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Postoperative plasma 8-iso-prostaglandin F2α levels are associated with delirium and cognitive dysfunction in elderly patients after hip fracture surgery
Clinica Chimica Acta 455 (2016) 149–153
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Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Postoperative plasma 8-iso-prostaglandin F2α levels are associated with delirium and cognitive dysfunction in elderly patients after hip fracture surgery Yuan-Bo Zheng, Guo-Mo Ruan, Jia-Xing Fu, Zhong-Liang Su, Peng Cheng, Jian-Zuo Lu ⁎ Department of Orthopedics, The People's Hospital of Wenzhou City, 57 Canghou Lane, Wenzhou 325000, China
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Article history: Received 23 December 2015 Received in revised form 4 February 2016 Accepted 9 February 2016 Available online 10 February 2016 Keywords: 8-iso-Prostaglandin F2α Delirium Cognitive dysfunction Postoperative Elderly Hip fracture
a b s t r a c t Background: Oxidative stress may be involved in occurrence of postoperative delirium (POD) and cognitive dysfunction (POCD). 8-iso-Prostaglandin F2α (8-iso-PGF2α), an isoprostane derived from arachidonic acid via lipid peroxidation, is considered a gold standard for measuring oxidative stress. The present study aimed to investigate the ability of postoperative plasma 8-iso-PGF2α levels to predict POD and POCD in elderly patients undergoing hip fracture surgery. Methods: Postoperative plasma 8-iso-PGF2α levels of 182 patients were measured by an enzyme-linked immunosorbent assay. We assessed the relationships between plasma 8-iso-PGF2α levels and the risk of POD and POCD using a multivariate analysis. Results: Plasma 8-iso-PGF2α levels and age were identified as the independent predictors for POD and POCD. Based on areas under receiver operating characteristic curve, the predictive values of 8-iso-PGF2α were obviously higher than those of age for POD and POCD. In a combined logistic-regression model, 8-iso-PGF2α significantly enhanced the areas under curve of age for prediction of POD and POCD. Conclusions: Postoperative plasma 8-iso-PGF2α levels may have the potential to predict POD and POCD in elder patients undergoing hip fracture surgery. © 2016 Elsevier B.V. All rights reserved.
1. Introduction
2. Materials and methods
Postoperative delirium (POD) and cognitive dysfunction (POCD) are the common complications in elderly patients after hip fracture surgery [1–3]. The occurrences of POD and POCD are associated with multiple adverse effects, such as prolonged hospital stay, increased health care cost and high mortality rate [4–6]. The pathophysiology of POD and POCD remains poorly understood, but the accumulating evidence shows that the oxidative stress plays an important role in these processes [7–9]. 8-iso-Prostaglandin F2α (8-iso-PGF2α) is derived from phospholipidbound arachidonic acid by reactive oxygen species-mediated lipid peroxidation and released from membranes by phospholipase A2 activity [10–13]. Measurement of 8-iso-PGF2α is a reliable tool for the identification of subjects with increased rates of lipid peroxidation [14–16]. Enhanced formation of 8-iso-PGF2α in peripheral blood is associated with the poor prognosis and severity of traumatic brain injury and spontaneous intracerebral hemorrhage [17,18]. Moreover, 8-iso-PGF2α is increased in the brain interstitial tissue from head trauma patients [19]. These findings suggest 8-iso-PGF2α may represent a potential biomarker of brain injury.
2.1. Study population
⁎ Corresponding author at: Department of Orthopedics, The People's Hospital of Wenzhou City, 57 Canghou Lane, Wenzhou 325000, China. E-mail address: [email protected] (J.-Z. Lu).
http://dx.doi.org/10.1016/j.cca.2016.02.007 0009-8981/© 2016 Elsevier B.V. All rights reserved.
This prospective, observatory study recruited the elderly patients (defined as ≥ age of 65 y) undergoing surgery for a femoral neck fracture or an intertrochanteric fracture during the period of January 2011 to January 2015 in The People's Hospital of Wenzhou City. We excluded those patients with a Mini-Mental State Examination score b 24 before surgery, a previous psychiatric disorder like dementia, delirium or depressive illness, any severe visual or auditory disorders, and inability to speak or understand Chinese. The study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of our hospital. Written informed consent from the subjects or from their legal guardians was obtained. 2.2. Clinical assessment The recorded information included age, gender, body mass index, medical comorbidity, fracture type, surgical delay, type of anesthesia, duration of anesthesia, amount of blood loss, type of operation (hip arthroplasty or internal fixation), hospitalization after surgery, and surgical risk on the American Society of Anesthesiologists (ASA) rating scale [20]. Medical comorbidities were assessed using the modified
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Charlson's Comorbidity Index, with possible total scores ranging from 0 to 15, where higher scores indicate a poorer health status [21]. 2.3. Delirium evaluation The Confusion Assessment Method (CAM) was performed to assess delirium [22,23]. CAM scores consist of 4 features as follows: (1) acute and fluctuating changes in mental status, (2) inattention, (3) disorganized or incoherent thinking, and (4) an altered level of consciousness. Delirium is considered if Features 1 and 2 are present and either Feature 3 or 4 is present. During the study phase, patients were assessed for delirium twice daily until the seventh postoperative day.
