Cerebral Mast Cells Participate In Postoperative Cognitive Dysfunction by Promoting Astrocyte Activation.
Zhang Xiang,Yao Hao,Qian Qingqing,Li Nana,Jin Wenjie,Qian Yanning
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
BACKGROUND:Astrocytes, the major glial cell type that has been increasingly recognized as contributing to neuroinflammation, are critical in the occurrence and development of postoperative cognitive dysfunction (POCD). Although emerging evidence showed that brain mast cells (MCs) are the "first responders" in neuroinflammation, little is known about the functional communication between MCs and astrocytes. METHODS:In this study, we investigated the potential regulation of astrocyte activation by MCs. Rats received an intracerebroventricular injection of Cromolyn (an MC stabilizer) or sterile saline 30 min before undergoing open tibial fracture surgery, and the levels of neuroinflammation and the degree of memory dysfunction were evaluated at 1 day and 3 days after surgery. In the in vitro study, the effect of activated MCs on astrocytes were further clarified. RESULTS:Surgery increased the number of MCs, the astrocyte activation and the production of inflammatory factors, and resulted in cognitive deficits. Site-directed pre-injection of Cromolyn can inhibit this effect. In the vitro study, the conditioned medium from C48/80-stimulated mast cells (P815) could induce primary astrocyte activation and subsequent production of inflammatory cytokines, which could be inhibited by Cromolyn. CONCLUSION:These findings indicate that activated MCs could trigger astrocyte activation, be involved in neuroinflammation and possibly contribute to POCD. Interactions between MCs and astrocytes could provide potential therapeutic targets for POCD.
Cerebral mast cells contribute to postoperative cognitive dysfunction by promoting blood brain barrier disruption.
Zhang Susu,Dong Hongquan,Zhang Xiang,Li Nana,Sun Jie,Qian Yanning
Behavioural brain research
Trauma induced neuroinflammation plays a key role in the development of postoperative cognitive dysfunction (POCD). The blood-brain barrier (BBB), a highly specialized endothelial layer, is exquisitely sensitive to inflammatory insults, which can result in numerous neurocognitive syndromes. While brain mast cells are the "first responder" in the injury, the functional interactions between mast cells and the BBB remain poorly understood. Our results demonstrate that tibial fracture surgery can induce cognitive impairment relating to an inflammatory response and destabilization of the BBB. Disodium cromoglycate (cromolyn)--which acts as a mast cell stabilizer--inhibited this effect. Specifically, cromolyn resulted in ameliorated cognitive ability, decrease of inflammatory cytokines and increase of BBB stability. Taken together, these results suggest that activated mast cells contributed to central nervous system inflammation and cognitive dysfunction by promoting BBB disruption, and interactions between mast cells and the BBB could constitute a new and unique therapeutic target for POCD.
Activated brain mast cells contribute to postoperative cognitive dysfunction by evoking microglia activation and neuronal apoptosis.
Zhang Xiang,Dong Hongquan,Li Nana,Zhang Susu,Sun Jie,Zhang Shu,Qian Yanning
Journal of neuroinflammation
BACKGROUND:Neuroinflammation plays a key role in the occurrence and development of postoperative cognitive dysfunction (POCD). Microglia, the resident immune cells in the brain, has been increasingly recognized to contribute to neuroinflammation. Although brain mast cells (MCs) are the "first responder" in the brain injury rather than microglia, little is known about the functional aspects of MCs-microglia interactions. METHODS:Male Sprague-Dawley (SD) rats were injected intracerebroventricular with MC stabilizer Cromolyn (100 μg/μl), MC stimulator C48/80 (1 μg/μl), or sterile saline 30 min before open tibial fracture surgery, and the levels of neuroinflammation and memory dysfunction were tested 1 and 3 days after surgery. In addition, the effect of activated MCs on microglia and neurons was determined in vitro. RESULTS:Tibial fracture surgery induced MCs degranulation, microglia activation, and inflammatory factors production, which initiated the acute brain inflammatory response and neuronal death and exhibited cognitive deficit. Site-directed preinjection of the "MCs stabilizer" disodium cromoglycate (Cromolyn) inhibited this effect, including decrease of inflammatory cytokines, reduced MCs degranulation, microglia activation, neuronal death, and improved cognitive function 24 h after the surgery. In vitro study, we found that the conditioned medium from lipopolysaccharide (LPS)-stimulated mast cells line (P815) could induce primary microglia activation through mitogen-activated protein kinase (MAPK) pathway signaling and subsequent production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In addition, the activated P815 could directly induce neuronal apoptosis and synapse injury with microglia independently. Cromolyn could inhibit P815 activation following improved microglia activation and neuronal loss. CONCLUSIONS:These results implicate that activated MCs could trigger microglia activation and neuronal damage, resulting in central nervous system (CNS) inflammation, and communications of MCs with microglia and neuron could constitute a new and unique therapeutic target for CNS immune inflammation-related diseases.
Inflammation caused by peripheral immune cells across into injured mouse blood brain barrier can worsen postoperative cognitive dysfunction induced by isoflurane.
Zhu Honghua,Liu Wei,Fang Hao
BMC cell biology
BACKGROUND:Disruption to the blood brain barrier (BBB) is a leading factor associated with the development of postoperative cognitive dysfunction (POCD). Despite this, the underlying mechanism by which BBB disruption promotes POCD in the elderly population has not yet been not fully elucidated. RESULTS:In this study, we established a POCD mice model using isoflurane, and observed the highly expressed occludin and claudin 5 in brain tissues concomitant with the increased enrichment of CD4 positive cells and NK cells in the hippocampus of POCD mice compared to normal and non-POCD control. CONCLUSIONS:Our data suggests that peripheral immune cells may participate in the inflammatory reaction within the hippocampus, following the administration of anesthesia via inhalation with the destruction of the blood-brain barrier.
Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives.
Hovens Iris B,Schoemaker Regien G,van der Zee Eddy A,Heineman Erik,Izaks Gerbrand J,van Leeuwen Barbara L
Brain, behavior, and immunity
Following surgery, patients may experience cognitive decline, which can seriously reduce quality of life. This postoperative cognitive dysfunction (POCD) is mainly seen in the elderly and is thought to be mediated by surgery-induced inflammatory reactions. Clinical studies tend to define POCD as a persisting, generalised decline in cognition, without specifying which cognitive functions are impaired. Pre-clinical research mainly describes early hippocampal dysfunction as a consequence of surgery-induced neuroinflammation. These different approaches to study POCD impede translation between clinical and pre-clinical research outcomes and may hamper the development of appropriate interventions. This article analyses which cognitive domains deteriorate after surgery and which brain areas might be involved. The most important outcomes are: (1) POCD encompasses a wide range of cognitive impairments; (2) POCD affects larger areas of the brain; and (3) individual variation in the vulnerability of neuronal networks to neuroinflammatory mechanisms may determine if and how POCD manifests itself. We argue that, for pre-clinical and clinical research of POCD to advance, the effects of surgery on various cognitive functions and brain areas should be studied. Moreover, in addition to general characteristics, research should take inter-relationships between cognitive complaints and physical and mental characteristics into account.
Cerebral protection: inflammation, endothelial dysfunction, and postoperative cognitive dysfunction.
