Editorial Views  |   January 2008
Taking the Lead in Research into Postoperative Cognitive Dysfunction
Author Affiliations & Notes
  • Mervyn Maze, M.B., Ch.B., F.R.C.P., F.R.C.A., F.Med.Sci.
  • Mario Cibelli, M.D.
  • Hilary P. Grocott, M.D., F.R.C.P.C., F.A.S.E.
  • *Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, United Kingdom. . †Department of Anesthesia, University of Manitoba, Winnipeg, Manitoba, Canada.
Article Information
Editorial Views / Geriatric Anesthesia
Editorial Views   |   January 2008
Taking the Lead in Research into Postoperative Cognitive Dysfunction
Anesthesiology 1 2008, Vol.108, 1-2. doi:10.1097/01.anes.0000296105.43657.05
Anesthesiology 1 2008, Vol.108, 1-2. doi:10.1097/01.anes.0000296105.43657.05
IN this issue of the Journal, Dr. Monk et al.  1,2 explore the effects of surgery and anesthesia on cognitive function in both the short and medium-term postoperative period; these articles follow up investigations conducted previously by the International Study Group on Postoperative Cognitive Dysfunction (ISPOCD).3 Using the ISPOCD measures of outcome, Monk et al.  have confirmed the risk factors for the development of postoperative cognitive dysfunction (POCD) that had been previously identified (age, low educational level). Interestingly, they also found that asymptomatic patients with a history of stroke had a higher incidence of POCD. Strikingly, they add critical insights into the overall significance of POCD by defining a relationship to mortality.
Regarding risk factors, the evidence garnered by these and other studies1–3 may be considered as a reduction in cognitive reserve that provides the milieu for the development of POCD. Stern4 refers to passive and active models of cognitive reserve; in the passive model, reserve is represented by increased brain size and/or number of synapses available. Within this model, any cognitive deterioration consequent to a brain injury can be compensated for by means of neuronal pathway substitution. The active model features an improved processing of the available information by exploitation of preexistent redundant neuronal networks. This theory of synaptic enrichment provides a convenient explanation for the observation that high levels of intelligence and educational attainment are good predictors of brain resistance to injuries before cognitive dysfunction is manifest.5 Conversely, it clarifies the role of previous stroke (even though there was no neurologic deficit) as an exacerbating factor. Aging, one of the aforementioned risk factors for POCD, causes several structural and morphologic changes to brain tissue, which are likely to be correlated with a reduction in cognitive reserve. These include reduced brain weight and volume6 as well as loss of cellular bodies and myelinated fibers in several brain regions7 including the hippocampus,8 an area of the brain that is critical for memory. Subcellular changes are documented as a reduction in synaptic density,9 rarefication of cerebral microvasculature,10 and alterations to DNA repair systems including the mechanisms for removal of neurons with damaged nuclear DNA11 among others. Oxidative stress has been cited as a likely cause of age-related neurodegeneration.12 Within the aging brain, there is a proinflammatory phenotype with up-regulation of markers, such as interleukin 6 and C-reactive protein, which have been correlated with cognitive decline in a study of elderly patients.13 
Is the deterioration of cognitive function seen in elderly postoperative patients after surgery (POCD) initiated by an exacerbation of processes already active during the aging process? If so, does surgery or anesthesia accelerate the mechanisms leading to age-related cognitive decline? There is now compelling evidence to suggest that inflammation occurs in the brain after nonneurologic, noncardiac surgery as evidenced by increased levels of proinflammatory cytokines in cerebrospinal fluid. Buvanendran et al.  14 found that hip replacement surgery was associated with postoperative up-regulation of interleukin 6, and prostaglandin E2, in the cerebrospinal fluid. Others observed increased concentrations of interleukin 6 in the cerebrospinal fluid during and immediately after off pump coronary artery bypass surgery.15 In addition, studies performed in animals after abdominal16 and orthopedic surgery17 have demonstrated inflammation in hippocampal tissue during the postoperative period; inflammatory changes in these brain regions are capable of adversely affecting learning and memory as well as other cognitive domains.18 However, neither the findings of the preclinical nor clinical studies of POCD can be causally attributed to these alterations in inflammatory markers; also, it is unclear whether the neuroinflammation is pathogenically linked to surgery, anesthesia, or other patient factors. Although plausible arguments can be made for each of these factors, further research is needed to establish the mechanisms for the associations that have been noted.