patients had a diagnosis of femoral neck fracture and 90 patients, intertrochanteric fracture. Mean Modified Charlson's Comorbidity Index was 1.2 ± 1.1. Ten patients had ASAI; 100 patients, ASA II; 71 patients, ASA III; 1 patient, ASA IV. According to type of anesthesia, 107 patients underwent spinal anesthesia and 75 patients obtained general anesthesia. Mean duration of anesthesia was 98.2 ± 18.3 min; mean amount of transfusion, 291.4 ± 142.5 ml; mean delay of surgery, 6.9 ± 5.3 days; mean hospitalization after surgery, 14.2 ± 3.7 days. In accordance with type of surgery, 142 cases underwent arthroplasty and 40 cases obtained internal fixation. 68 patients (37.4%) suffered from POD and 50 patients (27.5%) had POCD.
2.4. Neurocognitive evaluation
3.2. The changes of plasma 8-iso-PGF2α levels
Neuropsychological evaluation was performed 1 d before and 1 week after surgery. Totally, in accordance with a battery of 12 neuropsychological tests, a range of cognitive functions including attention, memory and executive function was assessed. The presence of POCD was defined according to the method used in the ISPOCD1 studies [24]: we calculated the standard deviation of the differences in neuropsychological test results conducted within the same time interval from 50 age- and sex-matched healthy individuals (control group). For patients, the differences between baseline (preoperative) scores and scores at one-week postoperatively were divided by the control group standard deviation to obtain a Z score for each individual test. Patients were defined as have POCD if they had a Z score greater than 1.96 on ≥2 tests.
The mean plasma 8-iso-PGF2α levels of all patients were 200.6 ± 92.8 pg/ml (range: 82.4–503.2 pg/ml). Plasma 8-iso-PGF2α levels were significantly higher in the POD patients than in the non-POD patients (274.4 ± 95.9 pg/ml vs. 156.5 ± 55.6 pg/ml, P b 0.001) and in the POCD patients than in the non-POCD patients (285.4 ± 102.4 pg/ml vs. 168.4 ± 64.8 pg/ml, P b 0.001).
2.5. Determination of 8-iso-PGF2α in plasma Blood samples were obtained between 7 and 8 a.m. on the first postoperative day. Samples were placed on ice, centrifuged at 3000g, aliquoted and frozen at −70 °C until assayed. 8-iso-PGF2α concentrations were in duplicate analyzed by an enzyme-linked immunosorbent assay using commercial kits (Cayman Chemicals) in accordance with the manufactures' instructions. All determinations were performed by laboratory technicians blinded to all clinical data.
3.3. Prediction of POD Based on the ROC curve, the optimal cutoff value of plasma 8-isoPGF2α levels as an indicator for POD was projected to be 182.4 pg/ml, which yielded a sensitivity of 83.8% and a specificity of 78.1%, with the AUC of 0.866 (95% CI = 0.808–0.912, P b 0.001; Fig. 1). According to the AUC, its predictive value was significantly higher than that of age (AUC: 0.744, 95% CI = 0.675–0.806, P = 0.014; Fig. 1).When a combined logistic-regression model was configure, 8-iso-PGF2α obviously improved the AUC of age to 0.900 (95% CI = 0.847–0.939, P b 0.001; Fig. 1). In Table 1, a univariate analysis demonstrated that plasma 8-isoPGF2α levels higher than 182.4 pg/ml and other parameters were significantly associated with POD. Plasma 8-iso-PGF2α levels higher than 182.4 pg/ml (OR = 17.066, 95% CI = 7.391–39.406, P b 0.001) and age (OR = 1.122, 95% CI = 1.060–1.189, P b 0.001) were identified as the independent predictors for POD in a multivariate Logistic model.
2.6. Statistical analysis Statistical analysis was carried out with SPSS 19.0 and MedCalc 9.6.4.0. Categorical variables were presented as numbers and percentages. Continuous variables were shown as mean ± SD. Intergroup comparisons were performed using χ2 test or Fisher exact test for the categorical data as well as Student's t test for the continuous variables. The predictors of POD and POCD were assessed using a multivariate logistic regression analysis. All parameters that were found to be significant in the univariate analysis were further analyzed using a multivariate regression to identify those parameters that retained significant while accounting for all relevant variables. The odds ratio (OR) values and 95% confidence intervals (CIs) were reported. Receiver operating characteristic (ROC) curves were generated to determine cutoff values for optimal predictive sensitivities and specificities. The area under curves (AUCs) and 95% CI were estimated. Combined logistic-regression models were configured to assess the combined predictive performances for POD and POCD. Statistical significance was defined as a probability value of less than 0.05. 3. Results 3.1. Patients characteristics This study eventually included 182 elderly patients after hip fracture surgery, who consisted of 70 males and 112 females and had a mean age of 75.7 ± 7.4 y. Mean body mass index was 22.6 ± 2.6 kg/m2. 92
Fig. 1. Receiver operating characteristic curve analysis of age, plasma 8-iso-prostaglandin F2α (8-iso-PGF2α) levels and age combined with plasma 8-iso-PGF2α levels for identifying postoperative delirium in elder patients after hip fracture surgery.
