg/dl) 2 Hematocrit (%) Non-POCD POCD Non-POCD POCD Non-POCD POCD Non-POCD POCD Non-POCD POCD t 0 81±13 83±9 33±6 34±4 277±56 267±66 123±26 115±20 30±7 31±6 t 1 78±10 80±11 37±7 37±6 361±54 341±34 152±68 162±63 29±5 28±6 t 2 75±9 78±9 38±8 39±8 362±31 342±38 206±62 216±72 27±6 26±7 t 3 73±6 76±7 43±7 49±6 * * 358±52 341±42 208±57 220±68 26±5 25±8 t 4 72±7 73±8 45±6 51±7 * * 340±33 336±28 212±49 214±52 25±8 23±5 t 5 78±9 79±10 36±8 40±6 279±76 249±80 133±36 124±34 24±8 23±8 Comparison of rSO 2 2 There were no statistical differences of rSO 2 , mean rSO 2 ( <math id="M1"><mrow><mover accent="true"><mrow><mi>r</mi><mi>S</mi><msub><mi>O</mi><mn>2</mn></msub></mrow><mo stretchy="true">¯</mo></mover></mrow></math> ), or minimum rSO 2 (rSO 2, min ) between the two groups at baseline. Compared with the non-POCD group, maximum percentage drop in rSO 2 (rSO 2, %max ) was observably greater in the POCD group ( P =0.001) (Table 4 4 ). Data are presented as median (5th–95th percentile). rSO 2 : regional cerebral oxygen saturation; <math id="M4"><mrow><mover accent="true"><mrow><mi>r</mi><mi>S</mi><msub><mi>O</mi><mn>2</mn></msub></mrow><mo stretchy="true">¯</mo></mover></mrow></math> : mean rSO 2 ; rSO 2, min : minimum rSO 2 ; rSO 2, %max : maximum percentage drop in rSO 2 P < 0.05, vs. non-POCD group Group Baseline (%) <math id="M3"><mrow><mover accent="true"><mrow><mi>r</mi><mi>S</mi><msub><mi>O</mi><mn>2</mn></msub></mrow><mo stretchy="true">¯</mo></mover></mrow></math> (%) rSO 2, min (%) rSO 2, %max (%) Non-POCD ( n =25) 69 (67–71) 71 (69–74) 62 (59–64) 8.64 (6.7–12.0) POCD ( n =21) 69 (63–75) 69 (61–76) 59 (52–66) 13 (8.3–18.5) * * 5 P 0.855 0.427 0.445 <0.001 Fig. 1 1 is a line chart of patients’ intra-operative rSO 2 trends of the two groups. The rSO 2 values of the two groups at different time points were statistically significantly different ( P < 0.05). In contrast, the trends of intra-operative rSO 2 values were similar in the two groups. rSO 2, %max was observably greater in the POCD group ( P < 0.01). Fig. 2 2 displays receiver operating characteristic (ROC) curve of rSO 2, %max , and the area under the curve (AUC) of which was 0.926 (95% confidence interval (CI) [0.842, 1.000]). When rSO 2, %max > 10.2% was taken as the cut-off value, the specificity and sensitivity of rSO 2, %max in predicting POCD were 88.0% and 85.7%, respectively. AUC: area under the curve; CI: confidence interval Aβ levels 2 In the POCD group, the plasma Aβ levels after 24 h were statistically significantly higher than pre-operative values ((100.27±6.79) pg/ml vs. (78.90±11.07) pg/ml; P < 0.01). After 24 h, the levels of plasma Aβ in the POCD group were significantly higher than those in the non-POCD group ((100.27±6.79) pg/ml vs. (78.23±11.16) pg/ml; P < 0.01) (Table 5 5 ). Data are presented as mean±SD P < 0.05, vs. non-POCD group P < 0.05, vs. baseline in either group 2 Time 2 Aβ level (pg/ml) 2 P Non-POCD ( n =25) POCD ( n =21) t 0 78.11±11.25 78.90±11.07 0.990 t 1 78.24±9.31 83.98±9.83 0.076 t 2 79.11±11.60 85.28±9.73 ** ** 0.060 t 3 80.72±11.55 90.88±9.66 * * , ** ** 0.003 t 4 89.65±10.73 ** ** , 101.70±9.25 * * ** ** <0.001 t 5 91.23±11.33 ** ** 114.57±10.27 * * , ** ** <0.001 24 h 78.23±11.16 100.27±6.79 * * , ** ** <0.001 Results from risk factor analysis are presented in Table 6 6 . In a multivariate logistic regression analysis, higher levels of basal body temperature, rSO 2, %max , PaCO 2 , and Aβ were significant intra-operative predictors