European Journal of Anaesthesiology:
Neuroinflammation and postoperative cognitive dysfunction: can anaesthesia be therapeutic?
Sanders, Robert D; Maze, Mervyn
Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, UK
Received 4 August, 2009
Accepted 4 August, 2009
Correspondence to Dr Robert D. Sanders, BSc, MBBS, FRCA, Academic Clinical Fellow and Medical Research Council Clinical Training Fellow, Department of Anaesthetics, Intensive Care and Pain Medicine, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK Tel: +44 2087468816; e-mail: email@example.com
Postoperative cognitive dysfunction (POCD) is an important complication of major surgery that predisposes to an increased risk of perioperative mortality and premature unemployment [1–5]. Although first recognized following cardiac surgery, in which 20–40% of patients are affected, long-term POCD also occurs after noncardiac surgery affecting more than 10% of patients greater than 60 years old . In cardiac surgery, hypoperfusion, cerebral embolism, atrial fibrillation, previous cerebral injury or impairment of cognition as well as the systemic inflammatory response have been implicated in the development of POCD . Risk factors for noncardiac surgical POCD include increasing age, duration of anaesthesia, previous cerebrovascular injury , paucity of higher education, a second operation, postoperative respiratory complications and infections . Despite differing cited causes, both forms of POCD involve surgical stimulation, with incipient neuroinflammatory consequences , in an elderly patient; known risk factors such as cerebrovascular injury  or further operations and infective complications  could predispose to, or exacerbate, a cognitive vulnerability to neuroinflammation. In a previously published issue of the European Journal of Anaesthesiology, Zhu et al.  provided fascinating preliminary evidence that myocardial ischaemia may contribute to the development of impaired cognitive function, via neuroinflammation, in an animal model of cardiac POCD.
Using in-vivo coronary artery ischaemia, following surgical thoracotomy in rats, the authors studied whether surgery or surgery along with myocardial ischaemia affected the induction of long-term potentiation (LTP), an electrophysiological surrogate of memory formation, in the hippocampus in vivo. The authors also measured mRNA levels of inflammatory cytokines in the hippocampus and correlated the observed changes in LTP with increased neuroinflammation. Their conclusion that myocardial ischaemia may be associated with the development of impaired cognition appears consistent with clinical studies showing association between atherosclerosis and cognitive decline in humans . Of course, in the animal model, rats do not have comorbidities prior to the insult unlike the typical patients who sustain myocardial ischaemia. Nonetheless, this study does indicate that acute organ ischaemia can induce inflammatory changes in the brain that may contribute to impaired hippocampal function. Although this is a fascinating finding, this first report remains far removed from clinical practice. Firstly, as the authors concede, the use of LTP is not equivalent to tests of cognitive dysfunction, and this requires direct testing after induced myocardial ischaemia in animals. Secondly, although systemic haemodynamics were unaltered by the insult, direct assessment of cerebral perfusion was not assessed, and, therefore, the changes in LTP could still represent a direct cerebral effect . Thirdly, although plausible , causal association between the neuroinflammatory response and changes in LTP was not definitively proven.
Myocardial injury and neuroinflammation
The possibility that myocardial ischaemia could induce cognitive impairments is intriguing, if not entirely novel. Induced renal (but not liver) ischaemia has been shown to produce neuromotor impairment in mice ; interestingly, this correlated with neuroinflammatory changes similar to the observations presented by Zhu et al.  and in other animal models of POCD . Although Zhu et al.  focus on the impact that myocardial ischaemia may confer to POCD, the importance of any association between myocardial injury and cognitive function may go beyond the boundaries of the operating room to affect patients undergoing acute coronary syndromes in all environments. Therefore, the hypothesis that myocardial ischaemia is associated with the production of cognitive deficits warrants further investigation, especially given the support from cohort studies .
Remote organ injury
The concept of an injury to one organ producing an injury in another is not new; however, little is known about the mechanisms involved. Studying how renal injury induces pulmonary  or brain dysfunction  or how liver injury induces renal failure  will likely identify novel therapeutic targets that may be modifiable to prevent remote organ injury. The same rationale could be applied to the development of therapeutics to stop the elaboration of multiple organ failure in traumatic, burn or septic injury. Multiple possible mechanisms may be involved in producing remote organ injury, although accumulating evidence suggests a prominent role for the immune system [10–12]. Indeed, acute kidney injury upregulates proinflammatory and proapoptotic markers in the lung ; likewise, liver ischaemia reperfusion injury induces similar changes in the kidney , adding to the evidence that myocardial ischaemia induces inflammatory changes in the brain . Whether enough can be learned of the immunological and other possible effectors involved to prevent remote organ injury remains to be seen.