Y.-B. Zheng et al. / Clinica Chimica Acta 455 (2016) 149–153 Table 1 Factors associated with delirium of elderly patients after hip fracture surgery. Delirium
Gender (male/female) Age (y) Body mass index (kg/m2) Diagnosis Femoral neck fracture Intertrochanteric fracture Modified Charlson's Comorbidity Index American Society of Anesthesiologists Scale I II III IV Type of anesthesia Spinal General Duration of anesthesia (minutes) Amount of transfusion (ml) Delay of surgery (days) Hospitalization after surgery (days) Type of surgery Arthroplasty Internal fixation Plasma 8-iso-PGF2α levels higher than 182.4 pg/ml
Yes n = 68
No n = 114
P value
25/43 79.6 ± 6.8 22.8 ± 2.5
45/69 73.4 ± 6.8 22.5 ± 2.6
NS b0.001 NS NS
36 32 1.6 ± 1.2
56 58 1.0 ± 1.0
3 25 39 1
7 75 32 0
29 39 102.2 ± 21.5 297.7 ± 129.7 7.1 ± 4.9 15.2 ± 4.2
78 36 95.8 ± 15.6 287.6 ± 150.1 6.7 ± 5.6 13.7 ± 3.2
60 8 57 (83.8%)
82 32 25 (21.9%)
0.003 b0.001
0.001
0.020 NS NS 0.010 0.010
b0.001
Numerical variables were presented as mean ± SD. Categorical variables were expressed as counts (percentage). Numerical variables were analyzed by unpaired Student's t test. Categorical variables were analyzed by χ2 test or Fisher exact test.
3.4. Prediction of POCD A ROC curve identified that a plasma 8-iso-PGF2α level N 194.4 pg/ml predicted POCD with 82.0% sensitivity and 75.0% specificity (AUC: 0.839; 95% CI = 0.777–0.889) in Fig. 2. Compared with age (AUC: 0.717, 95% CI = 0.645–0.781), plasma 8-iso-PGF2α level had higher predictive value (P = 0.030, Fig. 2). Moreover, 8-iso-PGF2α significantly enhanced the AUC of age to 0.870 (95% CI = 0.812–0.915, P b 0.001; Fig. 2) following configuration of a combined logistic-regression model.
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Plasma 8-iso-PGF2α levels higher than 194.4 pg/ml were significantly associated with POCD and other related variables were shown in Table 2. A multivariate logistic analysis confirmed that plasma 8-iso-PGF2α levels higher than 194.4 pg/ml (OR = 11.194, 95% CI = 4.817–26.011, P b 0.001) and age (OR = 1.088, 95% CI = 1.030–1.150, P b 0.001) were the independent predictors for POCD.
4. Discussion In this prospective collected data, the main findings were that plasma 8-iso-PGF2α levels were obviously higher in patients with POD and POCD than in those without POD and POCD; moreover, 8-isoPGF2α was identified as an independent predictor for POD and POCD in the multivariate logistic regression models and had higher predictive value for them based on the ROC curves. These abovementioned results indicate that 8-iso-PGF2α should have the potential to be a predictive biomarker for POD and POCD in elderly patients undergoing hip fracture surgery. As expected, and in agreement with other studies [25,26], in this study, POD and POCD showed a tendency to occur in older elderly patients who underwent hip fracture surgery. We further demonstrated that age was an independent risk factor of POD and POCD. To my best knowledge, there is a paucity of data on the predictive value of age for POD and POCD. The current study also configured a ROC curve to assess this sort of performance. Actually, age possessed a high predictive value, substantializing age as a good clinical variable to predict the patients at risk of POD and POCD. The pathophysiological mechanisms which lead to the eventual clinical picture of POD and POCD remain to be elucidated. However, it can be hypothesized that POD and POCD might be the consequence of cerebral neuronal damage caused by imbalance of noradrenergic/cholinergic neurotransmission, perioperative hypoxia, micro-embolisms or hypotension [27–29]. Oxidative stress, resulting from an imbalance in redox state in which pro-oxidants overwhelm antioxidant capacity, has emerged as a potential mechanism implicated in the pathogenesis and disease Table 2 Factors associated with cognitive dysfunction of elderly patients after hip fracture surgery. Cognitive dysfunction
Gender (male/female) Age (y) Body mass index (kg/m2) Diagnosis Femoral neck fracture Intertrochanteric fracture Modified Charlson's Comorbidity Index American Society of Anesthesiologists Scale I II III IV Type of anesthesia Spinal General Duration of anesthesia (minutes) Amount of transfusion (ml) Delay of surgery (days) Hospitalization after surgery (days) Type of surgery Arthroplasty Internal fixation Plasma 8-iso-PGF2α levels higher than 194.4 pg/ml Fig. 2. Receiver operating characteristic curve analysis of age, plasma 8-iso-prostaglandin F2α (8-iso-PGF2α) levels and age combined with plasma 8-iso-PGF2α levels for identifying postoperative cognitive dysfunction in elder patients after hip fracture surgery.