for POCD. OR: odds ratio; CI: confidence interval Variable OR (95% CI) P Age 0.305 (1.135‒2.865) 0.052 Gender 0.021 (0.288‒0.369) 0.807 Level of education 0.087 (0.021‒1.979) 0.236 Basal body temperature 0.391 (1.539‒2.461) 0.002 PaCO 2 0.425 (1.447‒2.553) 0.005 rSO 2, %max 0.794 (0.056‒0.103) <0.001 Aβ 0.577 (0.020‒0.033) <0.001 Discussion 1 POCD is a common post-anesthetic neurologic complication, manifested as mental confusion, anxiety, personality changes, and memory impairment. The pathogenesis of POCD is not clear, although it can be influenced by many factors. Most researchers think that POCD is related with age, operation, anesthesia, psychologic factors, sleeping disorder, and pain. There is no consistent outlook about POCD from the literature. The review reported by ISPOCD1 in 1998 was generally accepted. The incidence of POCD from 1218 elderly patients undergoing operation was 25.8% (Moller et al., 1998 1998 ). In the study of Evered et al. ( 2011 2011 ), the incidence of POCD at 7 d post-operation from 644 patients with CABG or total hip joint replacement (THJR) was 43% and 17%, respectively. Rasmussen et al. ( 1999 1999 ) observed that 17 elderly patients (≥60 years) from 35 cases who received abdominal operation with general anesthesia developed POCD (48.6%). In our study, the incidence of POCD with laparoscopic pancreaticoduodenectomy was up to 45.7%. The risk factors included advanced age and lower level education. These results are similar to other findings (Hong et al., 2008 2008 ; de Tournay-Jetté et al., 2010 2010 ). Interestingly, higher basal body temperature might be a significant predictor for POCD based on multivariate logistic regression analysis. Whether the patients with higher basal body temperature were in a proinflammatory state or a pronounced systemic inflammation pre-operatively was not assessed in this study. Regarding the relationship between metabolic imbalance caused by systemic inflammatory reaction and psychomotor slowing (Bokeriia et al., 2005 2005 ), further evaluation of the effect of peri-operative inflammatory state and body temperature on POCD seems to be required (Hong et al., 2008 2008 ). The development of POCD may be associated with operation, anesthesia type, evaluation methods of POCD, and diagnostic criteria. In addition, small sample size may also lead to bias of the incidence. Laparoscopic pancreaticoduodenectomy is one of the mostly reported and “popular” laparoscopic pancreatic surgical procedures, which may offer many benefits to patients, such as shorter length of hospital stay, fewer complications, and improved quality of life, but the average operative time is up to 10 h. The incidence of POCD after operation is also high (Jacobs and Kamyab, 2013 2013 ; Mesleh et al., 2013 2013 ). This may be associated with hypercarbia induced by the long duration of pneumoperitoneum and CO 2 absorption through the peritoneum. Hypercarbia may cause reduction of rSO 2 . Another possible reason for causing reduction of rSO 2 is cerebral vasodilation and increased intracranial pressure induced by increased CO 2 (Germon et al., 1995 1995 ; Konishi and Kikuchi, 1996 1996 ). CO 2 is a powerful regulator of cerebrovasculature. Cerebral blood flow will increase or decrease by 2 ml/(100 g∙min) correspondingly whenever PaCO 2 increases or decreases 0.13 kPa (1 mmHg). Although in normal circumstances, increasing cerebral blood flow will not decrease intracranial pressure and cerebral perfusion