REVIEW ARTICLE
Hippokratia 2018, 22(4): 147-154
Ntalouka MP1,2, Arnaoutoglou E2, Tzimas P1
1Department of Anesthesiology and Postoperative Intensive Care, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 2Department of Anesthesiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
Abstract
Background: Cognitive dysfunction is a common complication after surgery. It is a major cause for increased, sometimes long-term, morbidity and mortality.
Methods: In this narrative review we performed a literature search regarding postoperative cognitive decline regarding risk factors, the type of surgical intervention, potential neuroprotective effects of anesthetic drugs, and associated quality of life and healthcare costs.
Results: Several risk factors are implicated in postoperative cognitive impairment. Cardiac surgery and specific orthopedic interventions are associated with a higher incidence of postoperative cognitive disorders. Results regarding the neuroprotective effects of anesthetics agents are still controversial but promising. Postoperative cognitive alterations are a major public healthcare issue as they impair the everyday quality of life, and expand the yearlong expenses.
Conclusions: Postoperative cognitive disorders are devastating, potentially life-threatening complications. High-suspicion, especially in high-risk patients and operations, and adoption of available neuroprotective strategies may prove lifesaving. HIPPOKRATIA 2018, 22(4): 147-154.
Keywords: Cognitive dysfunction, risk factors, cardiac surgical procedures, neuroprotection
Corresponding author: Maria P. Ntalouka, Anesthetist, Department of Anesthesiology and Postoperative Intensive Care, Faculty of Medicine, School of Health Sciences, University of Ioannina, P.O. BOX 1186, 45110, Ioannina, Hellas, tel: +306973688099, e-mail: maria.ntalouka@icloud.com
Introduction
A significant proportion of cognitively normal patients undergoing surgery will develop symptoms of cognitive impairment postoperatively1,2. The most common types are postoperative delirium (POD) and postoperative cognitive dysfunction (POCD)1,3. Although the exact etiology of POD/POCD is still obscure, several risk factors have been recognised1,4. Moreover, certain types of operations are accompanied by higher risk, rendering patients more vulnerable to POD/POCD1,3.
Postoperative cognitive impairment is associated with increased morbidity and mortality5,6. Furthermore, it may lead to complete loss of independence and expand the yearlong expenses3,7,8. Although there is still no treatment for this complication, several studies suggest potential neuroprotective effects of the anesthetic drugs9. The existing evidence remains promising but controversial9,10.
Methods
We aimed at accumulating existing evidence regarding POD/POCD with respect to the risk factors, type of surgery, neuroprotective effects of the anesthetic agents, the quality of life, and healthcare costs. We used the PubMed, the online bibliographic database of the US National Library of Medicine. The following terms in free-text combinations were used: postoperative delirium; postoperative cognitive dysfunction; postoperative cognitive decline; anesthesia; postoperative cognitive disorders; cardiac surgery; non-cardiac surgery; focusing on the last decade (2008-2018). A manual selection by two authors ensured that only relevant articles were included. Duplicate and irrelevant articles were excluded from further analysis (Figure 1, Table 1).
Figure 1: Flow chart of the recovered and analyzed articles from PubMed regarding studies for postoperative cognition dysfunction with respect to risk factors, the type of surgical intervention, potential neuroprotective effects of anesthetic drugs, and associated quality of life and healthcare costs, focusing on the last ten years (2008-2018).
Definitions
Postoperative cognitive disorder is a broad definition, including several forms of cognitive dysfunctions. The most common types are POD and POCD1,3. Postoperative cognitive alterations are classified based on their onset and severity and are characterized by troubles on thinking and perception (Table 2)2,8,11.
POD is an acute dysfunction in cognition, that is not explained by a preexisting neurocognitive disorder or severe reduction in arousability2,3,8. Altered attention is the core symptom of POD and stands for the inability to direct, focus, sustain, or shift attention1-3. Impaired memory, disorientation or perceptual disturbances may also be present1-3. The alterations of cognitive capacity in patients suffering from POD develop within the first few days and fluctuate throughout the day2 Confusion Assessment Method (CAM) is a widely used screening tool for delirium3,12. It has been used for research in the Greek population12,13.
POD is classified based on the changes in psychomotor behavior. There are four categories: hypoactive, hyperactive, mixed variation, and sub-syndromal1,2,11. Hypoactive delirium presents with slow mentation and decreased movement in a lethargic state1,2,11. This type of POD is often under-diagnosed or misdiagnosed, and those patients are experiencing higher mortality1. On the other hand, hyperactive delirium is characterized by agitation, restlessness, and hyper-vigilance, combined with more prominent circadian rhythm abnormalities2. Sub-syndromal delirium stands for elderly patients who are experiencing one or more symptoms of but do not meet the defined diagnostic criteria for POD1. At this point, it would be worth saying that maybe sub-syndromal type of POD could be the answer regarding the under-diagnosed status of this well recognized public health problem.
