Postoperative Cognitive Dysfunction After Cardiac Surgery Lan Gao, Rame Taha, Dominique Gauvin, Lamia B. Othmen, Yang Wang and Gilbert Blaise Chest 2005;128;3664-3670 DOI: 10.1378/chest.128.5.3664

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CHEST is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright 2005 by the American College of Chest Physicians, 3300 Dundee Road, Northbrook IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. ISSN: 0012-3692.

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Postoperative Cognitive Dysfunction After Cardiac Surgery* Lan Gao, MD; Rame Taha, MD; Dominique Gauvin, BSc; Lamia B. Othmen, MD; Yang Wang, MD; and Gilbert Blaise, MD

Prolonged postoperative cognitive dysfunction (POCD) is reported to occur frequently after cardiac surgery. However, it is rarely assessed in routine clinical practice and receives little attention. Although the cerebral consequences of cardiopulmonary bypass have been measured clinically, insights into the resulting molecular and pathologic events within the brain have only begun to be investigated. POCD is likely to impair quality of life and constitutes a large burden on society when elderly patients prematurely lose their independence. Numerous studies have reported that neurocognitive deficit is associated with heightened mortality, increased length of hospital stay, and discharge to a nursing home. This is linked with a tremendous demand for health-care resources. Because of the magnitude of the clinical problem, serious consideration must be directed toward understanding its etiology and the development of neuroprotective strategies. Clearly identifying the mechanisms of POCD is challenging. The purpose of this review is to discuss recent developments in our understanding of the pathophysiologic mechanisms, prevention, and treatments that have been designed to ameliorate brain dysfunction after cardiac surgery. (CHEST 2005; 128:3664 –3670) Key words: anesthesia; cardiopulmonary bypass; cytokines; inflammatory cells; neurocognitive dysfunction; surgery Abbreviations: AD ⫽ Alzheimer disease; APO-⑀4 ⫽ apolipoprotein ⑀4; COX ⫽ cyclooxygenase; CPB ⫽ cardiopulmonary bypass; IL ⫽ interleukin; MMP ⫽ matrix metalloproteinase; NO ⫽ nitric oxide; POCD ⫽ prolonged postoperative cognitive dysfunction; TNF ⫽ tumor necrosis factor

North America, the cardiopulmonary bypass I n(CPB) technique is used ⬎ 500,000 times every year. Adverse cerebral outcomes after CPB for cardiac surgery have been well documented.1 These injuries encompass a wide spectrum, from subtle cognitive impairment to deadly stroke. Four neurologic and cognitive complications are observed after CPB: stroke (the most serious, with an incidence of 1.5 to 5.2%)1,2; postoperative delirium (10 to 30%)3–5; and short-term (33 to 83%)6,7 as well as long-term cognitive changes (20 to 60%).8 Prolonged postoperative cognitive dysfunction (POCD) occurs frequently after cardiac surgery. Its main cause was first thought to be the CPB technique, but POCD also afflicts noncardiac surgery *From the Laboratory of Anesthesia, Department of Anesthesia and Research Centre, Centre Hospitalier de l’University de Montreal, Hospital Notre-Dame, Montreal, QC, Canada. Manuscript received December 23, 2004; revision accepted April 18, 2005. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Gilbert Blaise, MD, Laboratory of Anesthesia, CHUM-Notre-Dame Hospital, Deschamps Pavilion, Room FS-1136, 1560 Sherbrooke St East, Montreal, QC, Canada H2L 4M1; e-mail: [email protected]

patients.9 Anesthesia is suspected to contribute to POCD.10 POCD is characterized by impairment of memory, concentration, language comprehension, and social integration. It can present days to weeks after surgery and may remain a permanent disorder.7,8 POCD is seen in 40% of patients several months after cardiac surgery. In patients ⬎ 60 years old, 25% demonstrated dysfunction 1 week after noncardiac surgery. This number fell to 10% 3 months later. In a nonsurgical, nonanesthetized, similarly aged control group, neurocognitive abilities deteriorated by only 3%.11 Brain imaging with functional magnetic nuclear resonance or single photon-emitting CT has disclosed brain swelling with reduced regional blood flow and a decreased neuronal cell population after CPB.12–14 The etiology of cerebral injuries associated with POCD probably represents a complex interaction between cerebral microemboli, global cerebral hypoperfusion, inflammation, and genetic susceptibility.15–18 There are several risk factors for cognitive dysfunction. Among them are preoperative elements, such as advancing age, low education, diabetes, and