with the presence of intracranial compliance, we cannot evaluate whether increasing intracranial pressure and decreasing cerebral blood flow will result in rSO 2 reduction on the basis of expanded cerebrovasculature after inhalational anesthesia. In a large prospective study (Monk et al., 2002 2002 ), the incidence of POCD in elderly patients correlated with intra-operative frequently low rSO 2 . It is reported that rSO 2 lower than 50% or a decrease in rSO 2 of 20% compared to baseline will prognosticate the possible presence of cerebral ischemia. This conclusion had been proven by the auditory evoked potential test (Blas et al., 1999 1999 ). Slater et al. ( 2009 2009 ) also came to a similar conclusion. The patients with rSO 2 score decreasing ≥3000%·s in CABG intra-operation would be more likely to develop POCD ( P =0.024). The risk increases nearly three-fold with prolonged hospital stay. In our study, the rSO 2, %max in the POCD group was significantly higher than that in the non-POCD group ( P < 0.001). In the non-POCD group, t 1 – t 4 rSO 2 values were significantly higher than t 0 rSO 2 value ( P < 0.05). There was no significant difference between rSO 2 values at t 5 and t 0 . In the POCD group, rSO 2 at t 1 was significantly higher than that at t 0 ( P < 0.05), while at t 5 it decreased significantly compared with t 0 ( P < 0.05). These data demonstrated that the rSO 2 could correspond to the occurrence of POCD. It was also highlighted that rSO 2, %max > 10.2% was a potential predictor of neurocognitive injury. Aβ is a polypeptide with a folded configuration and β sheet structure formed by 39–43 amino acids. The molecular weight is about 4 kD. Aβ is an initiating factor of senile plaque formation and the important component of senile plaque nucleus for AD. There is a close relationship between increased Aβ and cognitive dysfunction (Townsend et al., 2002 2002 ). The increased brain Aβ was related to increased Aβ precursor protein (β-APP) (Grilli et al., 1996 1996 ). APP is an acute reactive protein that is modulated by central inflammatory cytokines in transcription (Grilli et al., 1996 1996 ). The generation and accumulated increase of Aβ would further trigger neuronal apoptosis. Aβ can induce NMDA receptors and block transmission of information in neurons, resulting in dysfunction for learning and memory. Sevoflurane can alter the formation of amyloid precursor protein and increase the level of Aβ, which would result in neurotoxicity. Lu et al. ( 2010 2010 ) also reported that AD transgenic rats are prone to neurologic injury on inhalation of sevoflurane. Neurodegeneration and anesthesia may be contributing factors to the pathophysiology of POCD (Tang et al., 2010 2010 ). Inflammation is the bridge between POCD and AD; therefore, surgery and anesthesia may lead to brain inflammation, which may be one of the mechanisms of the increased incidence of POCD (Hu et al., 2010 2010 ). Recent studies show that Aβ is one of the potential markers of neurologic damage and persistent inflammation (Gold et al., 2005 2005 ). Aβ may be associated with increased cognitive dysfunction. A potential relationship between Aβ and POCD may exist and serve as one of the predictors of the increased incidence of POCD and other related biomarkers (Townsend et al., 2002 2002 ). Multivariate logistic regression analysis has shown that basal body temperature, PaCO 2 , rSO 2, %max and Aβ seem to play a more important role for the interpretation