Additionally, POD may be further classified with respect to the time point of diagnosis in relation to surgical intervention1-3. However, the evidence is controversial. Strom and Rasmussen1 suggest that the first 24-72 hours after surgery should be considered as “lucid interval” distinct from cognitive emergence phenomena due to transition from anesthesia to wakefulness1,2. On the other hand, Rengel et al3 suggest the following classification. The mental status changes during emergence from general anesthesia stand for emergence delirium3. Post-anesthesia care unit (PACU) delirium covers the cognitive impairment after emergence but before the discharge from a PACU3. The fluctuating status that meets the diagnostic criteria of delirium from the PACU to the ICU or ward is defined as emergence delirium3. Both opinions are well documented and established1,3. As there is a significant association between POD and increased mortality, the diagnosis of delirium in the preoperative settings proves to be of paramount importance2,3. That said, clinicians should be aware of the “sub-syndromal” POD during the whole preoperative period.
Contrary to POD, there is no formal definition for POCD2. Based on experts and current literature, it is defined as a newly diagnosed cognitive deterioration arising postoperatively1,2,8,11. The diagnosis of POCD should be based on both pre- and postoperative screening with the appropriate psychometric tests1,2,8,11. Experts suggest that the need for thorough diagnostic screening has contributed to the lack of code on the International Classification of Diseases (ICD-10) for POCD. Subsequently, POCD is not listed in the Statistical Manual of Mental Disorders (DSM)2
POCD is a prolonged and subtle, and affects several cognitive domains 1,8. More specifically, memory, executive function, attention, verbal fluency, and/or visual-spatial performance may be impaired1,8. Contrary to the more acute nature of POD, POCD may develop within seven days to one year postoperatively1,2,8,11. Several screening tools with respect to main cognitive domains have been validated for the Greek population such as the Stroop test, the Trail-making test, and the Rey auditory verbal learning test12,14.
Further categorization of POCD proves to be impossible due to currently limited understanding1,2. However, its complex nature should not be overlooked. Some patients will only experience mild symptoms, such as slight-although lifelong-memory loss1. Compared to more pronounced cognitive deterioration such as inability to process information or concentrate, mild symptoms may easily be overlooked or perceived as normal ageing1. When acknowledged in the everyday clinical practice, combined with the lack of diagnostic certainty, concerns could be raised. Do anesthetists underdiagnose their patients with POCD, underestimating the great impact of this common complication? High suspicion index for subjective symptoms or behavioral changes and appropriate screening perioperatively seems mandatory.
Dementia is a common diagnosis in the aged population, and several types have been recognized. The most prevalent form (60% of cases) is Alzheimer’s disease15. According to DSM-5 criteria, dementia is classified as a major neurocognitive disorder, being characterized by a significant decline in cognition (one or more domains), not explained by delirium or another mental disorder, which impairs everyday activities of daily living2,15. The four diagnostic criteria for a major neurocognitive disorder are i) Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains, ii) Interference with independence in the daily activities, iii) Not exclusively in the context of a delirium, and iv) No other diagnosis better explaining the symptoms2.
Mini-mental state examination (MMSE) is a brief screening tool for the clinical examination of patients with dementia. MMSE is validated in Greek population15 and assesses orientation, registration, attention, recall, and language. It should be highlighted that dementia develops progressively and is a lifelong condition with poor prognosis11.
Risk Factors
The exact etiology of POD/POCD is still obscure. However, various risk factors are acknowledged to be associated with their development1,4. Advanced age, fewer years of education, and lower preoperative cognitive test scores are identified as strong, non-modifiable risk factors for POCD/POD1,16. Moreover, sleep disruption, preoperative vitamin-D deficiency, and diabetes mellitus have also been recognized as independent risk factors for POCD (1.26-fold higher risk for POCD)16-19. Regarding the advanced age, it should be noted that patients older than 60 years are suffering from POCD more than twice as often compared to younger patients20. A possible explanation could be that older patients have many co-morbidities (cerebral, cardiac, and vascular diseases) which lead to a greater cerebral white matter damages5,21-23. Furthermore, advanced age raises the possibility of repeated exposure to surgery and anesthesia, which is reported to lead to statistically increased postoperative cognitive dysfunction24,25 which means that older patients are facing the risk of less cognitive reserve, which may lead to a failure of resilience of the perioperative stress.