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the severity of atherosclerotic disease. Intraoperative hypotension, hypoxia, medications, and postoperative infections have also been described as risk factors for POCD.15,16 As suggested by a few researchers, genetics may play a role in the pathogenesis of POCD. This is indicated by the presence of the apolipoprotein ⑀4 (APO-⑀4) allele in a subgroup of POCD patients.17 Previous data have confirmed the association between Alzheimer disease (AD) and APO-⑀4, and support the hypothesis that the APO-⑀4 allele either confers genetic susceptibility to AD or may be in linkage disequilibrium with another susceptibility locus.18 Ethnic variability in the allelic frequency of APO-⑀4 in the elderly warrants further investigation.

Role of Surgery and Anesthesia in the Pathogenesis of POCD Surgery is associated with the stress response, with increasing secretion of cortisol and catecholamines. Persistently high levels of stress may inhibit memory and interfere with hippocampal function. Surgery alone also activates specific homeostatic responses, triggering immune mechanisms and the inflammatory cascade through the release of various inflammatory mediators. Neurocognitive dysfunction occurs frequently in noncardiac surgery patients, indicating that some element of surgery and/or anesthesia contributes to this condition. The possibility that general anesthesia contributes to cognitive deterioration has not been tested directly, partly because clinical studies have not controlled for the anesthetics used and cannot differentiate between the effects of illness, hospitalization, surgery, and anesthesia. Publications19 –21 have documented a prolonged outcome of general anesthetics on gene expression, brain protein synthesis, and cognitive function in rats. Depression of CNS function is a part of anesthesia. This condition is expected to be perfectly reversible and transient, but several complications may arise, some of them causing serious disability. The aged brain is different from the younger brain in several important aspects, including size, distribution and type of neurotransmitters, metabolic function, and capacity for plasticity. For this reason, early POCD is more common in the elderly after major surgery, compared to middle-aged patients.22 General anesthesia affects brain function at all levels, including neuronal membranes, receptors, ion channels, neurotransmitters, cerebral blood flow, and metabolism. Short-term impairment of cognitive and psychomotor performance is common after general anesthesia and is typically attributed to incomwww.chestjournal.org

plete drug clearance. Postoperative pain is a possible etiologic factor in POCD mechanisms. Epidural analgesia with local anesthetics and/or opioids has been found to be probably better than parenteral opioids for the control of postoperative pain and the prevention of early POCD.23

Inflammation and POCD Pathogenesis Previous studies5,8,15 suggest that intraoperative hypotension and multiple emboli in brain microvessels are possible mechanisms for the cognitive decline after cardiac surgery. However, we and other investigators18,20 believe that it is an inflammatory phenomenon. Our understanding of the systemic inflammatory response to CPB has progressed considerably in the last decade. CPB activates the inflammatory response via distinct mechanisms, including the following: (1) Direct “contact activation” of the immune system after interaction between the patient’s circulating blood and the artificial material surfaces of the CPB circuit. (2) Aortic cross-clamping involves ischemia-reperfusion injury to the heart, lungs, and kidneys. Restoration of perfusion after release of aortic cross-clamping induces humoral and cellular activation, leading to a systemic inflammatory response. Jansen et al24 observed that dexamethasone prevents hemodynamic instability after CPB and thus improves early POCD by inhibiting leukocyte and tissue plasminogen activator activities generated after the release of aortic cross-clamping. (3) Nonspecific activators of the inflammatory response during surgery (eg, surgical trauma, blood loss, transfusion or hypothermia) that might enhance inflammation after surgery.25 The release of inflammatory mediators via the CPB procedure appears to be temperature dependent, with warm CPB associated with an increased inflammatory response compared to hypothermic CPB. Therefore, improving CPB circuit factors may be a valuable strategy to limit the inflammatory response and to modulate the extent of neurocognitive dysfunction.26 The cells involved in brain inflammation are mixtures of structural and inflammatory cells. In the brain, supporting cells of the glial family, known as microglial cells, act as scavengers, in much the same fashion as macrophages.27 They engulf and eliminate dead neurons that have been damaged by injury or illness. The presence of activated microglial cells is an indicator of chronic inflammation. Astrocytes and/or microglia secrete most cytokines in the brain.28 There is evidence that under certain conditions, neurons can also produce cytokines29 (Fig 1). Cerebral endothelial cells are actively engaged in CHEST / 128 / 5 / NOVEMBER, 2005