In their companion article, Monk et al.  suggest that different types of cognitive impairment may develop after surgery. This has been explored by separating the results of tests that assess the primary attention domain (often referred to as executive function) from that assessing the memory cognitive domain. Executive tasks (e.g.  , the Wisconsin Card Sorting Test) explore the activity of prefrontal cortices, thalamus, and white matter fibers. The successful accomplishment of these tests is associated with normal functioning in middle-aged and older individuals.19 Difficulty in completing the tasks implies an impairment (either functional or morphologic) of these structures in the brain of POCD patients. A dysfunction of memory domains, as referred to by the authors, can be accounted for by an impairment of hippocampus, entorhinal cortex, thalamus, and basal forebrain. Because different cognitive domains depend on different brain regions, it may be considered more likely that a common pathogenic mechanism (such as inflammation) impairs each of these structures concurrently, rather than separate mechanisms affecting them individually. Differences in the degree of postoperative cognitive impairment observed between individuals and between different regions of the brain may reflect site-specific variability in cognitive reserve.
Despite limitations of the studies by Monk et al.  (including use of age-matched [not disease-matched] controls, exclusion of patients with preexisting cognitive impairments, and the use of an unrestricted anesthetic protocol), the finding that cognitive loss is correlated with longer-term (1-yr) mortality is remarkable but unsurprising because longitudinal studies had previously demonstrated the relation between cognitive decline and mortality rate in nonsurgical settings.20 Although a causal relation between POCD and death cannot be strictly deduced, investigators in this field of inquiry will be better prepared to address the “so what” comment when seeking funding from relevant agencies. The call to seek a more meaningful overall global outcome measure of cognition that the everyday practitioner can apply and easily understand will continue but is not reason to ignore the results of other forms of testing when an association with mortality has been found. The mortality relationship that was noted must be corroborated, ideally in a multicenter fashion, to strengthen its broader applicability; also, it would be helpful to obtain further insight into the role of anesthetic techniques by standardizing these.
Amelioration of POCD can be seen as part of a quest to control the processes of aging and the postponement of cognitive decline. Those involved in the care of elderly patients scheduled to undergo surgery must identify the pathogenic mechanisms and orchestrate appropriate protective and therapeutic interventions to target the pathogenic processes that produce POCD. Although the anesthesiologist may not have all the necessary tools to undertake this quest, who is better placed to lead the response to this perioperative challenge?
*Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, United Kingdom. . †Department of Anesthesia, University of Manitoba, Winnipeg, Manitoba, Canada.
Monk TG, Weldon BC, Garvan CW, Dede DE, Van Der Aa MT, Heilman KM, Gravenstein JS: Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008; 108:18–30Monk, TG Weldon, BC Garvan, CW Dede, DE Van Der Aa, MT Heilman, KM Gravenstein, JS
Price CC, Garvan CW, Monk TG: Type and severity of cognitive decline in older adults after noncardiac surgery. Anesthesiology 2008; 108:8–17Price, CC Garvan, CW Monk, TG