Yes n = 50
No n = 132
P value
17/33 79.8 ± 7.5 22.7 ± 2.6
53/79 74.2 ± 6.8 22.6 ± 2.5
NS b0.001 NS ns
27 23 1.7 ± 1.3
65 67 1.1 ± 1.0
2 18 29 1
8 82 42 0
22 28 104.1 ± 21.6 294.3 ± 121.0 7.2 ± 4.7 15.6 ± 4.3
85 47 95.9 ± 16.3 290.2 ± 150.2 6.8 ± 5.5 13.7 ± 3.3
47 3 41 (82.0%)
95 37 33 (25.0%)
0.001 0.003
0.013
0.007 NS NS 0.009 0.001
b0.001
Numerical variables were presented as mean ± SD. Categorical variables were expressed as counts (percentage). Numerical variables were analyzed by unpaired Student's t test. Categorical variables were analyzed by χ2 test or Fisher exact test.
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progression of neurological diseases [30–34]. Moreover, oxidative stress is involved in the occurrence and development of POD and POCD [7–9]. 8-iso-PGF2α, an isoprostane derived from arachidonic acid via lipid peroxidation in vivo, is a potent vasoconstrictor and is considered a gold standard for measuring oxidative stress in vivo [10–16]. 8-iso-PGF2α is expressed in rat brain neuronal endings after oxidant stimuli [35] and generated in astrocytes following stretch-induced trauma [36] and its plasma level is also enhanced during animal spinal cord ischemia [37]. In humans, plasma 8-iso-PGF2α levels reflect the severity and prognosis of hemorrhagic stroke and head trauma [17,18]; moreover, 8-iso-PGF2α is increased in the brain interstitial tissue from head trauma patients [19], suggesting 8-iso-PGF2α may represent a potential biomarker of POD and POCD. The current study was designed to investigate the relationships between 8-iso-PGF2α levels and the risk of POD and POCD in elder patients following hip fracture surgery. In the univariate analyses, patients with POD and POCD had higher plasma 8-iso-PGF2α levels compared with those without POD and POCD. Even, in the multivariate logistic regression models, 8-iso-PGF2α was also found to be a predictor of POD and POCD independently of age, which is a common determinant of POD and POCD [1–6]. Interestingly, its discriminative power exceeded that of age according to AUC. Importantly, in the combined logistic-regression models, 8-iso-PGF2α significantly improved the predictive value of age for the risk of POD and POCD. Overall, our data suggest that postoperative plasma 8-iso-PGF2α levels could help to predict POD and POCD in elder patients after hip fracture surgery. The present study aimed to investigate the ability of postoperative plasma 8-iso-PGF2α levels to predict POD and POCD in elderly patients undergoing hip fracture surgery and further analyzed the mechanisms of occurrence of POD and POCD. It is well known that brain injury, partly derived from perioperative hypoxia, micro-embolisms or hypotension, may lead to POD and POCD and, if more severe, neurological deficit [27–29]. However, some postoperative circulating biomarkers can reflect the severity of brain injury, and therefore have the potential to predict the POD and POCD. Oxidative reaction is involved in the mechanisms of brain injury. Hence, 8-iso-PGF2α, a gold standard for measuring oxidative stress, is presumed to be a good biomarker to predict the POD and POCD in elderly patients undergoing hip fracture surgery. This study confirmed that 8-iso-PGF2α was an independent predictor of POD and POCD and possessed the higher predictive value. Consequently, whether the patients had neurological deficit or suffered from postoperative embolic episodes in this study, postoperative plasma 8-iso-PGF2α levels were found to be elevated, further indicating that oxidative stress associated with brain injury may be involved in the mechanisms of the occurrence and development of POD and POCD. Because of the aforementioned reasons, this study did not exclude those patients with neurological deficit and who suffered from postoperative embolic episodes. There are 2 limitations in the current study. At first, in this study, all blood samples were drawn from the patients on the first postoperative day. However, obtainment of the blood samples at serial time points could help to discover some information about the serial changes of plasma 8-iso-PGF2α levels. A second limitation of our study is that the 8-iso-PGF2α values were measured from peripheral blood and may not necessarily correspond to values in the brain. Therefore, the determination of 8-iso-PGF2α in cerebrospinal fluid may present us with some interesting information that can help to further discover the mechanisms of the occurrence and development of POD and POCD. 5. Conclusions In the current study, plasma 8-iso-PGF2α levels are associated independently with POD and POCD, as well as have high predictive performance for them in elder patients following hip fracture surgery. Therefore, 8-iso-PGF2α may be a useful, complementary tool to predict POD and POCD in elder patients following hip fracture surgery.