Regarding the intra-operative risk factors, extensive surgery with prolonged anesthesia is associated with a higher incidence of POD in cardiac surgery [odds ratio (OR) 1.37 for one hour increase]26. Intra-operative cerebral oxygen desaturation is another identified risk factor27. High doses of lidocaine and dexamethasone increase the incidence of early POD/POCD16,28. However, high doses of dexamethasone do not increase the risk of POCD one and twelve months postoperatively29. Regarding volume replacement strategies, a prospective study on 313 patients who underwent hip replacement surgery demonstrated that blood transfusion with more than three units of red blood cells increased the risk of POCD30. Furthermore, the use of hydroxyethyl starch is an independent risk factor for POD compared to the use of albumin15. Long surgery duration, high dexamethasone doses, and aggressive volume replacement could be translated into high levels of perioperative stress response aggravating the cognitive impairment1. This hypothesis is also supported by the fact that increased levels of C-reactive protein postoperatively were found to increase the incidence of POD (OR 2.16, two-fold increase)31.
For many years general anesthesia (GA) per se was blamed for POD/POCD, and anesthetists favored the regional techniques, especially for elderly patients13. In a recent randomized trial, GA was associated with higher cognitive decline compared to combined epidural and GA32. On the other side, various studies concluded that no differences exist between regional and GA concerning the incidence of long-term POCD. The potential neuroprotective effect of regional techniques subsides one week postoperatively13,25,26,33. Indeed, Tzimas et al13 found that the choice of anesthesia (GA versus spinal) does not influence the emergence of POCD thirty days after hip fracture surgery. Experts suggest that both surgery and anesthesia should be considered coincidences masquerading as causes and clinicians should focus on the optimization of the perioperative environment2-4,11,22.
POD/POCD and non-cardiac surgery
POD and POCD rates demonstrate a wide variation based on the type of surgery and procedural risk1,3,34. Patients undergoing otolaryngology and minor general surgical procedures are exposed to a lower risk for POD, 12 % and 13 % respectively. The prevalence rises in aortic surgery (>29 %), major abdominal (>50 %), and cardiac surgery (<51 %). In patients with hip fractures undergoing surgery, the incidence of POD may be as high as 62 %4. Factors such as advanced age, morbidities, the increased risk for fat micro-embolism, and the high blood transfusion requirements may be a possible explanation3. Last but not least, the highest incidence of POD has been reported in patients that require admission in the Intensive Care Unit (ICU) and mechanical ventilation. In these settings, 80 % of the patients may develop some form of POD3,35.
As far as the POCD is concerned, the existing evidence vary depending on the definition, the psychometric tests, and the time frame of assessment34. The incidence of POCD reported in the literature is 41-75 % (one week) and 18-45 % (three months)30. Major and more invasive procedures such as abdominal and vascular surgery carry a great risk for POCD, contrary to minor and outpatient interventions34. Patients undergoing cardiac and specific orthopedic procedures are experiencing the highest risk for short- or long-term POCD34.
It should be noted that the risk of POCD at three months postoperative, at patients older than 60 years, undergoing any type of major surgery (more than two hours) under GA is 10 %4. Contrary it seems that fast track approach may lower the risk of POCD early after total joint replacement. In a prospective multi-center study that included 225 elderly patients who underwent fast track knee and hip arthroplasty the incidence of POCD was 9.1 % (1-2 weeks) and 8.0 % (3 months)36. Evered et al37 demonstrated that the incidence of POCD was higher at seven days postoperatively in patients undergoing cardiac surgery compared to major orthopedic surgery but independent of the type of surgery at three months. This is supporting the current literature hypothesis that other factors, rather than surgery and anesthesia per se, are responsible for POCD/POD4,22,24.
POD/POCD and cardiac surgery
The first concerns regarding cognitive decline in cardiac surgery date back at the introduction of the cardiopulmonary bypass (CPB)38. Not long after that, it was noticed that POD/POCD was more prevalent after cardiac surgery38-42. Early research suggested that cognition decline was solely attributable to the use of CPB42. However, recent well-designed randomized trials report that the use of CPB should not be blamed for the increased risk of POD/POCD after cardiac surgery43-45. Moreover, CPB should not be avoided to prevent POCD, as avoiding CPB was not found to improve cognitive function5,43-45.
A significant risk factor for POD/POCD is surgical trauma leading to systemic inflammatory response syndrome (SIRS)38,45,46. The activation of the immune system make the brain more prone to cognitive decline45. Ischemia-reperfusion injury, complement activation, heparin neutralization and the contact of blood with the materials of the bypass circuit, contribute to the perioperative SIRS47. Moreover, SIRS is responsible for the blood-brain barrier dysfunction leading to cerebral inflammation with a potentially role in POCD pathogenesis45,48. Several studies considering the possible therapeutic role of corticosteroids in the systemic inflammation have investigated their potential protective role29,49. Low dose dexamethasone (0.1 mg/kg) administration, long (ten hours) before surgery, seems promising49.