Moller JT, Cluitmans P, Rasmussen LS, Hounx P, Rasmussen H, Canet J, Rabitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Bielder A, van Beem H, Fraidakis O, Silverstein JH, Beneken JEW, Gravenstein JS: Long-term postoperative dysfunction in the elderly: ISPOCD 1 Study. Lancet 1998; 351:857–61Moller, JT Cluitmans, P Rasmussen, LS Hounx, P Rasmussen, H Canet, J Rabitt, P Jolles, J Larsen, K Hanning, CD Langeron, O Johnson, T Lauven, PM Kristensen, PA Bielder, A van Beem, H Fraidakis, O Silverstein, JH Beneken, JEW Gravenstein, JS
Stern Y: What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc 2002; 8:448–60Stern, Y
Elkins JS, Longstreth WT Jr, Manolio TA, Newman AB, Bhadelia RA, Johnston SC: Education and the cognitive decline associated with MRI-defined brain infarct. Neurology 2006; 67:435–40Elkins, JS Longstreth, WT Manolio, TA Newman, AB Bhadelia, RA Johnston, SC
Schwartz M, Creasey H, Grady CL, DeLeo JM, Frederickson HA, Cutler NR, Rapoport SI: Computed tomographic analysis of brain morphometrics in 30 healthy men, aged 21 to 81 years. Ann Neurol 1985; 17:146–57Schwartz, M Creasey, H Grady, CL DeLeo, JM Frederickson, HA Cutler, NR Rapoport, SI
Pakkenberg B, Gundersen HJ: Neocortical neuron number in humans: Effect of sex and age. J Comp Neurol 1997; 384:312–20Pakkenberg, B Gundersen, HJ
Simić G, Kostović I, Winblad B, Bogdanović N: Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease. J Comp Neurol 1997; 379:482–94Simić, G Kostović, I Winblad, B Bogdanović, N
Morrison JH, Hof PR: Life and death of neurons in the aging brain. Science 1997; 278:412–9Morrison, JH Hof, PR
Riddle DR, Sonntag WE, Lichtenwalner RJ: Microvascular plasticity in aging. Aging Res Rev 2003; 2:149–68Riddle, DR Sonntag, WE Lichtenwalner, RJ
Rutten BP, Korr H, Steinbusch HW, Schmitz C: The aging brain: Less neurons could be better. Mechanisms Ageing Dev 2003; 124:349–55Rutten, BP Korr, H Steinbusch, HW Schmitz, C
Coyle JT, Puttfarcken P: Oxidative stress, glutamate, and neurodegenerative disorders. Science 1993; 262:689–95Coyle, JT Puttfarcken, P
Yaffe K, Lindquist K, Penninx BW, Simonsick EM, Pahor M, Kritchevsky S, Launer L, Kuller L, Rubin S, Harris T: Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology 2003; 61:76–80Yaffe, K Lindquist, K Penninx, BW Simonsick, EM Pahor, M Kritchevsky, S Launer, L Kuller, L Rubin, S Harris, T
Buvanendran A, Kroin JS, Berger RA, Hallab NJ, Saha C, Negrescu C, Moric M, Caicedo MS, Tuman KJ: Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology 2006; 104:403–10Buvanendran, A Kroin, JS Berger, RA Hallab, NJ Saha, C Negrescu, C Moric, M Caicedo, MS Tuman, KJ
Kalman J, Bogats G, Babik B, Rimanoczy A, Janka Z, Penke B, Palotas A: Elevated levels of inflammatory biomarkers in the cerebrospinal fluid after coronary artery bypass surgery are predictors of cognitive decline. Neurochem Intern 2006; 48:177–80Kalman, J Bogats, G Babik, B Rimanoczy, A Janka, Z Penke, B Palotas, A
Wan Y, Xu J, Ma D, Zeng Y, Cibelli M, Maze M: Postoperative impairment of cognitive function in rats: A possible role for cytokine-mediated inflammation in the hippocampus. Anesthesiology 2007; 106:436–43Wan, Y Xu, J Ma, D Zeng, Y Cibelli, M Maze, M
Cibelli M, Hossain M, Ma D, Mugnolo M, Maze M: Microglia and astrocyte activation in the hippocampus in a model of orthopedic surgery in adult mice. Anesthesiology 2007; 107:A1557Cibelli, M Hossain, M Ma, D Mugnolo, M Maze, M
Dantzer R, Kelley KW: Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 2007; 21:153–60Dantzer, R Kelley, KW
Gunning-Dixon FM, Raz N: Neuroanatomical correlates of selected executive functions in middle-aged and older adults: A prospective MRI study. Neuropsychologia 2003; 41:1929–41Gunning-Dixon, FM Raz, N
Bosworth HB, Schaie KW, Willis SL: Cognitive and sociodemographic risk factors for mortality in the Seattle Longitudinal. J Gerontol B Psychol Sci Soc Sci 1999; 54:273–82Bosworth, HB Schaie, KW Willis, SL