of POCD. Routine blood gas analysis, monitoring of rSO 2 , and detection of plasma Aβ might be useful tools for predicting the occurrence of POCD. Further studies are required to investigate the importance of plasma Aβ as a potential biomarker for POCD. Findings from the current study may have a significant impact on the promotion and application of laparoscopic pancreaticoduodenectomy and the improvement of prognosis. References EA Bittner , Y Yue , Z Xie . Brief review: anesthetic neurotoxicity in the elderly, congnitive dysfunction and Alzheimer’s disease . Can J Anesth , 2011 . 58 ( 2 ): 216 - 223 . 21174183 DOI: 10.1007/s12630-010-9418-x http://doi.org/10.1007/s12630-010-9418-x . Brief review: anesthetic neurotoxicity in the elderly, congnitive dysfunction and Alzheimer’s disease M Blas , C Sulek , T Martin , 等 . Use of near infrared spectroscopy to monitor cerebral oxygen at ion during coronary artery bypass surgery in a patient with bilateral internal carotid artery occlusion . J Cardioth Vasc Anesth , 1999 . 13 ( 6 ): 732 - 735 . DOI: 10.1016/S1053-0770(99)90131-3 http://doi.org/10.1016/S1053-0770(99)90131-3 . Use of near infrared spectroscopy to monitor cerebral oxygen at ion during coronary artery bypass surgery in a patient with bilateral internal carotid artery occlusion LA Bokeriia , EZ Golukhova , AG Polunina , 等 . Neural correlates of cognitive dysfunction after cardiac surgery . Brain Res Rev , 2005 . 50 ( 2 ): 266 - 274 . 16198423 DOI: 10.1016/j.brainresrev.2005.08.001 http://doi.org/10.1016/j.brainresrev.2005.08.001 . Neural correlates of cognitive dysfunction after cardiac surgery A Brawanski , R Fahermeier , RD Rothoerl , 等 . Comparison of near infrared spectroscopy and tissue PO 2 time series in patients after severe head injury and an eurysmal subarachnoid hemorrhage . J Cereb Blood Flow Metab , 2002 . 22 ( 5 ): 605 - 611 . 11973433 DOI: 10.1097/00004647-200205000-00012 http://doi.org/10.1097/00004647-200205000-00012 . Comparison of near infrared spectroscopy and tissue PO2 time series in patients after severe head injury and an eurysmal subarachnoid hemorrhage J Canet , J Raeder , LS Rasmussen , 等 . Cognitive dysfunction after minor surgery in the elderly . Acta Anaesthesiol Scand , 2003 . 47 ( 10 ): 1204 - 1210 . 14616316 DOI: 10.1046/j.1399-6576.2003.00238.x http://doi.org/10.1046/j.1399-6576.2003.00238.x . Cognitive dysfunction after minor surgery in the elderly A Casati , G Fanelli , P Pietropaoli , 等 . Continuous monitoring of cerebral oxygen saturation in elderly patients undergoing major abdominal surgery minimizes brain exposure to potential hypoxia . Anesth Analg , 2005 . 101 ( 3 ): 740 - 747 . 16115985 DOI: 10.1213/01.ane.0000166974.96219.cd http://doi.org/10.1213/01.ane.0000166974.96219.cd . Continuous monitoring of cerebral oxygen saturation in elderly patients undergoing major abdominal surgery minimizes brain exposure to potential hypoxia E de Tournay-Jetté , G Dupuis , L Bherer , 等 . The relationship between cerebral oxygen saturation changes and postoperative cognitive dysfunction in elderly patients after coronary artery bypass graft surgery . J Cardiothorac Vasc Anesth , 2010 . 24 ( 1 ): 95 - 104 . DOI: 10.1053/j.jvca.2010.03.019 http://doi.org/10.1053/j.jvca.2010.03.019 . The relationship between cerebral oxygen saturation changes and postoperative cognitive dysfunction in elderly patients after coronary artery bypass graft surgery L Evered , DA Scott , B Silbert , 等 . Postoperative cognitive dysfunction is independent of type of surgery and anesthetic . Anesth Analg , 2011 . 