Although CPB per se should not be blamed for POD/POCD after cardiac surgery, CPB related factors pose a significant risk for developing POD/POCD45,50. There is a hypothesis that the cerebral micro-emboli along with bad handling of CPB increase the risk for POD/POCD. However, several studies regarding beating-heart surgery were unable to demonstrate a reduction in POCD incidence43,51,52.
Finally, intra-operative management plays a vital role in postoperative cognitive status. Combined with the aforementioned risks factors that apply to all surgical patients, intra-operative hemodilution, hyper-coagulability, and extreme range of arterial blood pressure may contribute to the high prevalence of POD/POCD45,53. Hemodilution has a great impact and a decline in the hematocrit level greater than 12 %, intra-operatively, represents the threshold for cognitive decline45,54.
POD/POCD and the possible neuroprotective effect of anesthesia
Neuroprotection is a broad term including pharmacological and non-pharmacological interventions9. Pharmacological neuroprotection refers to the administration of drugs in order to reduce the clinical effects of cerebral damage. The main mechanisms are the increased tolerance of the brain tissue to ischemia and the change of intracellular response to energy supply deprivation10.
Thiopental was the first intravenous anesthetic agent tested for its potential ability to protect the brain9,10. It was thought that it could reduce the cerebral adenosine triphosphate (ATP) requirements and enhance the brains’ tolerance time to ischemia. However, the evidence is still conflicting9. A study in patients with acute aortic dissection, receiving thiopental, did not show a reduction in the permanent neurologic damage 55. In another study, the effect of thiopental on increased intracranial pressure was compared to that of hypertonic saline and was shown that thiopental might decrease the intracranial pressure, but not as effectively as the hypertonic saline56. Finally, when compared to propofol, thiopental increased the risk of POD, in adults undergoing major elective surgery57.
Propofol, the newest intravenous agent, may achieve more promising results on flow-metabolism coupling10. It maintains the cerebral blood flow reaction with respect to CO2 partial pressure changes. The final result is better ischemia handling10. Propofol has strong anti-inflammatory properties and reduces the stress-induced apoptosis10,58. Moreover, it increases the neuronal tolerance to hypoxia and may improve the quality of brain recovery9,58-60. In a randomized trial that assessed the effect of propofol titrated to burst suppression before and during clipping for intracranial aneurysm, no difference was found between the propofol and control groups regarding cognitive function testing61. However, propofol, when combined with dexmedetomidine in rats, shows more promising neuroprotective properties62. Based on its anti-inflammatory action, the administration of the optimal dose of propofol, during a more suitable time interval could be the approach to a less impaired postoperative cognition.
Volatile anesthetics have also been investigated regarding their neuroprotective action. Activation of antioxidant enzymes and inhibition of carboxy-terminal modulator protein could be the main pathways10. However, data are still lacking, especially regarding potential long-term benefits. Maintenance with desflurane results in a better quality of emergence, and less cognitive impairment after prolonged surgery, compared to sevoflurane22. On the other hand, sevoflurane has a negative influence on short- and long-term cognition when compared to propofol12. Propofol maintenance is associated with higher cerebral perfusion pressure when compared to volatile agents, but not with better brain relaxation scores10. Further data seems mandatory regarding the full neuroprotective spectrum of volatile agents.
Several agents and interventions have also been studied with respect to brain protection. Hudetz et al63 suggest that ketamine has intense anti-inflammatory action and attenuates POCD after cardiac surgery. Intra-operative magnesium administration may improve the cognitive function of patients undergoing carotid endarterectomy64. However, magnesium does not have neuroprotective properties in patients undergoing cardiac surgery65. Intravenous lidocaine does not decrease the postoperative cognitive impairment of cardiac patients66. Moreover, high doses of lidocaine are independent predictors of POCD16. Intravenous ondansetron administration postoperatively seems to protect the cognitive status of patients undergoing hip fracture surgery67. Current literature suggests the significance of anesthesia depth monitoring in an attempt to reduce the POD/POCD incidence68-70. Two studies have investigated the effects of the level of anesthesia on POCD, and the results are conflicting70,71. However, it seems that when the monitoring of the anesthetic depth is combined with the cerebral oxygenation monitoring the results are more promising68. It seems that neuroprotection is not a “one-man-show”. In order to achieve the best possible results, multimodal interventions may be the best strategy.
Quality of life
POD/POCD may affect multiple aspects of patients’ quality of life. Also, it is associated with increased morbidity and mortality5. There is a clear link between POD/POCD, impaired postoperative recovery, and prolonged rehabilitation1-3. The length of hospital stay rises at least two to five days, and the risk of hospital readmission is increased3,72. Moreover, patients with any form of cognitive decline are at a 2- to 5-fold increased risk of major complications such as cardiac arrest, thromboembolic disease and, respiratory failure3,72.