Postoperative cognitive dysfunction and surgery
Interestingly, in the model by Zhu et al. , the surgical insult, thoracotomy, did not induce a neuroinflammatory response or changes in LTP. This appears to contradict our recent work demonstrating that splenectomy  or tibial surgery  induces neuroinflammation with direct effects on animal cognition. Multiple reasons may explain this discordance; species differences and the sensitivity of the cytokine assays used may explain differences in the inflammatory markers, and while we used cognitive dysfunction, the authors used LTP as a surrogate marker of memory formation. It is certainly possible that effects on LTP in one brain region insufficiently model the more global cognitive effects on these animals, only identifying severe insults. Despite these differences, this work adds further credence to the working hypothesis that neuroinflammation is causally associated with the development of POCD. We have now demonstrated using two surgical models that animal POCD is associated with exposure to surgery and anaesthesia, and that this correlates with changes in inflammatory cytokines, including changes in interleukin (IL)-1β; furthermore, POCD is reduced with treatment with an antagonist of the IL-1 receptor [6,13]. As systemic IL-1β (among other cytokines) is measurable after myocardial infarction , systemic IL-1β may underlie the cognitive dysfunction observable in both Zhu et al.  and our model.
Could anaesthesia be protective against postoperative cognitive dysfunction?
Zhu et al.  also demonstrated that sevoflurane is able to precondition against both the inflammatory changes and impairment of LTP. Although it is unclear how sevoflurane achieved this benefit and whether this involved cardiac, neuronal or immunological targets, the anti-inflammatory effects of volatile anaesthetics are increasingly recognized . Sevoflurane has been shown to be able to precondition a wide variety of organs, including cardiac , liver , brain  and kidney , against various insults, with the suppression of inflammatory responses commonly cited as a potential mechanism of protection . However, it should be noted that sevoflurane also appears to protect against direct cellular injury . Translation to the clinical arena may yet be premature; the present data from cardiac surgery do not indicate that widespread adoption of preconditioning therapy for organ protection is warranted. De Hert et al.  demonstrated that administration of sevoflurane throughout cardiac surgery is more effective at cardiac protection than merely preconditioning with sevoflurane prior to the case [with anaesthetic maintenance with total intravenous anaesthesia (TIVA)]. Therefore, it appears that, to gain maximum benefit from the organ-protective properties of volatile anaesthetics, they should be administered throughout the insult and not just prior to the insult. Whether there is a case for continuing administration of volatile anaesthetics postoperatively for high-risk surgery, similar to prolonged hypothermic therapy , requires investigation.
Anaesthesia and postoperative cognitive dysfunction: a double-edged sword?
We must balance these potential benefits from the organ-protective and anti-inflammatory effects of volatile anaesthetics against any contribution to POCD. Although data so far suggest that anaesthetics do not appear to induce cognitive dysfunction in our model [6,13], volatile anaesthetic-induced cognitive impairment has been noted in young  and adult animals , though enhanced cognitive function  has also been reported. Therefore, in preclinical models, the contribution of volatile anaesthesia to POCD is unclear. Unfortunately, a clinical study into the effects of general versus regional anaesthesia in POCD was inconclusive due to premature cessation of the trial due to increased mortality in the general anaesthesia group, though a trend to improved cognition was noted in the regional anaesthesia group at 1 week but not at 3 months . Systematic review has been unable to discover any association between general anaesthesia and POCD ; that is not to say that it does not exist, but any link is yet to be identified. Could an anaesthetic be therapeutic for POCD? Possibly, an anaesthetic that inhibits various forms of injury may be therapeutic. Sevoflurane [15–20] and xenon  are good examples of organ-protective anaesthetics that may be useful in this context. Adjunctive therapies such as minocycline  or dexmedetomidine  may also have a role, but none of these agents have an evidence base indicating widespread clinical adoption.
The study in this issue of the European Journal of Anaesthesiology by Zhu et al.  is fascinating and has highlighted the potential for myocardial ischaemia to induce changes in cognition. If supported by further, in depth, preclinical and clinical work, this finding may have an impact across the spectrum of medical and surgical patients, from surgical intensive care to chronic cardiac therapies in the community. Furthermore, the authors have leant further credence to our working hypothesis that POCD has a significant inflammatory component; we hope that, by targeting the effectors in this process, we may identify therapeutics to inhibit the formation of POCD. Finally, the authors have shown the potential of sevoflurane preconditioning to combat this injury. Although the application of volatile anaesthetics for organ protection, including as a therapy for POCD in high-risk surgery, still requires evaluation, the balance between the protective and toxic qualities of different anaesthetics remains ill defined.
Professor Maze has acted as a paid consultant for Air Products, Allentown, Pennsylvania, and both Professor Maze and Dr Sanders have acted in this capacity for Air Liquide Sante International, Paris, France. In addition, Dr Sanders has received an unrestricted travel grant from BOC Ltd, Guildford, UK, to attend the World Congress in Anaesthesia. Air Products and BOC Ltd have funded and continue to fund work in these authors' laboratories. Professor Maze has been a consultant for Abbott Laboratories, Abbott Park, Illinois, USA, to facilitate registration of dexmedetomidine in the United States.