Riedel Bernhard,Browne Kimberley,Silbert Brendan
Current opinion in anaesthesiology
PURPOSE OF REVIEW:Postoperative cognitive dysfunction (POCD) is a well recognized perioperative syndrome, with approximately 15% of patients over the age of 60 years displaying objectively measured decrease in cognitive function as a consequence of anesthesia and surgery. The exact cause, however, remains unknown. This review aims to update anesthesiologists on the recent advancements in the understanding of the pathophysiology of POCD. RECENT FINDINGS:Recent evidence suggests that the observed predilection to POCD is likely mediated by a neuro-inflammatory response - with surgery being a major contributing factor. The blood-brain barrier, a highly specialized endothelial layer, is exquisitely sensitive to an inflammatory insult and implicated in the cause of other neurocognitive syndromes also characterized by neuro-inflammation such as cerebral malaria. Inflammatory changes may disrupt the blood-brain barrier and facilitate migration of macrophages into the brain, damaging synapses and neurones and ultimately lead to POCD. This review explores the important question of causality - the potential relationship between inflammation, endothelial dysfunction, and postoperative cognitive decline. SUMMARY:Recent research points to a central role of a neuro-inflammatory cascade in POCD, with endothelial dysfunction potentially aggravating the insult. Investigating the genomic and molecular mechanisms that underlie the intervariation in the inflammatory response to surgery, improving the identification of appropriate endothelial and inflammatory biomarkers, and developing endothelial modulatory and anti-inflammatory (prevention and resolution) strategies are key areas of future translational research. This is important as the elderly, who show increased susceptibility to this and other perioperative illness syndromes, represent an ever-increasing proportion of patients presenting for surgery.
Biomarkers of postoperative delirium and cognitive dysfunction.
Androsova Ganna,Krause Roland,Winterer Georg,Schneider Reinhard
Frontiers in aging neuroscience
Elderly surgical patients frequently experience postoperative delirium (POD) and the subsequent development of postoperative cognitive dysfunction (POCD). Clinical features include deterioration in cognition, disturbance in attention and reduced awareness of the environment and result in higher morbidity, mortality and greater utilization of social financial assistance. The aging Western societies can expect an increase in the incidence of POD and POCD. The underlying pathophysiological mechanisms have been studied on the molecular level albeit with unsatisfying small research efforts given their societal burden. Here, we review the known physiological and immunological changes and genetic risk factors, identify candidates for further studies and integrate the information into a draft network for exploration on a systems level. The pathogenesis of these postoperative cognitive impairments is multifactorial; application of integrated systems biology has the potential to reconstruct the underlying network of molecular mechanisms and help in the identification of prognostic and diagnostic biomarkers.
Bidirectional relationship of mast cells-neurovascular unit communication in neuroinflammation and its involvement in POCD.
Li Nana,Zhang Xiang,Dong Hongquan,Hu Youli,Qian Yanning
Behavioural brain research
Postoperative cognitive dysfunction (POCD) has been hypothesized to be mediated by surgery-induced neuroinflammation, which is also a key element in the pathobiology of neurodegenerative diseases, stroke, and neuropsychiatric disorders. There is extensive communication between the immune system and the central nervous system (CNS). Inflammation resulting from activation of the innate immune system cells in the periphery can impact central nervous system behaviors, such as cognitive performance. Mast cells (MCs), as the"first responders" in the CNS, can initiate, amplify, and prolong other immune and nervous responses upon activation. In addition, MCs and their secreted mediators modulate inflammatory processes in multiple CNS pathologies and can thereby either contribute to neurological damage or confer neuroprotection. Neuroinflammation has been considered to be linked to neurovascular dysfunction in several neurological disorders. This review will provide a brief overview of the bidirectional relationship of MCs-neurovascular unit communication in neuroinflammation and its involvement in POCD, providing a new and unique therapeutic target for the adjuvant treatment of POCD.
Does Dexmedetomidine Ameliorate Postoperative Cognitive Dysfunction? A Brief Review of the Recent Literature.
Carr Zyad J,Cios Theodore J,Potter Kenneth F,Swick John T
Current neurology and neuroscience reports
PURPOSE OF REVIEW:Postoperative cognitive dysfunction (POCD) occurs in 20-50% of postsurgical patients with a higher prevalence in elderly patients and patients with vascular disease and heart failure. In addition, POCD has been associated with many negative outcomes, such as increased hospital length of stay, increased rates of institutionalization, and higher patient mortality. This brief review discusses select evidence suggesting an association between neuroinflammation and POCD and whether the use of dexmedetomidine, a short-acting alpha 2 agonist, may ameliorate the incidence of POCD. We review the recent evidence for neuroinflammation in POCD, dexmedetomidine's properties in reducing inflammatory-mediated brain injury, and clinical studies of dexmedetomidine and POCD. RECENT FINDINGS:There is evidence to support the anti-inflammatory and immunomodulatory effects of dexmedetomidine in animal models. Several clinical investigations have demonstrated favorable outcomes using dexmedetomidine over placebo for the reduction of postoperative delirium. Few studies have used high-quality endpoints for the assessment of POCD and no demonstrable evidence supports the use of dexmedetomidine for the prevention of POCD. While evidence exists for the neural anti-inflammatory properties of dexmedetomidine, human trials have yielded incomplete results concerning its use for the management of POCD. Dexmedetomidine may reduce acute postoperative delirium, but further studies are needed prior to recommending the use of dexmedetomidine for the direct reduction of POCD.
Biomarkers and postoperative cognitive function: could it be that easy?
Schaefer Simon T,Koenigsperger Stephan,Olotu Cynthia,Saller Thomas
Current opinion in anaesthesiology
PURPOSE OF REVIEW:Neurocognitive dysfunction after surgery is highly relevant in the elderly. The multifactorial manner of this syndrome has made it hard to define an ideal biomarker to predict individual risk and assess diagnosis and severity of delirium [postoperative delirium (POD)] and subsequent postoperative cognitive decline (POCD). This review summarizes recent literature on blood biomarkers for POD/POCD. RECENT FINDINGS:Markers for delirium have been searched for in the cerebrospinal fluid to examine the pathologic cascade. However, cerebrospinal fluid cannot be easily obtained in the perioperative setting. Thus, attention shifts toward prediction markers from patients' blood to determine the individual risk. In this regard, three major groups of peripheral blood markers could be distinguished: first, global, but unspecific markers associated with POD/POCD; second, specific and established markers related to neurocognitive function; and third, upcoming or newly described markers with less evidence. Solely neuron-specific enolase is an adequate biomarker based on recent literature. SUMMARY:Single markers for postoperative cognitive impairment cannot predict POD/POCD in geriatric patients. However, a wisely arranged battery of promising biomarkers might achieve a satisfying sensitivity and specificity for the preoperative assessment of subsequent cognitive decline. Adequately powered studies to prove this hypothesis are required.
Postoperative cognitive dysfunction - current preventive strategies.