Abbreviations ASA American Society of Anesthesiologists CAM Confusion Assessment Method POCD postoperative cognitive dysfunction POD postoperative delirium ROC receiver operating characteristic 8-iso-PGF2α 8-iso-prostaglandin F2α Acknowledgments The authors thank all staffs in the Department of Orthopedics, People's Hospital of Wenzhou City (Wenzhou, China) for their technical support. References [1] Z.J. Lipowski, Delirium in the elderly patient, N. Engl. J. Med. 320 (1989) 578-2. [2] T. Kratz, M. Heinrich, E. Schlauß, A. Diefenbacher, Preventing postoperative delirium, Dtsch. Arztebl. Int. 112 (2015) 289–296. [3] H. Nie, B. Zhao, Y.Q. Zhang, Y.H. Jiang, Y.X. Yang, Pain and cognitive dysfunction are the risk factors of delirium in elderly hip fracture Chinese patients, Arch. Gerontol. Geriatr. 54 (2012) e172–e174. [4] A. Edlund, M. Lundstrom, G. Lundstrom, B. Hedqvist, Y. Gustafson, Clinical profile of delirium in patients treated for femoral neck fractures, Dement. Geriatr. Cogn. 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Postoperative plasma 8-iso-prostaglandin F2α levels are associated with delirium and cognitive dysfunction in elderly patients after hip fracture surgery Yuan-Bo Zheng, Guo-Mo Ruan, Jia-Xing Fu, Zhong-Liang Su, Peng Cheng, Jian-Zuo Lu ⁎ Department of Orthopedics, The People's Hospital of Wenzhou City, 57 Canghou Lane, Wenzhou 325000, China
a r t i c l e
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Article history: Received 23 December 2015 Received in revised form 4 February 2016 Accepted 9 February 2016 Available online 10 February 2016 Keywords: 8-iso-Prostaglandin F2α Delirium Cognitive dysfunction Postoperative Elderly Hip fracture
a b s t r a c t Background: Oxidative stress may be involved in occurrence of postoperative delirium (POD) and cognitive dysfunction (POCD). 8-iso-Prostaglandin F2α (8-iso-PGF2α), an isoprostane derived from arachidonic acid via lipid peroxidation, is considered a gold standard for measuring oxidative stress. The present study aimed to investigate the ability of postoperative plasma 8-iso-PGF2α levels to predict POD and POCD in elderly patients undergoing hip fracture surgery. Methods: Postoperative plasma 8-iso-PGF2α levels of 182 patients were measured by an enzyme-linked immunosorbent assay. We assessed the relationships between plasma 8-iso-PGF2α levels and the risk of POD and POCD using a multivariate analysis. Results: Plasma 8-iso-PGF2α levels and age were identified as the independent predictors for POD and POCD. Based on areas under receiver operating characteristic curve, the predictive values of 8-iso-PGF2α were obviously higher than those of age for POD and POCD. In a combined logistic-regression model, 8-iso-PGF2α significantly enhanced the areas under curve of age for prediction of POD and POCD. Conclusions: Postoperative plasma 8-iso-PGF2α levels may have the potential to predict POD and POCD in elder patients undergoing hip fracture surgery. © 2016 Elsevier B.V. All rights reserved.
1. Introduction
2. Materials and methods
Postoperative delirium (POD) and cognitive dysfunction (POCD) are the common complications in elderly patients after hip fracture surgery [1–3]. The occurrences of POD and POCD are associated with multiple adverse effects, such as prolonged hospital stay, increased health care cost and high mortality rate [4–6]. The pathophysiology of POD and POCD remains poorly understood, but the accumulating evidence shows that the oxidative stress plays an important role in these processes [7–9]. 8-iso-Prostaglandin F2α (8-iso-PGF2α) is derived from phospholipidbound arachidonic acid by reactive oxygen species-mediated lipid peroxidation and released from membranes by phospholipase A2 activity [10–13]. Measurement of 8-iso-PGF2α is a reliable tool for the identification of subjects with increased rates of lipid peroxidation [14–16]. Enhanced formation of 8-iso-PGF2α in peripheral blood is associated with the poor prognosis and severity of traumatic brain injury and spontaneous intracerebral hemorrhage [17,18]. Moreover, 8-iso-PGF2α is increased in the brain interstitial tissue from head trauma patients [19]. These findings suggest 8-iso-PGF2α may represent a potential biomarker of brain injury.
2.1. Study population
⁎ Corresponding author at: Department of Orthopedics, The People's Hospital of Wenzhou City, 57 Canghou Lane, Wenzhou 325000, China. E-mail address: [email protected] (J.-Z. Lu).
http://dx.doi.org/10.1016/j.cca.2016.02.007 0009-8981/© 2016 Elsevier B.V. All rights reserved.
This prospective, observatory study recruited the elderly patients (defined as ≥ age of 65 y) undergoing surgery for a femoral neck fracture or an intertrochanteric fracture during the period of January 2011 to January 2015 in The People's Hospital of Wenzhou City. We excluded those patients with a Mini-Mental State Examination score b 24 before surgery, a previous psychiatric disorder like dementia, delirium or depressive illness, any severe visual or auditory disorders, and inability to speak or understand Chinese. The study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of our hospital. Written informed consent from the subjects or from their legal guardians was obtained. 2.2. Clinical assessment The recorded information included age, gender, body mass index, medical comorbidity, fracture type, surgical delay, type of anesthesia, duration of anesthesia, amount of blood loss, type of operation (hip arthroplasty or internal fixation), hospitalization after surgery, and surgical risk on the American Society of Anesthesiologists (ASA) rating scale [20]. Medical comorbidities were assessed using the modified
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Charlson's Comorbidity Index, with possible total scores ranging from 0 to 15, where higher scores indicate a poorer health status [21]. 2.3. Delirium evaluation The Confusion Assessment Method (CAM) was performed to assess delirium [22,23]. CAM scores consist of 4 features as follows: (1) acute and fluctuating changes in mental status, (2) inattention, (3) disorganized or incoherent thinking, and (4) an altered level of consciousness. Delirium is considered if Features 1 and 2 are present and either Feature 3 or 4 is present. During the study phase, patients were assessed for delirium twice daily until the seventh postoperative day.