Support was provided solely from institutional and/or departmental sources.
1 Newman MF, Kirchner JL, Phillips-Bute B, et al, Neurological Outcome Research Group and the Cardiothoracic Anesthesiology Research Endeavors Investigators. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 2001; 344:395–402.
2 Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 1998; 351:857–861.
3 Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008; 108:18–30.
4 Steinmetz J, Christensen KB, Lund T, et al, ISPOCD Group. Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 2009; 110:548–555.
5 Newman MF, Mathew JP, Grocott HP, et al. Central nervous system injury associated with cardiac surgery. Lancet 2006; 368:694–703.
6 Wan Y, Xu J, Ma D, et al. Postoperative impairment of cognitive function in rats: a possible role for cytokine-mediated inflammation in the hippocampus. Anesthesiology 2007; 106:436–443.
7 Zhu J, Jiang X, Shi E, et al. Sevoflurane preconditioning reverses impairment of hippocampal long-term potentiation induced by myocardial ischaemia–reperfusion injury. Eur J Anaesthesiol 2009; 26:961–968.
8 Vinkers DJ, Stek ML, van der Mast RC, et al. Generalized atherosclerosis, cognitive decline, and depressive symptoms in old age. Neurology 2005; 65:107–112.
9 Calabresi P, Saulle E, Centonze D, et al. Postischaemic long-term synaptic potentiation in the striatum: a putative mechanism for cell type-specific vulnerability. Brain 2002; 125:844–860.
10 Liu M, Liang Y, Chigurupati S, et al. Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol 2008; 19:1360–1370.
11 Hassoun HT, Lie ML, Grigoryev DN, et al. Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis. Am J Physiol Renal Physiol 2009; 297:F125–F137.
12 Lee HT, Park SW, Kim M, D'Agati VD. Acute kidney injury after hepatic ischemia and reperfusion injury in mice. Lab Invest 2009; 89:196–208.
13 Cibelli M, Ma D, Rei Fidalgo A, et al. Microglial activation in the hippocampus is related to postoperative cognitive dysfunction in mice. Anesthesiology 2008; 109:A21.
14 Guillen I, Blanes M, Gomez-Lechon MJ, Castell JV. Cytokine signaling during myocardial infarction: sequential appearance of IL-1 beta and IL-6. Am J Physiol 1995; 269:R229–R235.
15 Zhong C, Zhou Y, Liu H. Nuclear factor kappaB and anesthetic preconditioning during myocardial ischemia-reperfusion. Anesthesiology 2004; 100:540–546.
16 Frässdorf J, Borowski A, Ebel D, et al. Impact of preconditioning protocol on anesthetic-induced cardioprotection in patients having coronary artery bypass surgery. J Thorac Cardiovasc Surg 2009; 137:1436–1442.
17 Beck-Schimmer B, Breitenstein S, Urech S, et al. A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic. Ann Surg 2008; 248:909–918.
18 Luo Y, Ma D, Ieong E, et al. Xenon and sevoflurane protect against brain injury in a neonatal asphyxia model. Anesthesiology 2008; 109:782–789.
19 Julier K, da Silva R, Garcia C, et al. Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: a double-blinded, placebo-controlled, multicenter study. Anesthesiology 2003; 98:1315–1327.
20 De Hert SG, Van der Linden PJ, Cromheecke S, et al. Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration. Anesthesiology 2004; 101:299–310.
21 de Lange F, Jones WL, Mackensen GB, Grocott HP. The effect of limited rewarming and postoperative hypothermia on cognitive function in a rat cardiopulmonary bypass model. Anesth Analg 2008; 106:739–744.
22 Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23:876–882.
23 Culley DJ, Baxter MG, Yukhananov R, Crosby G. Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats. Anesthesiology 2004; 100:309–314.
24 Rammes G, Starker LK, Haseneder R, et al. Isoflurane anaesthesia reversibly improves cognitive function and long-term potentiation (LTP) via an up-regulation in NMDA receptor 2B subunit expression. Neuropharmacology 2009; 56:626–636.
25 Rasmussen LS, Johnson T, Kuipers HM, et al, ISPOCD2 (International Study of Postoperative Cognitive Dysfunction) Investigators. Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiol Scand 2003; 47:260–266.
26 Newman S, Stygall J, Hirani S, et al. Postoperative cognitive dysfunction after noncardiac surgery: a systematic review. Anesthesiology 2007; 106:572–590.
27 Sanders RD, Ju X, Shu Y, et al. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology 2009; 110:1077–1085.
This article has been cited 1 time(s).
Journal of Huazhong University of Science and Technology-Medical SciencesRole of GSK-3 beta in Isoflurane-induced Neuroinflammation and Cognitive Dysfunction in Aged RatsJournal of Huazhong University of Science and Technology-Medical Sciences
© 2010 European Society of Anaesthesiology