Kotekar Nalini,Shenkar Anshul,Nagaraj Ravishankar
Clinical interventions in aging
Improving trends in global health care have resulted in a steady increase in the geriatric population. However, as the population ages, surgery is being performed more frequently in progressively older patients and those with higher prevalence of comorbidities. A significant percentage of elderly patients experience transient postoperative delirium following surgery or long-term postoperative cognitive dysfunction (POCD). Increasing age, educational level, pre-existing mental health, and comorbidities are contributory factors. Comprehensive geriatric assessment provides an objective evaluation on overall medical, social, mental, and functional well-being with scope for preoperative optimization. Preventive strategies for POCD target the surgical and patient-related factors as well as the utilization of the concept of stress-free anesthesia and surgery, that is, Enhanced Recovery After Surgery. This includes care bundles and protocols for the perioperative period which improves outcomes in the elderly. Research on biomarkers of neural injury in POCD is gaining momentum. Pharmacologic agents such as acetylcholine esterase inhibitors promise to have a vital role in the management of POCD but exhibit undesired side effects. Interventions to reduce oxidative stress and neuroinflammation could prove beneficial. Preventive strategies, early recognition, and management of perioperative risk factors seems to be, by far, the best modality to deal with POCD till further progress in therapeutic interventions evolve.
Postoperative Cognitive Decline After Cardiac Surgery: A Narrative Review of Current Knowledge in 2019.
Glumac Sandro,Kardum Goran,Karanovic Nenad
Medical science monitor : international medical journal of experimental and clinical research
The growing number of publications concerning postoperative cognitive decline (POCD) after cardiac surgery is indicative of the health-related and economic-related importance of this intriguing issue. Significantly, the reported POCD incidence over the years has remained steady due to various unresolved challenges regarding the examination of this multidisciplinary topic. In particular, a universally accepted POCD definition has not been established, and the pathogenesis is still vaguely understood. However, numerous recent studies have focused on the role of the inflammatory response to a surgical procedure in POCD occurrence. Therefore, this traditional narrative review summarizes and evaluates the latest findings, with special attention paid to the difficulties of defining POCD as well as the involvement of inflammation in POCD development. We searched the MEDLINE, Scopus, PsycINFO and CENTRAL databases for the best evidence, which was classified according to the Oxford Centre for Evidence-based Medicine. To our knowledge, this is the first narrative review that identified class-1 evidence (systematic review of randomized trials), although most evidence is still at class-2 or below. Furthermore, we revealed that defining POCD is a very controversial matter and that the inflammatory response plays an important role in the mutually overlapping processes included in POCD development. Thus, developing the definition of POCD represents an absolute priority in POCD investigations, and the inflammatory response to cardiac surgery merits further research.
Cerebrospinal Fluid Biomarker for Alzheimer Disease Predicts Postoperative Cognitive Dysfunction.
Evered Lisbeth,Silbert Brendan,Scott David A,Ames David,Maruff Paul,Blennow Kaj
BACKGROUND:Postoperative cognitive dysfunction (POCD) affects 16 to 21% of the elderly 3 months after anesthesia and surgery and is associated with adverse outcomes. The exact cause of POCD remains unknown. The authors hypothesized that elderly individuals with Alzheimer disease (AD) neuropathology, identified by cerebrospinal fluid (CSF) analysis, would have increased the risk for POCD. METHODS:CSF samples were collected from 59 patients 60 yr or older who received combined spinal and general anesthesia for elective total hip replacement. Patients underwent neuropsychological testing preoperatively and at 7 days, 3 months, and 12 months postoperatively. POCD at 3 months and cognitive decline at 12 months were calculated by using the reliable change index. CSF amyloid β1-42 (Aβ1-42), total-tau, phosphorylated-tau, and neurofilament light were assayed with enzyme-linked immunosorbent assay methods. RESULTS:POCD was identified in 5 of 57 patients (8.8%) at 3 months. For Aβ1-42, 11 patients were below the cut-point for AD neuropathology of whom 3 were classified with POCD (27.3%; 95% CI, 6.0 to 61%), whereas of the 46 patients above the cut-point, 2 were classified with POCD (4.3%; 95% CI, 0.5 to 14.8%) (P = 0.01). There was no significant difference in the incidence of POCD in relation to the cut-points for any of the other analytes. CONCLUSIONS:Low CSF Aβ1-42 may be a significant predictor of POCD at 3 months. This indicates that patients with AD neuropathology even in the absence of clinically detectable AD symptoms may be susceptible to POCD.
Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice.
Feng Xiaomei,Valdearcos Martin,Uchida Yosuke,Lutrin David,Maze Mervyn,Koliwad Suneil K
Surgery can induce cognitive decline, a risk that increases with advancing age. In rodents, postoperative cognitive decline (POCD) is associated with the inflammatory activation of hippocampal microglia. To examine the role of microglia in POCD, we inhibited the colony-stimulating factor 1 receptor (CSF1R) in adult mice, effectively depleting CNS microglia. Surgical trauma (tibial fracture) reduced the ability of mice to remember a conditioned response learned preoperatively, a deficit more pronounced and persistent in mice with diet-induced obesity (DIO). Whereas microglial depletion by itself did not affect learning or memory, perioperative microglial depletion remarkably protected mice, including those with DIO, from POCD. This protection was associated with reduced hippocampal levels of inflammatory mediators, abrogation of hippocampal recruitment of CCR2 leukocytes, and higher levels of circulating inflammation-resolving factors. Targeting microglia may thus be a viable strategy to mitigate the development of POCD, particularly in those with increased vulnerability.
Circulating mitochondrial DAMPs cause inflammatory responses to injury.
Zhang Qin,Raoof Mustafa,Chen Yu,Sumi Yuka,Sursal Tolga,Junger Wolfgang,Brohi Karim,Itagaki Kiyoshi,Hauser Carl J
Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors. Similarly, cellular injury can release endogenous 'damage'-associated molecular patterns (DAMPs) that activate innate immunity. Mitochondria are evolutionary endosymbionts that were derived from bacteria and so might bear bacterial molecular motifs. Here we show that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. MTDs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through formyl peptide receptor-1 and Toll-like receptor (TLR) 9, respectively. MTDs promote PMN Ca(2+) flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTDs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial 'enemies within' by cellular injury is a key link between trauma, inflammation and SIRS.
The INTUIT Study: Investigating Neuroinflammation Underlying Postoperative Cognitive Dysfunction.
Berger Miles,Oyeyemi Deborah,Olurinde Mobolaji O,Whitson Heather E,Weinhold Kent J,Woldorff Marty G,Lipsitz Lewis A,Moretti Eugene,Giattino Charles M,Roberts Kenneth C,Zhou Junhong,Bunning Thomas,Ferrandino Michael,Scheri Randall P,Cooter Mary,Chan Cliburn,Cabeza Roberto,Browndyke Jeffrey N,Murdoch David M,Devinney Michael J,Shaw Leslie M,Cohen Harvey Jay,Mathew Joseph P,
Journal of the American Geriatrics Society
BACKGROUND/OBJECTIVES:Every year, up to 40% of the more than 16 million older Americans who undergo anesthesia/surgery develop postoperative cognitive dysfunction (POCD) or delirium. Each of these distinct syndromes is associated with decreased quality of life, increased mortality, and a possible increased risk of Alzheimer's disease. One pathologic process hypothesized to underlie both delirium and POCD is neuroinflammation. The INTUIT study described here will determine the extent to which postoperative increases in cerebrospinal fluid (CSF) monocyte chemoattractant protein 1 (MCP-1) levels and monocyte numbers are associated with delirium and/or POCD and their underlying brain connectivity changes. DESIGN:Observational prospective cohort. SETTING:Duke University Medical Center, Duke Regional Hospital, and Duke Raleigh Hospital. PARTICIPANTS:Patients 60 years of age or older (N = 200) undergoing noncardiac/nonneurologic surgery. MEASUREMENTS:Participants will undergo cognitive testing before, 6 weeks, and 1 year after surgery. Delirium screening will be performed on postoperative days 1 to 5. Blood and CSF samples are obtained before surgery, and 24 hours, 6 weeks, and 1 year after surgery. CSF MCP-1 levels are measured by enzyme-linked immunosorbent assay, and CSF monocytes are assessed by flow cytometry. Half the patients will also undergo pre- and postoperative functional magnetic resonance imaging scans. 32-channel intraoperative electroencephalogram (EEG) recordings will be performed to identify intraoperative EEG correlates of neuroinflammation and/or postoperative cognitive resilience. Eighty patients will also undergo home sleep apnea testing to determine the relationships between sleep apnea severity, neuroinflammation, and impaired postoperative cognition. Additional assessments will help evaluate relationships between delirium, POCD, and other geriatric syndromes. CONCLUSION:INTUIT will use a transdisciplinary approach to study the role of neuroinflammation in postoperative delirium and cognitive dysfunction and their associated functional brain connectivity changes, and it may identify novel targets for treating and/or preventing delirium and POCD and their sequelae. J Am Geriatr Soc 67:794-798, 2019.