patients had a diagnosis of femoral neck fracture and 90 patients, intertrochanteric fracture. Mean Modified Charlson's Comorbidity Index was 1.2 ± 1.1. Ten patients had ASAI; 100 patients, ASA II; 71 patients, ASA III; 1 patient, ASA IV. According to type of anesthesia, 107 patients underwent spinal anesthesia and 75 patients obtained general anesthesia. Mean duration of anesthesia was 98.2 ± 18.3 min; mean amount of transfusion, 291.4 ± 142.5 ml; mean delay of surgery, 6.9 ± 5.3 days; mean hospitalization after surgery, 14.2 ± 3.7 days. In accordance with type of surgery, 142 cases underwent arthroplasty and 40 cases obtained internal fixation. 68 patients (37.4%) suffered from POD and 50 patients (27.5%) had POCD.
2.4. Neurocognitive evaluation
3.2. The changes of plasma 8-iso-PGF2α levels
Neuropsychological evaluation was performed 1 d before and 1 week after surgery. Totally, in accordance with a battery of 12 neuropsychological tests, a range of cognitive functions including attention, memory and executive function was assessed. The presence of POCD was defined according to the method used in the ISPOCD1 studies [24]: we calculated the standard deviation of the differences in neuropsychological test results conducted within the same time interval from 50 age- and sex-matched healthy individuals (control group). For patients, the differences between baseline (preoperative) scores and scores at one-week postoperatively were divided by the control group standard deviation to obtain a Z score for each individual test. Patients were defined as have POCD if they had a Z score greater than 1.96 on ≥2 tests.
The mean plasma 8-iso-PGF2α levels of all patients were 200.6 ± 92.8 pg/ml (range: 82.4–503.2 pg/ml). Plasma 8-iso-PGF2α levels were significantly higher in the POD patients than in the non-POD patients (274.4 ± 95.9 pg/ml vs. 156.5 ± 55.6 pg/ml, P b 0.001) and in the POCD patients than in the non-POCD patients (285.4 ± 102.4 pg/ml vs. 168.4 ± 64.8 pg/ml, P b 0.001).
2.5. Determination of 8-iso-PGF2α in plasma Blood samples were obtained between 7 and 8 a.m. on the first postoperative day. Samples were placed on ice, centrifuged at 3000g, aliquoted and frozen at −70 °C until assayed. 8-iso-PGF2α concentrations were in duplicate analyzed by an enzyme-linked immunosorbent assay using commercial kits (Cayman Chemicals) in accordance with the manufactures' instructions. All determinations were performed by laboratory technicians blinded to all clinical data.
3.3. Prediction of POD Based on the ROC curve, the optimal cutoff value of plasma 8-isoPGF2α levels as an indicator for POD was projected to be 182.4 pg/ml, which yielded a sensitivity of 83.8% and a specificity of 78.1%, with the AUC of 0.866 (95% CI = 0.808–0.912, P b 0.001; Fig. 1). According to the AUC, its predictive value was significantly higher than that of age (AUC: 0.744, 95% CI = 0.675–0.806, P = 0.014; Fig. 1).When a combined logistic-regression model was configure, 8-iso-PGF2α obviously improved the AUC of age to 0.900 (95% CI = 0.847–0.939, P b 0.001; Fig. 1). In Table 1, a univariate analysis demonstrated that plasma 8-isoPGF2α levels higher than 182.4 pg/ml and other parameters were significantly associated with POD. Plasma 8-iso-PGF2α levels higher than 182.4 pg/ml (OR = 17.066, 95% CI = 7.391–39.406, P b 0.001) and age (OR = 1.122, 95% CI = 1.060–1.189, P b 0.001) were identified as the independent predictors for POD in a multivariate Logistic model.
2.6. Statistical analysis Statistical analysis was carried out with SPSS 19.0 and MedCalc 9.6.4.0. Categorical variables were presented as numbers and percentages. Continuous variables were shown as mean ± SD. Intergroup comparisons were performed using χ2 test or Fisher exact test for the categorical data as well as Student's t test for the continuous variables. The predictors of POD and POCD were assessed using a multivariate logistic regression analysis. All parameters that were found to be significant in the univariate analysis were further analyzed using a multivariate regression to identify those parameters that retained significant while accounting for all relevant variables. The odds ratio (OR) values and 95% confidence intervals (CIs) were reported. Receiver operating characteristic (ROC) curves were generated to determine cutoff values for optimal predictive sensitivities and specificities. The area under curves (AUCs) and 95% CI were estimated. Combined logistic-regression models were configured to assess the combined predictive performances for POD and POCD. Statistical significance was defined as a probability value of less than 0.05. 3. Results 3.1. Patients characteristics This study eventually included 182 elderly patients after hip fracture surgery, who consisted of 70 males and 112 females and had a mean age of 75.7 ± 7.4 y. Mean body mass index was 22.6 ± 2.6 kg/m2. 92
Fig. 1. Receiver operating characteristic curve analysis of age, plasma 8-iso-prostaglandin F2α (8-iso-PGF2α) levels and age combined with plasma 8-iso-PGF2α levels for identifying postoperative delirium in elder patients after hip fracture surgery.