POD/POCD may lead to increased physical frailty and a 3-fold higher risk for health care institution admission with the potential complete loss of independence4. Moreover, 70 % of patients suffering from some form of postoperative cognitive decline will die within five years, compared to 35 % of patients with intact cognition4. POD/POCD can lead to great disability and to an unacceptable everyday quality of life. Although it cannot be considered as a direct life-threatening condition, it seems that patients suffering from POD/POCD are facing a significantly increased risk of death within a 5-year time-frame.
Enumerating the actual economic burden
Ongoing research confirms that POD/POCD surpassingly expand the yearlong expenses3,7,8. In 2004 the additional healthcare cost was estimated at €2,281 minimum per patient7,33,69,72,73. Thinking about the actual expenses, one should keep in mind that every year, 12.5 million individuals over 65 years of age are hospitalized and at least 20 % of them will experience some form of postoperative cognitive disorder73. More importantly, the median everyday expenses per patient developing some form of postoperative cognitive dysfunction proved to be 2.5 times higher compared to the everyday costs of the rest surgical patients73.
Vacas et al7 described the healthcare-associated costs as “astronomic” as the delirium alone costs at least €139 billion every year in the United States. Those expenses range along with the severity of the underlying disease, and one can compare them with the annual costs for cardiovascular disease and diabetes7,73. Additionally, the aforementioned numbers refer strictly to the in-hospital care of these patients and not to the expenses related to morbidity7. More specifically, patients suffering from POD/POCD remain in hospital two to five days longer and are experiencing an increased risk of health care institution admission 72. All the above could be translated into additional costs of €54,752 per patient every year72.
Conclusion
POD/POCD is a common postoperative complication. Several risk factors have been recognized, and certain types of operations are accompanied by a higher risk of POD/POCD. Given the complex nature of POD/POCD high-suspicion index and the adoption of a multimodal neuroprotective approach could be lifesaving.
References
1. Strøm C, Rasmussen LS, Sieber FE. Should general anaesthesia be avoided in the elderly? Anaesthesia. 2014; 69 Suppl 1: 35-44.
2. Needham MJ, Webb CE, Bryden DC. Postoperative cognitive dysfunction and dementia: what we need to know and do. Br J Anaesth. 2017; 119: i115-i125.
3. Rengel KF, Pandharipande PP, Hughes CG. Postoperative delirium. Presse Med. 2018; 47: e53-e64.
4. Tomaszewski D. Biomarkers of Brain Damage and Postoperative Cognitive Disorders in Orthopedic Patients: An Update. Biomed Res Int. 2015; 2015: 402959.
5. Sauër AC, Nathoe HM, Hendrikse J, Peelen LM, Regieli J, Veldhuijzen DS, et al. Cognitive outcomes 7.5 years after angioplasty compared with off-pump coronary bypass surgery. Ann Thorac Surg. 2013; 96: 1294-1300.
6. Zywiel MG, Prabhu A, Perruccio AV, Gandhi R. The influence of anesthesia and pain management on cognitive dysfunction after joint arthroplasty: a systematic review. Clin Orthop Relat Res. 2014; 472: 1453-1466.
7. Vacas S, Degos V, Feng X, Maze M. The neuroinflammatory response of postoperative cognitive decline. Br Med Bull. 2013; 106: 161-178.
8. Hood R, Budd A, Sorond FA, Hogue CW. Peri-operative neurological complications. Anaesthesia. 2018; 73 Suppl 1: 67-75.
9. Zwerus R, Absalom A. Update on anesthetic neuroprotection. Curr Opin Anaesthesiol. 2015; 28: 424-430.
10. Bilotta F, Stazi E, Zlotnik A, Gruenbaum SE, Rosa G. Neuroprotective effects of intravenous anesthetics: a new critical perspective. Curr Pharm Des. 2014; 20: 5469-5475.
11. Rundshagen I. Postoperative cognitive dysfunction. Dtsch Arztebl Int. 2014; 111: 119-125.
12. Micha G, Tzimas P, Zalonis I, Kotsis K, Papdopoulos G, Arnaoutoglou E. Propofol vs Sevoflurane anaesthesia on postoperative cognitive dysfunction in the elderly. A randomized controlled trial. Acta Anaesthesiol Belg. 2016; 67: 129-137.
13. Tzimas P, Samara E, Petrou A, Korompilias A, Chalkias A, Papadopoulos G. The influence of anesthetic techniques on postoperative cognitive function in elderly patients undergoing hip fracture surgery: General vs spinal anesthesia. Injury. 2018; 49: 2221-2226.