Age-related differences of neural connectivity during mental rotation.
International journal of psychophysiology : official journal of the International Organization of Psychophysiology
The purpose of the present study was to investigate age-related effects on functional brain networks during a mental rotation task. At behavioral level age-related cognitive deficits have been shown. Cognitive deficits in older adults are associated with structural decline, especially in frontal and parietal areas and in the corpus callosum. In consequence, functional networks are affected by old age as well. To this end, a graph theoretical approach was taken, which quantifies the global and local efficiency as well as the cost efficiency of frontal and parietal intrahemispheric and interhemispheric networks. Main results indicate that intrahemispheric and interhemispheric networks are differently affected by older age: in the left frontal and the left and right parietal intrahemispheric networks global and local efficiency was reduced, whereas in frontal and parietal interhemispheric networks cost efficiency was decreased.
Preoperative Salivary Cortisol AM/PM Ratio Predicts Early Postoperative Cognitive Dysfunction After Noncardiac Surgery in Elderly Patients.
Han Yuan,Han Liu,Dong Meng-Meng,Sun Qing-Chun,Zhang Zhen-Feng,Ding Ke,Zhang Yao-Dong,Mannan Abdul,Xu Yi-Fan,Ou-Yang Chang-Li,Li Zhi-Yong,Gao Can,Cao Jun-Li
Anesthesia and analgesia
BACKGROUND:The diagnosis of postoperative cognitive dysfunction (POCD) requires complicated neuropsychological testing and is often delayed. Possible biomarkers for early detection or prediction are essential for the prevention and treatment of POCD. Preoperative screening of salivary cortisol levels may help to identify patients at elevated risk for POCD. METHODS:One hundred twenty patients >60 years of age and undergoing major noncardiac surgery underwent neuropsychological testing 1 day before and 1 week after surgery. Saliva samples were collected in the morning and the evening 1 day before surgery. POCD was defined as a Z-score of ≤-1.96 on at least 2 different tests. The primary outcome was the presence of POCD. The primary objective of this study was to assess the relationship between the ratio of AM (morning) to PM (evening) salivary cortisol levels and the presence of POCD. The secondary objective was to assess the relationship between POCD and salivary cortisol absolute values in the morning or in the evening. RESULTS:POCD was observed in 17.02% (16 of 94; 95% confidence interval [CI], 9.28%-24.76%) of patients 1 week after the operation. A higher preoperative AM/PM salivary cortisol ratio predicted early POCD onset (odds ratio [OR], 1.56; 95% CI, 1.20-2.02; P = .001), even after adjusting for the Mini-Mental Sate Examination score (odds ratio, 1.55; 95% CI, 1.19-2.02; P = .001). The area under the receiver operating characteristic curve for the salivary cortisol AM/PM ratio in individuals with POCD was 0.72 (95% CI, 0.56-0.88; P = .006). The optimal cutoff value was 5.69, with a sensitivity of 50% and specificity of 91%. CONCLUSIONS:The preoperative salivary cortisol AM/PM ratio was significantly associated with the presence of early POCD. This biomarker may have potential utility for screening patients for an increased risk and also for further elucidating the etiology of POCD.
Postoperative cognitive dysfunction and mortality following lung transplantation.
Smith P J,Blumenthal J A,Hoffman B M,Davis R D,Palmer S M
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Preliminary evidence suggests that postoperative cognitive dysfunction (POCD) is common after lung transplantation. The impact of POCD on clinical outcomes has yet to be studied. The association between POCD and longer-term survival was therefore examined in a pilot study of posttransplantation survivors. Forty-nine participants from a prior randomized clinical trial underwent a neurocognitive assessment battery pretransplantation and 6 months posttransplantation, including assessments of the domains of Executive Function (Trail Making Test, Stroop, Digit Span), Processing Speed (Ruff 2 and 7 Test, Digit Symbol Substitution Test), and Verbal Memory (Verbal Paired Associates, Logical Memory, Animal Naming, and Controlled Oral Word Association Test). During a 13-year follow-up, 33 (67%) participants died. Greater neurocognition was associated with longer survival (hazard ratio [HR] = 0.49 [0.25-0.96], P = .039), and this association was strongest on tests assessing Processing Speed (HR = 0.58 [0.36-0.95], P = .03) and Executive Function (HR = 0.52 [0.28-0.97], P = .040). In addition, unadjusted analyses suggested an association between greater Memory performance and lower risk of CLAD (HR = 0.54 [0.29-1.00], P = .050). Declines in Executive Function tended to be predictive of worse survival. These preliminary findings suggest that postoperative neurocognition is predictive of subsequent mortality among lung transplant recipients. Further research is needed to confirm these findings in a larger sample and to examine mechanisms responsible for this relationship.
Age exacerbates surgery-induced cognitive impairment and neuroinflammation in Sprague-Dawley rats: the role of IL-4.
Li Zhe,Liu Fang,Ma Hong,White Paul F,Yumul Roya,Jiang Yanhua,Wang Na,Cao Xuezhao
Age is the most prominent risk factor for the development of postoperative cognitive dysfunction. This study investigated the potential role of anti-inflammatory interleukin (IL)-4 in age-related differences of surgery-induced cognitive deficits and neuroinflammatory responses. Both adult and aged Sprague-Dawley male rats were subjected to partial hepatectomy or partial hepatectomy with a cisterna magna infusion of IL-4. On postoperative days 1, 3, and 7, the rats were subjected to a reversed Morris water maze test. Hippocampal IL-1β, IL-6, IL-4, and IL-4 receptor (IL-4R) were measured at each time point. Brain derived neurotrophic factor (BDNF), synaptophysin, Ionized calcium-binding adapter molecule 1 (Iba-1), microglial M2 phenotype marker Arg1, and CD200 were also examined in the hippocampus. Age induced an exacerbated cognitive impairment and an amplified neuroinflammatory response triggered by surgical stress on postoperative days 1 and 3. A corresponding decline in the anti-inflammatory cytokine IL-4 and BDNF were also found in the aged rats at the same time point. Treatment with IL-4 downregulated the expression of proinflammatory cytokines (e.g., IL-1β and IL-6), increased the levels of BDNF and synaptophysin in the brain and improved the behavioral performance. An increased Arg1 expression and a high level of CD200 were also observed after a cisterna magna infusion of IL-4. An age-related decrease in IL-4 expression exacerbated surgery-induced cognitive deficits and exaggerated the neuroinflammatory responses. Treatment with IL-4 potentially attenuated these effects by enhancing BDNF and synaptophysin expression, inhibiting microglia activation and decreasing the associated production of proinflammatory cytokines.