Y.-B. Zheng et al. / Clinica Chimica Acta 455 (2016) 149–153 Table 1 Factors associated with delirium of elderly patients after hip fracture surgery. Delirium
Gender (male/female) Age (y) Body mass index (kg/m2) Diagnosis Femoral neck fracture Intertrochanteric fracture Modified Charlson's Comorbidity Index American Society of Anesthesiologists Scale I II III IV Type of anesthesia Spinal General Duration of anesthesia (minutes) Amount of transfusion (ml) Delay of surgery (days) Hospitalization after surgery (days) Type of surgery Arthroplasty Internal fixation Plasma 8-iso-PGF2α levels higher than 182.4 pg/ml
Yes n = 68
No n = 114
P value
25/43 79.6 ± 6.8 22.8 ± 2.5
45/69 73.4 ± 6.8 22.5 ± 2.6
NS b0.001 NS NS
36 32 1.6 ± 1.2
56 58 1.0 ± 1.0
3 25 39 1
7 75 32 0
29 39 102.2 ± 21.5 297.7 ± 129.7 7.1 ± 4.9 15.2 ± 4.2
78 36 95.8 ± 15.6 287.6 ± 150.1 6.7 ± 5.6 13.7 ± 3.2
60 8 57 (83.8%)
82 32 25 (21.9%)
0.003 b0.001
0.001
0.020 NS NS 0.010 0.010
b0.001
Numerical variables were presented as mean ± SD. Categorical variables were expressed as counts (percentage). Numerical variables were analyzed by unpaired Student's t test. Categorical variables were analyzed by χ2 test or Fisher exact test.
3.4. Prediction of POCD A ROC curve identified that a plasma 8-iso-PGF2α level N 194.4 pg/ml predicted POCD with 82.0% sensitivity and 75.0% specificity (AUC: 0.839; 95% CI = 0.777–0.889) in Fig. 2. Compared with age (AUC: 0.717, 95% CI = 0.645–0.781), plasma 8-iso-PGF2α level had higher predictive value (P = 0.030, Fig. 2). Moreover, 8-iso-PGF2α significantly enhanced the AUC of age to 0.870 (95% CI = 0.812–0.915, P b 0.001; Fig. 2) following configuration of a combined logistic-regression model.
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Plasma 8-iso-PGF2α levels higher than 194.4 pg/ml were significantly associated with POCD and other related variables were shown in Table 2. A multivariate logistic analysis confirmed that plasma 8-iso-PGF2α levels higher than 194.4 pg/ml (OR = 11.194, 95% CI = 4.817–26.011, P b 0.001) and age (OR = 1.088, 95% CI = 1.030–1.150, P b 0.001) were the independent predictors for POCD.
4. Discussion In this prospective collected data, the main findings were that plasma 8-iso-PGF2α levels were obviously higher in patients with POD and POCD than in those without POD and POCD; moreover, 8-isoPGF2α was identified as an independent predictor for POD and POCD in the multivariate logistic regression models and had higher predictive value for them based on the ROC curves. These abovementioned results indicate that 8-iso-PGF2α should have the potential to be a predictive biomarker for POD and POCD in elderly patients undergoing hip fracture surgery. As expected, and in agreement with other studies [25,26], in this study, POD and POCD showed a tendency to occur in older elderly patients who underwent hip fracture surgery. We further demonstrated that age was an independent risk factor of POD and POCD. To my best knowledge, there is a paucity of data on the predictive value of age for POD and POCD. The current study also configured a ROC curve to assess this sort of performance. Actually, age possessed a high predictive value, substantializing age as a good clinical variable to predict the patients at risk of POD and POCD. The pathophysiological mechanisms which lead to the eventual clinical picture of POD and POCD remain to be elucidated. However, it can be hypothesized that POD and POCD might be the consequence of cerebral neuronal damage caused by imbalance of noradrenergic/cholinergic neurotransmission, perioperative hypoxia, micro-embolisms or hypotension [27–29]. Oxidative stress, resulting from an imbalance in redox state in which pro-oxidants overwhelm antioxidant capacity, has emerged as a potential mechanism implicated in the pathogenesis and disease Table 2 Factors associated with cognitive dysfunction of elderly patients after hip fracture surgery. Cognitive dysfunction
Gender (male/female) Age (y) Body mass index (kg/m2) Diagnosis Femoral neck fracture Intertrochanteric fracture Modified Charlson's Comorbidity Index American Society of Anesthesiologists Scale I II III IV Type of anesthesia Spinal General Duration of anesthesia (minutes) Amount of transfusion (ml) Delay of surgery (days) Hospitalization after surgery (days) Type of surgery Arthroplasty Internal fixation Plasma 8-iso-PGF2α levels higher than 194.4 pg/ml Fig. 2. Receiver operating characteristic curve analysis of age, plasma 8-iso-prostaglandin F2α (8-iso-PGF2α) levels and age combined with plasma 8-iso-PGF2α levels for identifying postoperative cognitive dysfunction in elder patients after hip fracture surgery.