14. Plitas A, Plakiotis C. Neuropsychological testing of culturally and linguistically diverse individuals: the case of Greek-speaking individuals. Curr Opin Psychiatry. 2010; 23: 261-266.
15. Steinmetz J, Rasmussen LS. Anesthesia and the risk of dementia in the elderly. Presse Med. 2018; 47: e45-e51.
16. Mathew JP, Mackensen GB, Phillips-Bute B, Grocott HP, Glower DD, Laskowitz DT, et al. Randomized, double-blinded, placebo controlled study of neuroprotection with lidocaine in cardiac surgery. Stroke. 2009; 40: 880-887.
17. Todd OM, Gelrich L, MacLullich AM, Driessen M, Thomas C, Kreisel SH. Sleep Disruption at Home As an Independent Risk Factor for Postoperative Delirium. J Am Geriatr Soc. 2017; 65: 949-957.
18. Hermanides J, Qeva E, Preckel B, Bilotta F. Perioperative hyperglycemia and neurocognitive outcome after surgery: a systematic review. Minerva Anestesiol. 2018; 84: 1178-1188.
19. Zhang Y, Shan GJ, Zhang YX, Cao SJ, Zhu SN, Li HJ, et al. Preoperative vitamin D deficiency increases the risk of postoperative cognitive dysfunction: a predefined exploratory sub-analysis. Acta Anaesthesiol Scand. 2018; 62: 924-935.
20. Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT, Heilman KM, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology. 2008; 108: 18-30.
21. Kline RP, Pirraglia E, Cheng H, De Santi S, Li Y, Haile M, et al. Surgery and brain atrophy in cognitively normal elderly subjects and subjects diagnosed with mild cognitive impairment. Anesthesiology. 2012; 116: 603-612.
22. Tachibana S, Hayase T, Osuda M, Kazuma S,Yamakage M. Recovery of postoperative cognitive function in elderly patients after a long duration of desflurane anesthesia: a pilot study. J Anesth. 2015; 29: 627-630.
23. Rappold T, Laflam A, Hori D, Brown C, Brandt J, Mintz CD, et al. Evidence of an association between brain cellular injury and cognitive decline after non-cardiac surgery. Br J Anaesth. 2016; 116: 83-89.
24. Dokkedal U, Hansen TG, Rasmussen LS, Mengel-From J, Christensen K. Cognitive Functioning after Surgery in Middle-aged and Elderly Danish Twins. Anesthesiology. 2016; 124: 312-321.
25. Tzimas P, Andritsos E, Arnaoutoglou E, Papathanakos G, Papadopoulos G. SHORT-TERM POSTOPERATIVE COGNITIVE FUNCTION OF ELDERLY PATIENTS UNDERGOING FIRST VERSUS REPEATED EXPOSURE TO GENERAL ANESTHESIA. Middle East J Anaesthesiol. 2016; 23: 535-542.
26. Hutton M, Brull R, Macfarlane AJR. Regional anaesthesia and outcomes. BJA Education. 2018; 18: 52-56.
27. Slater JP, Guarino T, Stack J, Vinod K, Bustami RT, Brown JM 3rd, et al. Cerebral oxygen desaturation predicts cognitive decline and longer hospital stay after cardiac surgery. Ann Thorac Surg. 2009; 87: 36-44; discussion 44-45.
28. Fang Q, Qian X, An J, Wen H, Cope DK, Williams JP. Higher dose dexamethasone increases early postoperative cognitive dysfunction. J Neurosurg Anesthesiol. 2014; 26: 220-225.
29. Ottens TH, Dieleman JM, Sauër AM, Peelen LM, Nierich AP, de Groot WJ, et al. Effects of dexamethasone on cognitive decline after cardiac surgery: a randomized clinical trial. Anesthesiology. 2014; 121: 492-500.
30. Zhu SH, Ji MH, Gao DP, Li WY, Yang JJ. Association between perioperative blood transfusion and early postoperative cognitive dysfunction in aged patients following total hip replacement surgery. Ups J Med Sci. 2014; 119: 262-267.
31. Cereghetti C, Siegemund M, Schaedelin S, Fassl J, Seeberger MD, Eckstein FS, et al. Independent Predictors of the Duration and Overall Burden of Postoperative Delirium After Cardiac Surgery in Adults: An Observational Cohort Study. J Cardiothorac Vasc Anesth. 2017; 31: 1966-1973.
32. Chen C, Li M, Wnag K, Shen J, Yang L, Bu X, et al. Postoperative effect of combined general and regional anesthesia on postoperative cognitive function in older arthroplasy patients. Int J Clin Exp Med. 2017; 10: 15453-15458.
33. Ellard L, Katznelson R, Wasowicz M, Ashworth A, Carroll J, Lindsay T, et al. Type of anesthesia and postoperative delirium after vascular surgery. J Cardiothorac Vasc Anesth. 2014; 28: 458-461.