Mind Over Matter? The Hidden Epidemic of Cognitive Dysfunction in the Older Surgical Patient.
O' Brien Helen,Mohan Helen,Hare Celia O',Reynolds John Vincent,Kenny Rose Anne
Annals of surgery
OBJECTIVE:The aim of this study was to highlight the vulnerability of the aging brain to surgery and anesthesia, examine postoperative cognitive outcomes, and recommend possible interventions. BACKGROUND:Surgeons are facing increasingly difficult ethical and clinical decisions given the rapidly expanding aging demographic. Cognitive function is not routinely assessed either preoperatively or postoperatively. Potential short and long-term cognitive implications are rarely discussed with the patient despite evidence that postoperative cognitive impairment occurs in up to 65% of older patients. Furthermore, surgery may accelerate the trajectory of cognitive decline and dementia. METHODS:An electronic search was conducted using Pubmed/Medline. References from selected studies were cross-referenced and relevant articles retrieved. Data were summarized in a narrative format. RESULTS:There is a hidden epidemic of cognitive dysfunction in the perioperative setting. Up to 40% of patients who develop postoperative delirium (POD) never return to their preoperative cognitive baseline. POD can lead to postoperative cognitive dysfunction (POCD), a more prolonged cognitive impairment associated with longer length of hospital stay and cost, premature withdrawal from the workforce, and greater 1-year mortality. Standardized perioperative cognitive assessment is needed to enable progress. Improving outcomes will depend on a multifaceted approach, including correction of modifiable preoperative risk factors and prompt treatment of POD. Risk factors are discussed and possible interventional strategies are presented. CONCLUSION:Closer preoperative collaboration between surgeons, geriatricians, and anesthetists will enable identification of complex at-risk older patients. A paradigm shift in the approach to management of the older surgical patient is critical to improve postoperative cognitive outcomes in modern surgery.
Post-Operative Cognitive Dysfunction: An exploration of the inflammatory hypothesis and novel therapies.
Skvarc David R,Berk Michael,Byrne Linda K,Dean Olivia M,Dodd Seetal,Lewis Matthew,Marriott Andrew,Moore Eileen M,Morris Gerwyn,Page Richard S,Gray Laura
Neuroscience and biobehavioral reviews
Post-Operative Cognitive Dysfunction (POCD) is a highly prevalent condition with significant clinical, social and financial impacts for patients and their communities. The underlying pathophysiology is becoming increasingly understood, with the role of neuroinflammation and oxidative stress secondary to surgery and anaesthesia strongly implicated. This review aims to describe the putative mechanisms by which surgery-induced inflammation produces cognitive sequelae, with a focus on identifying potential novel therapies based upon their ability to modify these pathways.
Emerging Roles of Immune Cells in Postoperative Cognitive Dysfunction.
Liu Yue,Yin Yiqing
Mediators of inflammation
Postoperative cognitive dysfunction (POCD), a long-lasting cognitive decline after surgery, is currently a major clinical problem with no clear pathophysiological mechanism or effective therapy. Accumulating evidence suggests that neuroinflammation plays a critical role in POCD. After surgery, alarmins are leaked from the injury sites and proinflammatory cytokines are increased in the peripheral circulation. Neurons in the hippocampus, which is responsible for learning and memory, can be damaged by cytokines transmitted to the brain parenchyma. Microglia, bone marrow-derived macrophages, mast cells, and T cells in the central nervous system (CNS) can be activated to secrete more cytokines, further aggravating neuroinflammation after surgery. Conversely, blocking the inflammation network between these immune cells and related cytokines alleviates POCD in experimental animals. Thus, a deeper understanding of the roles of immune cells and the crosstalk between them in POCD may uncover promising therapeutic targets for POCD treatment and prevention. Here, we reviewed several major immune cells and discussed their functional roles in POCD.
Intravenous versus inhalational maintenance of anaesthesia for postoperative cognitive outcomes in elderly people undergoing non-cardiac surgery.
Miller David,Lewis Sharon R,Pritchard Michael W,Schofield-Robinson Oliver J,Shelton Cliff L,Alderson Phil,Smith Andrew F
The Cochrane database of systematic reviews
BACKGROUND:The use of anaesthetics in the elderly surgical population (more than 60 years of age) is increasing. Postoperative delirium, an acute condition characterized by reduced awareness of the environment and a disturbance in attention, typically occurs between 24 and 72 hours after surgery and can affect up to 60% of elderly surgical patients. Postoperative cognitive dysfunction (POCD) is a new-onset of cognitive impairment which may persist for weeks or months after surgery.Traditionally, surgical anaesthesia has been maintained with inhalational agents. End-tidal concentrations require adjustment to balance the risks of accidental awareness and excessive dosing in elderly people. As an alternative, propofol-based total intravenous anaesthesia (TIVA) offers a more rapid recovery and reduces postoperative nausea and vomiting. Using TIVA with a target controlled infusion (TCI) allows plasma and effect-site concentrations to be calculated using an algorithm based on age, gender, weight and height of the patient.TIVA is a viable alternative to inhalational maintenance agents for surgical anaesthesia in elderly people. However, in terms of postoperative cognitive outcomes, the optimal technique is unknown. OBJECTIVES:To compare maintenance of general anaesthesia for elderly people undergoing non-cardiac surgery using propofol-based TIVA or inhalational anaesthesia on postoperative cognitive function, mortality, risk of hypotension, length of stay in the postanaesthesia care unit (PACU), and hospital stay. SEARCH METHODS:We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 11), MEDLINE (1946 to November 2017), Embase (1974 to November 2017), PsycINFO (1887 to November 2017). We searched clinical trials registers for ongoing studies, and conducted backward and forward citation searching of relevant articles. SELECTION CRITERIA:We included randomized controlled trials (RCTs) with participants over 60 years of age scheduled for non-cardiac surgery under general anaesthesia. We planned to also include quasi-randomized trials. We compared maintenance of anaesthesia with propofol-based TIVA versus inhalational maintenance of anaesthesia. DATA COLLECTION AND ANALYSIS:Two review authors independently assessed studies for inclusion, extracted data, assessed risk of bias, and synthesized findings. MAIN RESULTS:We included 28 RCTs with 4507 randomized participants undergoing different types of surgery (predominantly cardiovascular, laparoscopic, abdominal, orthopaedic and ophthalmic procedures). We found no quasi-randomized trials. Four studies are awaiting classification because we had insufficient information to assess eligibility.All studies compared maintenance with propofol-based TIVA versus inhalational maintenance of anaesthesia. Six studies were multi-arm and included additional TIVA groups, additional inhalational maintenance or both. Inhalational maintenance agents included sevoflurane (19 studies), isoflurane (eight studies), and desflurane (three studies), and was not specified in one study (reported as an abstract). Some studies also reported use of epidural analgesia/anaesthesia, fentanyl and remifentanil.We found insufficient reporting of randomization methods in many studies and all studies were at high risk of performance bias because it was not feasible to blind anaesthetists to study groups. Thirteen studies described blinding of outcome assessors. Three studies had a high of risk of attrition bias, and we noted differences in the use of analgesics