Yes n = 50
No n = 132
P value
17/33 79.8 ± 7.5 22.7 ± 2.6
53/79 74.2 ± 6.8 22.6 ± 2.5
NS b0.001 NS ns
27 23 1.7 ± 1.3
65 67 1.1 ± 1.0
2 18 29 1
8 82 42 0
22 28 104.1 ± 21.6 294.3 ± 121.0 7.2 ± 4.7 15.6 ± 4.3
85 47 95.9 ± 16.3 290.2 ± 150.2 6.8 ± 5.5 13.7 ± 3.3
47 3 41 (82.0%)
95 37 33 (25.0%)
0.001 0.003
0.013
0.007 NS NS 0.009 0.001
b0.001
Numerical variables were presented as mean ± SD. Categorical variables were expressed as counts (percentage). Numerical variables were analyzed by unpaired Student's t test. Categorical variables were analyzed by χ2 test or Fisher exact test.
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progression of neurological diseases [30–34]. Moreover, oxidative stress is involved in the occurrence and development of POD and POCD [7–9]. 8-iso-PGF2α, an isoprostane derived from arachidonic acid via lipid peroxidation in vivo, is a potent vasoconstrictor and is considered a gold standard for measuring oxidative stress in vivo [10–16]. 8-iso-PGF2α is expressed in rat brain neuronal endings after oxidant stimuli [35] and generated in astrocytes following stretch-induced trauma [36] and its plasma level is also enhanced during animal spinal cord ischemia [37]. In humans, plasma 8-iso-PGF2α levels reflect the severity and prognosis of hemorrhagic stroke and head trauma [17,18]; moreover, 8-iso-PGF2α is increased in the brain interstitial tissue from head trauma patients [19], suggesting 8-iso-PGF2α may represent a potential biomarker of POD and POCD. The current study was designed to investigate the relationships between 8-iso-PGF2α levels and the risk of POD and POCD in elder patients following hip fracture surgery. In the univariate analyses, patients with POD and POCD had higher plasma 8-iso-PGF2α levels compared with those without POD and POCD. Even, in the multivariate logistic regression models, 8-iso-PGF2α was also found to be a predictor of POD and POCD independently of age, which is a common determinant of POD and POCD [1–6]. Interestingly, its discriminative power exceeded that of age according to AUC. Importantly, in the combined logistic-regression models, 8-iso-PGF2α significantly improved the predictive value of age for the risk of POD and POCD. Overall, our data suggest that postoperative plasma 8-iso-PGF2α levels could help to predict POD and POCD in elder patients after hip fracture surgery. The present study aimed to investigate the ability of postoperative plasma 8-iso-PGF2α levels to predict POD and POCD in elderly patients undergoing hip fracture surgery and further analyzed the mechanisms of occurrence of POD and POCD. It is well known that brain injury, partly derived from perioperative hypoxia, micro-embolisms or hypotension, may lead to POD and POCD and, if more severe, neurological deficit [27–29]. However, some postoperative circulating biomarkers can reflect the severity of brain injury, and therefore have the potential to predict the POD and POCD. Oxidative reaction is involved in the mechanisms of brain injury. Hence, 8-iso-PGF2α, a gold standard for measuring oxidative stress, is presumed to be a good biomarker to predict the POD and POCD in elderly patients undergoing hip fracture surgery. This study confirmed that 8-iso-PGF2α was an independent predictor of POD and POCD and possessed the higher predictive value. Consequently, whether the patients had neurological deficit or suffered from postoperative embolic episodes in this study, postoperative plasma 8-iso-PGF2α levels were found to be elevated, further indicating that oxidative stress associated with brain injury may be involved in the mechanisms of the occurrence and development of POD and POCD. Because of the aforementioned reasons, this study did not exclude those patients with neurological deficit and who suffered from postoperative embolic episodes. There are 2 limitations in the current study. At first, in this study, all blood samples were drawn from the patients on the first postoperative day. However, obtainment of the blood samples at serial time points could help to discover some information about the serial changes of plasma 8-iso-PGF2α levels. A second limitation of our study is that the 8-iso-PGF2α values were measured from peripheral blood and may not necessarily correspond to values in the brain. Therefore, the determination of 8-iso-PGF2α in cerebrospinal fluid may present us with some interesting information that can help to further discover the mechanisms of the occurrence and development of POD and POCD. 5. Conclusions In the current study, plasma 8-iso-PGF2α levels are associated independently with POD and POCD, as well as have high predictive performance for them in elder patients following hip fracture surgery. Therefore, 8-iso-PGF2α may be a useful, complementary tool to predict POD and POCD in elder patients following hip fracture surgery.
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