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Figure 1. A schematic diagram of the inflammatory response to CPB. PMN ⫽ polymorphonuclear neutrophils; TGF ⫽ transforming growth factor.

processes of microvascular stasis as well as leukocyte infiltration by evoking a plethora of bioactive inflammatory cytokines and chemokines.30 The key players in inflammatory processes are numerous cytokines, including tumor necrosis factor (TNF)-␣; interleukin (IL)-1, IL-8, and IL-6. The myocardium is a major source of these cytokines during CPB.31,32 Several studies suggest that the marked and sustained expression of inflammation-related enzymes such as cyclooxygenase (COX)-2 plays an important role in secondary events that amplify cerebral injury after ischemia. The contribution of COX-2 to peripheral inflammation is well documented, but little is known about its involvement in brain inflammation.33 It has been reported that COX-2 is significantly induced in astrocyte and microglial cultures by radiation injury.34 Moreover, the brain from rats undergoing CPB expresses a high level of COX-2 messenger RNA.35 The beneficial effects of COX-2 selective inhibitors in the management of CNS inflammation have been revealed.36 Matrix metalloproteinases (MMPs) have been im-

plicated in early breakdown of the blood/brain barrier in neuroinflammatory disease. MMPs comprise a group of proteolytic enzymes that act as mediators of brain injury in a wide variety of disease processes, including multiple sclerosis, AD, stroke, tumor invasion, and other inflammatory brain disorders.37– 40 Interruption of the MMP proteolytic cascade may be a possible therapeutic approach to preventing the secondary progression of damage after brain injury. The incidence of chronic cerebral diseases such as AD has been linked to cardiac surgery.41 Sparks et al42 found evidence of AD-like lesions in the brains of nondemented individuals with mitral valve prolapse. They and others43,44 suggested that cognitive dysfunction occurring after CPB with coronary artery grafting or valve repair/replacement is a functional sequel of AD-like neuropathology. Considerable evidence gained over the past decade supports the conclusion that neuroinflammation is associated with AD pathology. Inflammatory brain cells, such as microglia and astrocytes, as well as cytokines, including IL-6, TNF-␣, and transform-

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ing growth factor-␤, have clearly been implicated in this inflammatory process.45–50 Many varieties of chemokines, such as IL-8, monocyte chemoattractant protein, and RANTES (regulated upon activation, normal T-cell expressed and secreted), are also expressed in brain tissue from humans in conjunction with dementia.51–53 It has been shown that IL-8 is a key mediator of neuroinflammation in severe traumatic brain injuries and is constitutively expressed in the brain. These inflammatory mediators should be widely investigated and considered as targets in the inflammatory process associated with POCD after CPB.54 –56 Nonpulsatile flow generated by the CPB machine could lower shear stress on endothelial cells, reduce nitric oxide (NO) release, and induce nonhomogenous blood flow distribution in ischemic areas presenting reperfusion injury after weaning from CPB. Deficient NO production affects the inflammatory cascade, allowing the vascular adhesion of inflammatory cells primed by contact with the extracorporeal circuit. This initial deficit in endothelial NO synthase is particularly marked in older patients. It is conceivable that therapeutic interventions aimed at attenuating the inflammatory response might result in better outcomes.