between groups in six studies, and differences in baseline characteristics in five studies. Few studies reported clinical trials registration, which prevented assessment of risk of selective reporting bias.We found no evidence of a difference in incidences of postoperative delirium according to type of anaesthetic maintenance agents (odds ratio (OR) 0.59, 95% confidence interval (CI) 0.15 to 2.26; 321 participants; five studies; very low-certainty evidence); we noted during sensitivity analysis that using different time points in one study may influence direction of this result. Thirteen studies (3215 participants) reported POCD, and of these, six studies reported data that could not be pooled; we noted no difference in scores of POCD in four of these and in one study, data were at a time point incomparable to other studies. We excluded one large study from meta-analysis because study investigators had used non-standard anaesthetic management and this study was not methodologically comparable to other studies. We combined data for seven studies and found low-certainty evidence that TIVA may reduce POCD (OR 0.52, 95% CI 0.31 to 0.87; 869 participants).We found no evidence of a difference in mortality at 30 days (OR 1.21, 95% CI 0.33 to 4.45; 271 participants; three studies; very low-certainty evidence). Twelve studies reported intraoperative hypotension. We did not perform meta-analysis for 11 studies for this outcome. We noted visual inconsistencies in these data, which may be explained by possible variation in clinical management and medication used to manage hypotension in each study (downgraded to low-certainty evidence); one study reported data in a format that could not be combined and we noted little or no difference between groups in intraoperative hypotension for this study. Eight studies reported length of stay in the PACU, and we did not perform meta-analysis for seven studies. We noted visual inconsistencies in these data, which may be explained by possible differences in definition of time points for this outcome (downgraded to very low-certainty evidence); data were unclearly reported in one study. We found no evidence of a difference in length of hospital stay according to type of anaesthetic maintenance agent (mean difference (MD) 0 days, 95% CI -1.32 to 1.32; 175 participants; four studies; very low-certainty evidence).We used the GRADE approach to downgrade the certainty of the evidence for each outcome. Reasons for downgrading included: study limitations, because some included studies insufficiently reported randomization methods, had high attrition bias, or high risk of selective reporting bias; imprecision, because we found few studies; inconsistency, because we noted heterogeneity across studies. AUTHORS' CONCLUSIONS:We are uncertain whether maintenance with propofol-based TIVA or with inhalational agents affect incidences of postoperative delirium, mortality, or length of hospital stay because certainty of the evidence was very low. We found low-certainty evidence that maintenance with propofol-based TIVA may reduce POCD. We were unable to perform meta-analysis for intraoperative hypotension or length of stay in the PACU because of heterogeneity between studies. We identified 11 ongoing studies from clinical trials register searches; inclusion of these studies in future review updates may provide more certainty for the review outcomes.
Postoperative cognitive dysfunction in the aged: the collision of neuroinflammaging with perioperative neuroinflammation.
Luo AiLin,Yan Jing,Tang XiaoLe,Zhao YiLin,Zhou BiYun,Li ShiYong
The aging population is burgeoning globally and this trend presents great challenges to the current healthcare system as the growing number of aged individuals receives procedures of surgery and anesthesia. Postoperative cognitive dysfunction (POCD) is a severe postoperative neurological sequela. Advanced age is considered as an independent risk factor of POCD. Mounting evidence have shown that neuroinflammation plays an essential role in POCD. However, it remains debatable why this complication occurs highly in the aged individuals. As known, aging itself is the major common high-risk factor for age-associated disorders including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. Chronic low-grade neuroinflammation (dubbed neuroinflammaging in the present paper) is a hallmark alternation and contributes to age-related cognitive decline in the normal aging. Interestingly, several lines of findings show that the neuroinflammatory pathogenesis of POCD is age-dependent. It suggests that age-related changes, especially the neuroinflammaging, are possibly associated with the postoperative cognitive impairment. Understanding the role of neuroinflammaging in POCD is crucial to elucidate the mechanism of POCD and develop strategies to prevent or treat POCD. Here the focus of this review is on the potential role of neuroinflammaging in the mechanism of POCD. Lastly, we briefly review promising interventions for this neurological sequela.
The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment.
Safavynia Seyed A,Goldstein Peter A
Frontiers in psychiatry
Postoperative cognitive dysfunction (POCD) is a common complication of the surgical experience and is common in the elderly and patients with preexisting neurocognitive disorders. Animal and human studies suggest that neuroinflammation from either surgery or anesthesia is a major contributor to the development of POCD. Moreover, a large and growing body of literature has focused on identifying potential risk factors for the development of POCD, as well as identifying candidate treatments based on the neuroinflammatory hypothesis. However, variability in animal models and clinical cohorts makes it difficult to interpret the results of such studies, and represents a barrier for the development of treatment options for POCD. Here, we present a broad topical review of the literature supporting the role of neuroinflammation in POCD. We provide an overview of the cellular and molecular mechanisms underlying the pathogenesis of POCD from pre-clinical and human studies. We offer a brief discussion of the ongoing debate on the root cause of POCD. We conclude with a list of current and hypothesized treatments for POCD, with a focus on recent and current human randomized clinical trials.
The potential mechanism of postoperative cognitive dysfunction in older people.
Lin Xianyi,Chen Yeru,Zhang Piao,Chen Gang,Zhou Youfa,Yu Xin
Postoperative cognitive dysfunction (POCD) is a common disorder following surgery, which seriously threatens the quality of patients' life, especially the older people. Accumulating attention has been paid to POCD worldwide in pace with the popularization of anesthesia/surgery. The development of medical humanities and rehabilitation medicine sets higher demands on accurate diagnosis and safe treatment system of POCD. Although the research on POCD is in full swing, underlying pathogenesis is still inconclusive due to these conflicting results and controversial evidence. Generally, POCD is closely related to neuropsychiatric diseases such as dementia, depression and Alzheimer's disease in molecular pathways. Researchers have come up with various hypotheses to reveal the mechanisms of POCD, including neuroinflammation, oxidative stress, autophagy disorder, impaired synaptic function, lacking neurotrophic support, etc. Recent work focused on molecular mechanism of POCD in older people has been thoroughly reviewed and summed up here, concerning the changes of peripheral circulation, pathological pathways of central nervous system (CNS), the microbiota-gut-brain axis and the related brain regions. Accordingly, this article provides a better perspective to understand the development situation of POCD in older people, which is conductive to uncover the pathological mechanism and exploit reasonable treatment strategy of POCD.
Application of Acupuncture to Attenuate Immune Responses and Oxidative Stress in Postoperative Cognitive Dysfunction: What Do We Know So Far?