34. Wang W, Wang Y, Wu H, Lei L, Xu S, Shen X, et al. Postoperative cognitive dysfunction: current developments in mechanism and prevention. Med Sci Monit. 2014; 20: 1908-1912.
35. Vasilevskis EE, Han JH, Hughes CG, Ely EW. Epidemiology and risk factors for delirium across hospital settings. Best Pract Res Clin Anaesthesiol. 2012; 26: 277-287.
36. Krenk L, Kehlet H, Bæk Hansen T, Solgaard S, Soballe K, Rasmussen LS. Cognitive dysfunction after fast-track hip and knee replacement. Anesth Analg. 2014; 118: 1034-1040.
37. Evered L, Scott DA, Silbert B, Maruff P. Postoperative cognitive dysfunction is independent of type of surgery and anesthetic. Anesth Analg. 2011; 112: 1179-1185.
38. Berger M, Terrando N, Smith SK, Browndyke JN, Newman MF, Mathew JP. Neurocognitive Function after Cardiac Surgery: From Phenotypes to Mechanisms. Anesthesiology. 2018; 129: 829-851.
39. Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, et al. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012; 367: 30-39.
40. Mu DL, Li LH, Wang DX, Li N, Shan GJ, Li J, et al. High postoperative serum cortisol level is associated with increased risk of cognitive dysfunction early after coronary artery bypass graft surgery: a prospective cohort study. PLoS One. 2013; 8: e77637.
41. Evered L, Silbert B, Scott DA. Pre-existing cognitive impairment and post-operative cognitive dysfunction: should we be talking the same language? Int Psychogeriatr. 2016; 28: 1053-1055.
42. Kok WF, Koerts J, Tucha O, Scheeren TW, Absalom AR. Neuronal damage biomarkers in the identification of patients at risk of long-term postoperative cognitive dysfunction after cardiac surgery. Anaesthesia. 2017; 72: 359-369.
43. Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Paolasso E, et al. Effects of off-pump and on-pump coronary-artery bypass grafting at 1 year. N Engl J Med. 2013; 368: 1179-1188.
44. Patel N, Minhas JS, Chung EM. Intraoperative Embolization and Cognitive Decline After Cardiac Surgery: A Systematic Review. Semin Cardiothorac Vasc Anesth. 2016; 20: 225-231.
45. Salameh A, Dhein S, Dähnert I, Klein N. Neuroprotective Strategies during Cardiac Surgery with Cardiopulmonary Bypass. Int J Mol Sci. 2016; 17: pii: E1945.
46. Bhamidipati D, Goldhammer JE, Sperling MR, Torjman MC, McCarey MM, Whellan DJ. Cognitive Outcomes After Coronary Artery Bypass Grafting. J Cardiothorac Vasc Anesth. 2017; 31: 707-718.
47. Hudetz JA, Patterson KM, Iqbal Z, Gandhi SD, Pagel PS. Remote ischemic preconditioning prevents deterioration of short-term postoperative cognitive function after cardiac surgery using cardiopulmonary bypass: results of a pilot investigation. J Cardiothorac Vasc Anesth. 2015; 29: 382-388.
48. Abrahamov D, Levran O, Naparstek S, Refaeli Y, Kaptson S, Abu Salah M, et al. Blood-Brain Barrier Disruption After Cardiopulmonary Bypass: Diagnosis and Correlation to Cognition. Ann Thorac Surg. 2017; 104: 161-169.
49. Glumac S, Kardum G, Sodic L, Supe-Domic D, Karanovic N. Effects of dexamethasone on early cognitive decline after cardiac surgery: A randomised controlled trial. Eur J Anaesthesiol. 2017; 34: 776-784.
50. Kok WF, van Harten AE, Koene BM, Mariani MA, Koerts J, Tucha O, et al. A pilot study of cerebral tissue oxygenation and postoperative cognitive dysfunction among patients undergoing coronary artery bypass grafting randomised to surgery with or without cardiopulmonary bypass*. Anaesthesia. 2014; 69: 613-622.
51. Indja B, Fanning JP, Maller JJ, Fraser JF, Bannon PG, Vallely M, et al. Neural network imaging to characterize brain injury in cardiac procedures: the emerging utility of connectomics. Br J Anaesth. 2017; 118: 680-688.
52. Knipp SC, Weimar C, Schlamann M, Schweter S, Wendt D, Thielmann M, et al. Early and long-term cognitive outcome after conventional cardiac valve surgery. Interact Cardiovasc Thorac Surg. 2017; 24: 534-540.