Biological Markers Biochemical markers and new sensitive methods are needed to detect early POCD after cardiac and noncardiac surgery.57 Stable NO products represent a potential biochemical predictor of POCD. It has been demonstrated that preoperative and postoperative plasma concentrations of stable NO products (nitrate/nitrite) are associated with the early detection of POCD after cardiac surgery. A recent study by Iohom et al58 found that preoperative and postoperative plasma concentrations of stable NO products are linked with early POCD after laparoscopic cholecystomy. S100B, a promising predictive marker, is a calcium-binding peptide produced mainly by astrocytes that exert paracrine and autocrine effects on neurons and glia. A significant positive correlation has been established between neuropsychological function and serum concentrations of S100B protein in patients with traumatic head injuries, or stroke, and after cardiac or noncardiac surgery.59 A study by Mathew et al60 suggests that reduced preoperative endotoxin immunity is a predictor of increased postoperative cognitive dysfunction in patients undergoing cardiac surgery, particularly in those ⬎ 60 years old. www.chestjournal.org

Therapeutic Approach Currently, there is no single therapy that can be recommended for POCD. Primary prevention is probably the most effective treatment strategy. Our goal is early diagnosis, and early intervention may help to prevent the late cognitive functional decline. Prevention It is important to assess the risk factors predisposing to POCD preoperatively and modulate preexisting disorders in patients before proceeding to major surgery.61 The risk factors that need to be assessed preoperatively and intraoperatively are as follows: (1) hemodynamic stability: the optimization of hemodynamic stability is beneficial for postoperative outcome. It is important to maintain organ perfusion during the preoperative period. (2) Temperature: hypothermia decreases the metabolism and permits longer tolerance of hypoxia. It seems to be effective in reducing cognitive dysfunction after cardiac surgery. Grigore et al62 show that slower rewarming during CPB could prevent neurocognitive decline. (3) Minimal surgical invasiveness. (4) Mechanical devices including intra-aortic filter, ultrafiltration, and leukocyte depletion: (A) Use of an intra-aortic filter has been shown to reduce intraoperative cerebral embolic events and improve postoperative neurocognitive outcomes. Intra-aortic filtration is a feasible method of capturing particulate emboli during CPB.63 However, more prospective studies are needed to further delineate its safety and efficacy. (B) Ultrafiltration removes water and low-molecularweight substances from plasma. It may also trap some inflammatory mediators released during CPB.64 The choice of filter material and pore size, the hemofiltration rate, and timing of the procedure may all influence its efficacy and outcome. (C) Leukocyte depletion in animals has been shown to reduce oxygen free radical-mediated lung injury associated with CPB and to prevent cardiac dysfunction.65 These protective effects are correlated with a diminution of leukocyte sequestration in the coronary vascular bed and a decrease in coronary vascular resistance. Pharmacotherapy Neuroprotective therapy mainly aims at minimizing the activation of toxic pathways and at enhancing endogenous neuroprotective mechanisms. To date, prophylactic or therapeutic interventions are quite limited. (1) Aprotinin, a serine protease inhibitor with important homeostatic and antiinflammatory CHEST / 128 / 5 / NOVEMBER, 2005

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properties, decreases the incidence of stroke after CPB.66 (2) Heparin coating of CPB circuits, which improves its biocompatibility, thereby reducing contact activation of the inflammatory response, may diminish the incidence of neurologic dysfunction in humans.67,68 (3) In humans, barbiturates that antagonize excitatory transmitters have been found to provide effective neuroprotection.69 (4) Data suggest that CPB-induced neurologic and neurocognitive dysfunction can be attenuated by the administration of xenon, potentially related to its neuroprotective action via N-methyl-D-aspartate receptor antagonism.70 (5) Steroid pretreatment before CPB was recommended recently to inhibit ischemia-reperfusion injury as well as the inflammatory response associated with CPB.71 Future Work More research needs to be conducted into the mechanisms of cognitive dysfunction following CPB so that preventive procedures can be developed to improve patient outcomes. Techniques and technology will be the best way to reduce the incidence of neurocognitive dysfunction. Improvements in coronary artery bypass procedures are always being developed to help preserve cognitive function. These include heartlung bypass machine advances, new warming techniques, and the “beating-heart” procedure. The beating-heart procedure (off-pump coronary artery bypass surgery) is one of the most promising surgical innovations in the past decade. This surgical technique entails immobilizing certain areas of the heart with cardiac stabilizers, allowing the heart to continue beating during surgery instead of stopping it and placing the patient on a heart-lung machine. Several studies have recently highlighted the potential benefits of off-pump coronary artery bypass surgery, particularly in the elderly and other high-risk patients. The off-pump technique avoids cross-clamping and aortic cannulation, which can traumatize the aorta, and it can therefore reduce systemic inflammatory effects after CPB. The procedure can greatly diminish complications and shorten recovery time after more traditional bypass surgery. The identification of patients at high risk for cognitive changes has been difficult, possibly due to issues of study design. Our priority is to identify this high-risk group and to develop future protocols, which may include intraoperative and pharmacologic interventions. Conclusion A review of currently available data reveals that postoperative cognitive deterioration is a common