Ho Yuen-Shan,Zhao Fei-Yi,Yeung Wing-Fai,Wong Gordon Tin-Chun,Zhang Hong-Qi,Chang Raymond Chuen-Chung
Oxidative medicine and cellular longevity
Postoperative cognitive dysfunction (POCD) is a common sequela following surgery and hospitalization. The prevention and management of POCD are important during clinical practice. POCD more commonly affects elderly patients who have undergone major surgery and can result in major decline in quality of life for both patients and their families. Acupuncture has been suggested as an effective intervention for many neurological disorders. In recent years, there are increasing interest in the use of acupuncture to prevent and treat POCD. In this review, we summarized the clinical and preclinical evidence of acupuncture on POCD using a narrative approach and discussed the potential mechanisms involved. The experimental details and findings of studies were summarized in tables and analyzed. Most of the clinical studies suggested that acupuncture before surgery could reduce the incidence of POCD and reduce the levels of systematic inflammatory markers. However, their reliability is limited by methodological flaws. Animal studies showed that acupuncture reduced cognitive impairment and the associated pathology after various types of surgery. It is possible that acupuncture modulates inflammation, oxidative stress, synaptic changes, and other cellular events to mitigate POCD. In conclusion, acupuncture is a potential intervention for POCD. More clinical studies with good research design are required to confirm its effectiveness. At the same time, findings from animal studies will help reveal the protective mechanisms, in which systematic inflammation is likely to play a major role.
The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction.
VanDusen Keith W,Eleswarpu Sarada,Moretti Eugene W,Devinney Michael J,Crabtree Donna M,Laskowitz Daniel T,Woldorff Marty G,Roberts Kenneth C,Whittle John,Browndyke Jeffrey N,Cooter Mary,Rockhold Frank W,Anakwenze Oke,Bolognesi Michael P,Easley Mark E,Ferrandino Michael N,Jiranek William A,Berger Miles,
Journal of Alzheimer's disease : JAD
BACKGROUND:Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer's disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity. OBJECTIVE:MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity. METHODS:201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive placebo or drug before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications. CONCLUSION:MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.
Could intraoperative magnesium sulphate protect against postoperative cognitive dysfunction?
Hassan Wael F,Tawfik Mona H,Nabil Tamer M,Abd Elkareem Rehab M
BACKGROUND:Although there is much concern about the pathogenesis of postoperative cognitive dysfunction (POCD); no effective prevention strategies are currently described. The aim of this work was to study whether intraoperative magnesium sulphate could have a protective effect against developing POCD and to study its impact on serum level of S100B, a marker of neuronal degeneration. METHODS:This is a prospective randomized controlled trial carried out on 80 participants undergoing elective laparoscopic cholecystectomy, 40 participants received conventional general anesthesia (conventional anesthesia group) and 40 participants received conventional general anesthesia with extra administration of intraoperative magnesium sulphate (Mg sulphate group). Cognitive assessment for both groups was done preoperatively and 1 week postoperatively using Paired Associate Learning test (PALT) and Benton Visual Retention Test (BVRT). Quantitative determination of serum S100B was done for both groups preoperatively and one week postoperatively by using an enzyme- linked immunoabsorbent assay technique. RESULTS:Postoperative PALT and BVRT were significantly lower than preoperative PALT and BVRT in the conventional anesthesia group (P value =0.043, P value =0.015 respectively), but not in the Mg sulphate group (P value =0.134, P value =0.151 respectively). Postoperative S100B was significantly higher than preoperative S100B in the conventional anesthesia group (P value =0.006), but not in the Mg sulphate group (P value =0.293). CONCLUSIONS:Administration of intravenous infusion of magnesium sulphate during conventional general anesthesia can protect against POCD and attenuate the post operative elevation of serum S100B.
Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial.
Subramaniam Balachundhar,Shankar Puja,Shaefi Shahzad,Mueller Ariel,O'Gara Brian,Banner-Goodspeed Valerie,Gallagher Jackie,Gasangwa Doris,Patxot Melissa,Packiasabapathy Senthil,Mathur Pooja,Eikermann Matthias,Talmor Daniel,Marcantonio Edward R
Importance:Postoperative delirium is common following cardiac surgery and may be affected by choice of analgesic and sedative. Objective:To evaluate the effect of postoperative intravenous (IV) acetaminophen (paracetamol) vs placebo combined with IV propofol vs dexmedetomidine on postoperative delirium among older patients undergoing cardiac surgery. Design, Setting, and Participants:Randomized, placebo-controlled, factorial clinical trial among 120 patients aged 60 years or older undergoing on-pump coronary artery bypass graft (CABG) surgery or combined CABG/valve surgeries at a US center. Enrollment was September 2015 to April 2018, with follow-up ending in April 2019. Interventions:Patients were randomized to 1 of 4 groups receiving postoperative analgesia with IV acetaminophen or placebo every 6 hours for 48 hours and postoperative sedation with dexmedetomidine or propofol starting at chest closure and continued for up to 6 hours (acetaminophen and dexmedetomidine: n = 29; placebo and dexmedetomidine: n = 30; acetaminophen and propofol: n = 31; placebo and propofol: n = 30). Main Outcomes and Measures:The primary outcome was incidence of postoperative in-hospital delirium by the Confusion Assessment Method. Secondary outcomes included delirium duration, cognitive decline, breakthrough analgesia within the first 48 hours, and ICU and hospital length of stay. Results:Among 121 patients randomized (median age, 69 years; 19 women [15.8%]), 120 completed the trial. Patients treated with IV acetaminophen had a significant reduction in delirium (10% vs 28% placebo; difference, -18% [95% CI, -32% to -5%]; P = .01; HR, 2.8 [95% CI, 1.1-7.8]). Patients receiving dexmedetomidine vs propofol had no significant difference in delirium (17% vs 21%; difference, -4% [95% CI, -18% to 10%]; P = .54; HR, 0.8 [95% CI, 0.4-1.9]). There were significant differences favoring acetaminophen vs placebo for 3 prespecified secondary outcomes: delirium duration (median, 1 vs 2 days; difference, -1 [95% CI, -2 to 0]), ICU length of stay (median, 29.5 vs 46.7 hours; difference, -16.7 [95% CI, -20.3 to -0.8]), and breakthrough analgesia (median, 322.5 vs 405.3 µg morphine equivalents; difference, -83 [95% CI, -154 to -14]). For dexmedetomidine vs propofol, only breakthrough analgesia was significantly different (median, 328.8 vs 397.5 µg; difference, -69 [95% CI, -155 to -4]; P = .04). Fourteen patients in both the placebo-dexmedetomidine and acetaminophen-propofol groups (46% and 45%) and 7 in the acetaminophen-dexmedetomidine and placebo-propofol groups (24% and 23%) had hypotension. Conclusions and Relevance:Among older patients undergoing cardiac surgery, postoperative scheduled IV acetaminophen, combined with IV propofol or dexmedetomidine, reduced in-hospital delirium vs placebo. Additional research, including comparison of IV vs oral acetaminophen and other potentially opioid-sparing analgesics, on the incidence of postoperative delirium is warranted. Trial Registration:ClinicalTrials.gov Identifier: NCT02546765.
Continuous-flow cell saver reduces cognitive decline in elderly patients after coronary bypass surgery.