53. Siepe M, Pfeiffer T, Gieringer A, Zemann S, Benk C, Schlensak C, et al. Increased systemic perfusion pressure during cardiopulmonary bypass is associated with less early postoperative cognitive dysfunction and delirium. Eur J Cardiothorac Surg. 2011; 40: 200-207.
54. Del Felice A, Tessari M, Formaggio E, Menon T, Petrilli G, Gamba G, et al. Hemoglobin Concentration Affects Electroencephalogram During Cardiopulmonary Bypass: An Indication for Neuro-Protective Values. Artif Organs. 2016; 40: 169-175.
55. Krüger T, Hoffmann I, Blettner M, Borger MA, Schlensak C, Weigang E, et al. Intraoperative neuroprotective drugs without beneficial effects? Results of the German Registry for Acute Aortic Dissection Type A (GERAADA). Eur J Cardiothorac Surg. 2013; 44: 939-946.
56. Colton K, Yang S, Hu PF, Chen HH, Bonds B, Scalea TM, et al. Intracranial pressure response after pharmacologic treatment of intracranial hypertension. J Trauma Acute Care Surg. 2014; 77: 47-53; discussion 53.
57. Saporito A, Sturini E. Incidence of postoperative delirium is high even in a population without known risk factors. J Anesth. 2014; 28: 198-201.
58. Schifilliti D, Grasso G, Conti A, Fodale V. Anaesthetic-related neuroprotection: intravenous or inhalational agents? CNS Drugs. 2010; 24: 893-907.
59. Shi SS, Yang WZ, Chen Y, Chen JP, Tu XK. Propofol reduces inflammatory reaction and ischemic brain damage in cerebral ischemia in rats. Neurochem Res. 2014; 39: 793-799.
60. Zhang DX, Ding HZ, Jiang S, Zeng YM, Tang QF. An in vitro study of the neuroprotective effect of propofol on hypoxic hippocampal slice. Brain Inj. 2014; 28: 1758-1765.
61. Mahajan C, Chouhan RS, Rath GP, Dash HH, Suri A, Chandra PS, et al. Effect of intraoperative brain protection with propofol on postoperative cognition in patients undergoing temporary clipping during intracranial aneurysm surgery. Neurol India. 2014; 62: 262-268.
62. Wang Z, Kou D, Li Z, He Y, Yu W, Du H. Effects of propofol-dexmedetomidine combination on ischemia reperfusion-induced cerebral injury. NeuroRehabilitation. 2014; 35: 825-834.
63. Hudetz JA, Iqbal Z, Gandhi SD, Patterson KM, Byrne AJ, Hudetz AG, et al. Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol Scand. 2009; 53: 864-872.
64. Mack WJ, Kellner CP, Sahlein DH, Ducruet AF, Kim GH, Mocco J, et al. Intraoperative magnesium infusion during carotid endarterectomy: a double-blind placebo-controlled trial. J Neurosurg. 2009; 110: 961-967.
65. Mathew JP, White WD, Schinderle DB, Podgoreanu MV, Berger M, Milano CA, et al. Intraoperative magnesium administration does not improve neurocognitive function after cardiac surgery. Stroke. 2013; 44: 3407-3413.
66. Mitchell SJ, Merry AF, Frampton C, Davies E, Grieve D, Mills BP, et al. Cerebral protection by lidocaine during cardiac operations: a follow-up study. Ann Thorac Surg. 2009; 87: 820-825.
67. Papadopoulos G, Pouangare M, Papathanakos G, Arnaoutoglou E, Petrou A, Tzimas P. The effect of ondansetron on postoperative delirium and cognitive function in aged orthopedic patients. Minerva Anestesiol. 2014; 80: 444-451.
68. Ballard C, Jones E, Gauge N, Aarsland D, Nilsen OB, Saxby BK, et al. Optimised anaesthesia to reduce post operative cognitive decline (POCD) in older patients undergoing elective surgery, a randomised controlled trial. PLoS One. 2012; 7: e37410.
69. Chan MT, Cheng BC, Lee TM, Gin T; CODA Trial Group. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol. 2013; 25: 33-42.
70. Radtke FM, Franck M, Lendner J, Krüger S, Wernecke KD, Spies CD. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction. Br J Anaesth. 2013; 110 Suppl 1: i98-i105.
71. Steinmetz J, Funder KS, Dahl BT, Rasmussen LS. Depth of anaesthesia and post-operative cognitive dysfunction. Acta Anaesthesiol Scand. 2010; 54: 162-168.
72. Marcantonio ER. Postoperative delirium: a 76-year-old woman with delirium following surgery. JAMA. 2012; 308: 73-81.
73. Shim JJ, Leung JM. An update on delirium in the postoperative setting: prevention, diagnosis and management. Best Pract Res Clin Anaesthesiol. 2012; 26: 327-243.