and potentially devastating complication. It may affect length of hospital stay, quality of life, the rehabilitation process, and work performance. The incidence of POCD is higher after cardiac than noncardiac surgery, and the risk increases with age. The pathophysiology of POCD is poorly understood, and multicomponent interventions that target welldocumented risk factors would be helpful. A better understanding of the time course and consequences of neuroinflammation may aide in therapeutically promoting the beneficial and reducing the harmful aspects of neuroinflammation. The development of more effective prevention strategies remains an important goal. As research continues to define the roles of the various inflammatory mediators involved in the pathophysiology of POCD, more specific antiinflammatory therapies will be available in the field. References 1 McKhann GM, Goldsborough MA, Borowicz LM Jr, et al. Cognitive outcome after coronary artery bypass: a one-year prospective study. Ann Thorac Surg 1997; 63:510 –515 2 McKhann GM, Goldsborough MA, Borowicz LM Jr, et al. Predictors of stroke risk in coronary artery bypass patients. Ann Thorac Surg 1997; 63:516 –521 3 Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery: Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335:1857–1863 4 Tuman KJ, McCarthy RJ, Najafi H, et al. Differential effects of advanced age on neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc Surg 1992; 104:1510 – 1517 5 Rolfson DB, McElhaney JE, Rockwood K, et al. Incidence and risk factors for delirium and other adverse outcomes in older adults after coronary artery bypass graft surgery. Can J Cardiol 1999; 15:771–776 6 Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal assessment of neurocognitive function after coronaryartery bypass surgery. N Engl J Med 2001; 344:395– 402 7 Arrowsmith JE, Grocott HP, Reves JG, et al. Central nervous system complications of cardiac surgery. Br J Anaesth 2000; 84:378 –393 8 Hornick P, Smith PL, Taylor KM, et al. Cerebral complications after coronary bypass grafting. Curr Opin Cardiol 1994; 9:670 – 679 9 Rasmussen LS, Moller JT. Central nervous system dysfunction after anesthesia in the geriatric patient. Anesthesiol Clin North Am 2000; 18:59 –70 10 Bekker AY, Weeks EJ. Cognitive function after anaesthesia in the elderly. Best Pract Res Clin Anaesthesiol 2003; 17:259 – 272 11 Selnes OA, Grega MA, Borowicz LM Jr, et al. Cognitive changes with coronary artery disease: a prospective study of coronary artery bypass graft patients and nonsurgical controls. Ann Thorac Surg 2003; 75:1377–1384; discussion 1384 –1386 12 Schmidt R, Fazekas F, Offenbacher H, et al. Brain magnetic resonance imaging in coronary artery bypass grafts: a pre- and postoperative assessment. Neurology 1993; 43:775–778 13 Harris DN, Bailey SM, Smith PL, et al. Brain swelling in first

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Postoperative Cognitive Dysfunction After Cardiac Surgery Lan Gao, Rame Taha, Dominique Gauvin, Lamia B. Othmen, Yang Wang and Gilbert Blaise Chest 2005;128;3664-3670 DOI: 10.1378/chest.128.5.3664 This information is current as of February 28, 2006 Updated Information & Services

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