112 ( 5 ): 1179 - 1185 . 21474666 DOI: 10.1213/ANE.0b013e318215217e http://doi.org/10.1213/ANE.0b013e318215217e . Postoperative cognitive dysfunction is independent of type of surgery and anesthetic E Farag , GJ Chelune , A Schubert , 等 . Is depth of anaesthesia, as assessed by Bispectral Index, related to post-operative cognitive dysfunction and recovery? . Anesth Analg , 2006 . 103 ( 3 ): 633 - 640 . DOI: 10.1213/01.ane.0000228870.48028.b5 http://doi.org/10.1213/01.ane.0000228870.48028.b5 . Is depth of anaesthesia, as assessed by Bispectral Index, related to post-operative cognitive dysfunction and recovery? V Fodale , LB Santamaria , D Schifilliti , 等 . Anaesthetics and postoperative cognitive dysfunction: a pathological mechanism mimicking Alzheimer’s disease . Anaesthesia , 2010 . 65 ( 4 ): 388 - 395 . 20136805 DOI: 10.1111/j.1365-2044.2010.06244.x http://doi.org/10.1111/j.1365-2044.2010.06244.x . Anaesthetics and postoperative cognitive dysfunction: a pathological mechanism mimicking Alzheimer’s disease TJ Germon , AE Young , AR Manara , 等 . Extracerebral absorption of near infrared light influences the detection of increased cerebral oxygenation monitored by near infrared spectroscopy . J Neurol Neurosurg Psychiatry , 1995 . 58 ( 4 ): 477 - 479 . 7738560 DOI: 10.1136/jnnp.58.4.477 http://doi.org/10.1136/jnnp.58.4.477 . Extracerebral absorption of near infrared light influences the detection of increased cerebral oxygenation monitored by near infrared spectroscopy SM Gold , I Dziobek , K Rogers , 等 . Hypertension and hypothalamo-pituitary-adrenal axis hyperactivity affect frontal lobe integrity . J Clin Endocrinol Metab , 2005 . 90 ( 6 ): 3262 - 3267 . 15784710 DOI: 10.1210/jc.2004-2181 http://doi.org/10.1210/jc.2004-2181 . Hypertension and hypothalamo-pituitary-adrenal axis hyperactivity affect frontal lobe integrity S Goldman , F Sutter , F Ferdinand , 等 . Optimizing intraoperative cerebral oxygen delivery using noninvasive cerebral oximetry decreases the incidence of stroke for cardiac surgical patients . Heart Surg Forum , 2004 . 7 ( 5 ): 376 - 381 . DOI: 10.1532/HSF98.20041062 http://doi.org/10.1532/HSF98.20041062 . Optimizing intraoperative cerebral oxygen delivery using noninvasive cerebral oximetry decreases the incidence of stroke for cardiac surgical patients M Grilli , F Goffi , M Memo , 等 . Interleukin-1β and glutamate activate the NF-κB/Rel binding site from the regulatory region of the amyloid precursor protein gene in primary neuronal cultures . J Biol Chem , 1996 . 271 ( 25 ): 15002 - 15007 . 8663145 DOI: 10.1074/jbc.271.25.15002 http://doi.org/10.1074/jbc.271.25.15002 . Interleukin-1β and glutamate activate the NF-κB/Rel binding site from the regulatory region of the amyloid precursor protein gene in primary neuronal cultures SW Hong , JK Shim , YS Choi , 等 . Prediction of cognitive dysfunction and patients’ outcome following valvular heart surgery and the role of cerebral oximetry . Eur J Cardiothorac Surg , 2008 . 33 ( 4 ): 560 - 565 . 18272385 DOI: 10.1016/j.ejcts.2008.01.012 http://doi.org/10.1016/j.ejcts.2008.01.012 . Prediction of cognitive dysfunction and patients’ outcome following valvular heart surgery and the role of cerebral oximetry Z Hu , Y Ou , K Duan , 等 . Inflammation: a bridge between postoperative cognitive dysfunction and Alzheimer’s disease . Med Hypotheses , 2010 . 74 ( 4 ): 722 - 724 . 