Djaiani George,Fedorko Ludwik,Borger Michael A,Green Robin,Carroll Jo,Marcon Michael,Karski Jacek
BACKGROUND:Cerebral microembolization during cardiopulmonary bypass may lead to cognitive decline after cardiac surgery. Transfusion of the unprocessed shed blood (major source of lipid microparticulates) into the patient during cardiopulmonary bypass is common practice to reduce blood loss and blood transfusion. Processing of shed blood with cell saver before transfusion may limit cerebral microembolization and reduce cognitive decline after surgery. METHODS AND RESULTS:A total of 226 elderly patients were randomly allocated to either cell saver or control groups. Anesthesia and surgical management were standardized. Epiaortic scanning of the proximal thoracic aorta was performed in all patients. Transcranial Doppler was used to measure cerebral embolic rates. Standardized neuropsychological testing was conducted 1 week before and 6 weeks after surgery. The raw scores for each test were converted to Z scores, and then a combined Z score of 10 main variables was calculated for both study groups. The primary analysis was based on dichotomous composite cognitive outcome with a 1-SD rule. Cognitive dysfunction was present in 6% (95% confidence interval, 1.3% to 10.7%) of patients in the cell saver group and 15% (95% confidence interval, 8% to 22%) of patients in the control group 6 weeks after surgery (P=0.038). The severity of aortic atheroma and cerebral embolic count were similar between the 2 groups. CONCLUSIONS:The present report demonstrates that processing of shed blood with cell saver results in clinically significant reduction in postoperative cognitive dysfunction after cardiac surgery. These findings emphasize the clinical importance of lipid embolization in contributing to postoperative cognitive decline in patients exposed to cardiopulmonary bypass.
Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction.
Moller J T,Cluitmans P,Rasmussen L S,Houx P,Rasmussen H,Canet J,Rabbitt P,Jolles J,Larsen K,Hanning C D,Langeron O,Johnson T,Lauven P M,Kristensen P A,Biedler A,van Beem H,Fraidakis O,Silverstein J H,Beneken J E,Gravenstein J S
Lancet (London, England)
BACKGROUND:Long-term postoperative cognitive dysfunction may occur in the elderly. Age may be a risk factor and hypoxaemia and arterial hypotension causative factors. We investigated these hypotheses in an international multicentre study. METHODS:1218 patients aged at least 60 years completed neuropsychological tests before and 1 week and 3 months after major non-cardiac surgery. We measured oxygen saturation by continuous pulse oximetry before surgery and throughout the day of and the first 3 nights after surgery. We recorded blood pressure every 3 min by oscillometry during the operation and every 15-30 min for the rest of that day and night. We identified postoperative cognitive dysfunction with neuropsychological tests compared with controls recruited from the UK (n=176) and the same countries as study centres (n=145). FINDINGS:Postoperative cognitive dysfunction was present in 266 (25.8% [95% CI 23.1-28.5]) of patients 1 week after surgery and in 94 (9.9% [8.1-12.0]) 3 months after surgery, compared with 3.4% and 2.8%, respectively, of UK controls (p<0.0001 and p=0.0037, respectively). Increasing age and duration of anaesthesia, little education, a second operation, postoperative infections, and respiratory complications were risk factors for early postoperative cognitive dysfunction, but only age was a risk factor for late postoperative cognitive dysfunction. Hypoxaemia and hypotension were not significant risk factors at any time. INTERPRETATION:Our findings have implications for studies of the causes of cognitive decline and, in clinical practice, for the information given to patients before surgery.
Cognitive Reserve and the Risk of Postoperative Cognitive Dysfunction.
Feinkohl Insa,Winterer Georg,Spies Claudia D,Pischon Tobias
Deutsches Arzteblatt international
BACKGROUND:Post-operative cognitive dysfunction (POCD) occurs in 10 to 54% of older patients during the first few weeks after surgery, but little is known about risk factors predisposing to POCD. METHODS:Systematic literature review and meta-analysis of cognitive reserve indicators and POCD risk. RESULTS:Fifteen studies on 5104 patients were included. Follow-up periods spanned 1 day to 6 months. Educational level was the most commonly assessed cognitive reserve indicator, and a longer time spent in education was associated with a reduced risk of POCD (relative risk [RR] per year increment 0.90; 95% confidence interval: [0.87; 0.94]), i.e. each year increase in education was associated with a 10% reduced risk. Similar findings were made for some analyses on education as a categorical predictor (high school versus further/higher education, RR 1.71, [1.30; 2.25]; lower than high school versus further/higher education, RR 1.69, [1.17; 2.44]) though risk was equivalent for patients with high school education and those with lower than high school education (RR 1.02; [0.78; 1.32]). CONCLUSION:Patients with a relatively higher level of education are at reduced risk of POCD. Risk stratification of surgical patients according to educational level may prove useful.
Postoperative Cognitive Dysfunction.
Kapoor Indu,Prabhakar Hemanshu,Mahajan Charu
Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine
Cognitive dysfunction is a common complication in primary or metastatic brain tumors and can be correlated to disease itself or various treatment modalities. The symptoms of cognitive deficits may include problems with memory, attention and information processing. Primary brain tumors are highly associated with neurocognitive deficit and poor quality of life. This review discusses the pathophysiology, risk factors and assessment of cognitive dysfunction. It also gives an overview of the effect of anesthetics on postoperative cognitive dysfunction and its management.
Postoperative cognitive dysfunction and dementia: what we need to know and do.
Needham M J,Webb C E,Bryden D C
British journal of anaesthesia
Approximately 12% of apparently previously cognitively well patients undergoing anaesthesia and noncardiac surgery will develop symptoms of cognitive dysfunction after their procedure. Recent articles in this Journal have highlighted the difficulties of confirming any clear links between anaesthesia and cognitive dysfunction, in part because of the lack of consistency regarding definition and diagnosis. Postoperative cognitive dysfunction (POCD) is usually self-limiting and rarely persists in the longer term, although plausible biological mechanisms for an impact on brain protein deposition do exist. Clinical research studies are frequently confounded by a lack of agreed definitions and consistency of testing. Preoperative assessment of neurocognitive function and risk factor identification is imperative in order to ascertain the true extent of POCD and any causative link to anaesthesia and surgery. At present a multidisciplinary care bundle approach to risk factor stratification and reduction is the most attractive management plan based on evidence of slight benefit from individual interventions. As yet no individual anaesthetic technique, drug or mode of monitoring has been proved to reduce the incidence of POCD. Providing patients with appropriate and accurate information can be difficult because of conflicting evidence. The Royal College of Anaesthetists' patient liaison group has produced a useful patient information leaflet that is designed to provide guidance in discussions of individual risks whilst considerable uncertainties remain.
Postoperative Cognitive Dysfunction and Noncardiac Surgery.
Evered Lisbeth A,Silbert Brendan S
Anesthesia and analgesia
Postoperative cognitive dysfunction (POCD) is an objectively measured decline in cognition postoperatively compared with preoperative function. POCD has been considered in the anesthetic and surgical literature in isolation of cognitive decline which is common in the elderly within the community and where it is labeled as mild cognitive impairment, neurocognitive disorder, or dementia. This narrative review seeks to place POCD in the broad context of cognitive decline in the general population. Cognitive change after anesthesia and surgery was described over 100 years ago, initially as delirium and dementia. The term POCD was applied in the 1980s to refer to cognitive decline assessed purely on the basis of a change in neuropsychological test results, but the construct has been the subject of great heterogeneity. The cause of POCD remains unknown. Increasing age, baseline cognitive impairment, and fewer years of education are consistently associated with POCD.In geriatric medicine, cognitive disorders defined and classified as mild cognitive impairment, neurocognitive disorder, and dementia have definitive clinical features. To identify the clinical impact of cognitive impairment associated with the perioperative period, POCD has recently been redefined in terms of these geriatric medicine constructs so that the short-, medium-, and long-term clinical and functional impact can be elucidated. As the aging population present in ever increasing numbers for surgery, many individuals with overt or subclinical dementia require anesthesia. Anesthesiologists must be equipped to understand and manage these patients.