19944539 DOI: 10.1016/j.mehy.2009.10.040 http://doi.org/10.1016/j.mehy.2009.10.040 . Inflammation: a bridge between postoperative cognitive dysfunction and Alzheimer’s disease MJ Jacobs , A Kamyab . Total laparoscopic pancreaticoduodenectomy . JSLS , 2013 . 17 ( 2 ): 188 - 193 . 23925010 DOI: 10.4293/108680813X13654754534792 http://doi.org/10.4293/108680813X13654754534792 . Total laparoscopic pancreaticoduodenectomy T Johnson , T Monk , LS Rasmussen , 等 . Postoperative cognitive dysfunction in middle-aged patients . Anesthesiology , 2002 . 96 ( 6 ): 1351 - 1357 . 12170047 DOI: 10.1097/00000542-200206000-00014 http://doi.org/10.1097/00000542-200206000-00014 . Postoperative cognitive dysfunction in middle-aged patients A Konishi , K Kikuchi . Association of postoperative brain dysfunction and atherosclerosis, intraoperative rSO 2 and CO 2 reaction in open heart surgery . Masui , 1996 . 45 ( 3 ): 287 - 292 . (in Japanese) 8721125 . Association of postoperative brain dysfunction and atherosclerosis, intraoperative rSO2 and CO2 reaction in open heart surgery L Krenk , LS Rasmussen , H Kehlet . New insights into the pathophysiology of postoperative cognitive dysfunction . Acta Anaesthesiol Scand , 2010 . 54 ( 8 ): 951 - 956 . 20626359 DOI: 10.1111/j.1399-6576.2010.02268.x http://doi.org/10.1111/j.1399-6576.2010.02268.x . New insights into the pathophysiology of postoperative cognitive dysfunction R Lin , FJ Zhang , QS Xue , 等 . Accuracy of regional cerebral oxygen saturation in predicting postoperative cognitive dysfunction after total hip arthroplasty . J Arthroplasty , 2013 . 28 ( 3 ): 494 - 497 . 23151365 DOI: 10.1016/j.arth.2012.06.041 http://doi.org/10.1016/j.arth.2012.06.041 . Accuracy of regional cerebral oxygen saturation in predicting postoperative cognitive dysfunction after total hip arthroplasty Y Lu , X Wu , Y Dong , 等 . Anesthetic sevoflurane causes neurotoxicity differently in neonatal naive and Alzheimer disease transgenic mice . Anesthesiology , 2010 . 112 ( 6 ): 1404 - 1416 . 20460993 DOI: 10.1097/ALN.0b013e3181d94de1 http://doi.org/10.1097/ALN.0b013e3181d94de1 . Anesthetic sevoflurane causes neurotoxicity differently in neonatal naive and Alzheimer disease transgenic mice MG Mesleh , JA Stauffer , SP Bowers , 等 . Cost analysis of open and laparoscopic pancreaticoduodenectomy: a single institution comparison . Surg Endosc , 2013 . 27 ( 12 ): 4518 - 4523 . 23943116 DOI: 10.1007/s00464-013-3101-6 http://doi.org/10.1007/s00464-013-3101-6 . Cost analysis of open and laparoscopic pancreaticoduodenectomy: a single institution comparison JT Moller , P Cluitmans , LS Rasmussen , 等 . Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study . Lancet , 1998 . 351 ( 9106 ): 857 - 861 . 9525362 DOI: 10.1016/S0140-6736(97)07382-0 http://doi.org/10.1016/S0140-6736(97)07382-0 . Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study TG Monk , BC Weldon , JE Weldon . Cerebral oxygen desaturations are associated with postoperative cognitive dysfunction in elderly patients . Anesthesiology , 2002 . 96 A40 . Cerebral oxygen desaturations are associated with postoperative cognitive dysfunction in elderly patients JM Murkin , SJ Adams , RJ Novick , 等 . Monitoring brain oxygen saturation during coronary bypass surgery: a randomized, prospective study . Anesth Analg , 2007 . 104 ( 1 ): 51 - 58 . 17179242 DOI: 10.1213/01.ane.0000246814.29362.f4 http://doi.org/10.1213/01.ane.0000246814.29362.f4 . Monitoring brain oxygen saturation during coronary bypass surgery: a randomized, prospective study KS Olsen , LB Svendsen , FS Larsen . Validation of transcranial near-infrared spectroscopy for evaluation of cerebral blood flow autoregulation . J Neurosurg Anesthesiol , 1996 . 8 ( 4 ): 280 - 285 . 8884624 DOI: 10.1097/00008506-199610000-00004 http://doi.org/10.1097/00008506-199610000-00004 . Validation of transcranial near-infrared spectroscopy for evaluation of cerebral blood flow autoregulation LS Rasmussen , A Steentoft , H Rasmussen , 等 . Benzodiazepines and postoperative cognitive dysfunction in the elderly . Br J Anaesth , 1999 . 83 ( 4 ): 585 - 589 . 10673874 DOI: 10.1093/bja/83.4.585 http://doi.org/10.1093/bja/83.4.585 . Benzodiazepines and postoperative cognitive dysfunction in the elderly D Rohan , DJ Buggy , S Crowley , 等 . Increased incidence of postoperative cognitive dysfunction 24 hr after minor surgery in the elderly . Can J Anaesth , 2005 . 52 ( 2 ): 137 - 142 . 15684252 DOI: 10.1007/BF03027718 http://doi.org/10.1007/BF03027718 . Increased incidence of postoperative cognitive dysfunction 24 hr after minor surgery in the elderly JP Slater , T Guarino , J Stack , 等 . Cerebral oxygen desaturation predicts cognitive decline and longer hospital stay after cardiac surgery . Ann Thorac Surg , 2009 . 87 ( 1 ): 36 - 44 . 19101265 DOI: 10.1016/j.athoracsur.2008.08.070 http://doi.org/10.1016/j.athoracsur.2008.08.070 . Cerebral oxygen desaturation predicts cognitive decline and longer hospital stay after cardiac surgery J Tang , MF Eckenhoff , RG Eckenhoff . Anesthesia and the old brain . Anesth Analg , 2010 . 110 ( 2 ): 421 - 426 . 19820235 DOI: 10.1213/ANE.0b013e3181b80939 http://doi.org/10.1213/ANE.0b013e3181b80939 . Anesthesia and the old brain KP Townsend , D Obregon , A Quadros , 等 . Proinflammatory and vasoactive effects of Aβ in the cerebrovasculature . Ann N Y Acad Sci , 2002 . 977 ( 1 ): 65 - 76 . 12480734 DOI: 10.1111/j.1749-6632.2002.tb04799.x http://doi.org/10.1111/j.1749-6632.2002.tb04799.x . Proinflammatory and vasoactive effects of Aβ in the cerebrovasculature T Vanderweyde , MM Bednar , SA Forman , 等 . Iatrogenic risk factors for Alzheimer’s disease: surgery and anesthesia . J Alzheimer’s Dis , 2010 . 22 ( Suppl. 3 ): 91 - 104 . DOI: 10.3233/JAD-2010-100843 http://doi.org/10.3233/JAD-2010-100843 . Iatrogenic risk factors for Alzheimer’s disease: surgery and anesthesia FS Yao , CC Tseng , CY Ho , 等 . Cerebral oxygen desaturation is associated with early postoperative neuropsychological dysfunction in patients undergoing cardiac surgery . J Cardiothorac Vasc Anesth , 2004 . 18 ( 5 ): 552 - 558 . 15578464 DOI: 10.1053/j.jvca.2004.07.007 http://doi.org/10.1053/j.jvca.2004.07.007 . Cerebral oxygen desaturation is associated with early postoperative neuropsychological dysfunction in patients undergoing cardiac surgery We sincerely thank Dr. Xiang-wei ZHANG (an anesthesiologist of the Massachusetts General Hospital, USA) for providing valuable help in this study. Compliance with ethics guidelines Xi-ming LI, Ming-tao SHAO, Jian-juan WANG, and Yue-lan WANG declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for which identifying information is included in this article. 10.1631/jzus.B1400130 Project supported by the Shandong Science and Technology Development Project (No. 2011YD18070), China 2014-05-06 2014-09-21 2014-08-07 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2014 2014 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 10 15