Journal of Anesthesia

, Volume 25, Issue 1, pp 1–9

Elevated postoperative inflammatory biomarkers are associated with short- and medium-term cognitive dysfunction after coronary artery surgery

  • Judith A. Hudetz
  • Sweeta D. Gandhi
  • Zafar Iqbal
  • Kathleen M. Patterson
  • Paul S. Pagel
Original Article

Abstract

Purpose

We tested the hypothesis that elevated postoperative interleukin-6 (IL-6) and C-reactive protein (CRP) concentrations are associated with short- and medium-term impairment of cognitive functions in patients after coronary artery surgery using cardiopulmonary bypass.

Methods

Eighty-six age- and education-balanced patients ≥55 years of age undergoing elective coronary artery bypass surgery with cardiopulmonary bypass and 28 nonsurgical controls with coronary artery disease were enrolled. Recent verbal and nonverbal memory and executive functions were assessed before surgery and at 1 week and 3 months after surgery using a cognitive test battery. IL-6 concentrations were measured before surgery and 4 h after cardiopulmonary bypass, and CRP concentrations were measured before surgery and at 24 and 72 h after anesthetic induction. Overall cognitive function between high and low biomarker concentration groups was analyzed by the Wilcoxon rank-sum test.

Results

Recent memory was at least 1 standard deviation (SD) impaired at 1 week and 3 months in the high-CRP compared with low-CRP and in the high-IL-6 compared with low-IL-6 concentration groups. Overall cognitive function was significantly (P = 0.04 and P = 0.01, respectively) different between the high- and low-CRP concentration groups (CRP assayed 24 h after anesthetic induction) at both 1 week and 3 months. Overall cognitive function was also significantly (P = 0.04) different between the high- and low-IL-6 concentration groups at 1 week after surgery.

Conclusion

The results suggest that elevated postoperative IL-6 and CRP concentrations are associated with the subsequent development of short- and medium-term impairment of cognitive functions after coronary artery surgery.

Keywords

C-reactive protein Interleukin-6 Coronary artery bypass graft Cardiopulmonary bypass Postoperative cognitive dysfunction 

References

  1. 1.
    Newman MF, Kirchner JL, Phillips-Bute B, Gaver V, Grocott H, Jones RH, Mark DB, Reves JG, Blumenthal JA. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med. 2001;344(6):395–402.CrossRefPubMedGoogle Scholar
  2. 2.
    Selnes OA, Goldsborough MA, Borowicz LM, McKhann GM. Neurobehavioural sequelae of cardiopulmonary bypass. Lancet. 1999;353(9164):1601–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Bedford PD. Adverse cerebral effects of anaesthesia on old people. Lancet. 1955;269(6884):259–63.CrossRefPubMedGoogle Scholar
  4. 4.
    Phillips-Bute B, Mathew JP, Blumenthal JA, Grocott HP, Laskowitz DT, Jones RH, Mark DB, Newman MF. Association of neurocognitive function and quality of life 1 year after coronary artery bypass graft (CABG) surgery. Psychosom Med. 2006;68(3):369–75.CrossRefPubMedGoogle Scholar
  5. 5.
    Rasmussen LS, Christiansen M, Hansen PB, Moller JT. Do blood levels of neuron-specific enolase and S-100 protein reflect cognitive dysfunction after coronary artery bypass? Acta Anaesthesiol Scand. 1999;43(5):495–500.CrossRefPubMedGoogle Scholar
  6. 6.
    Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Biedler A, van Beem H, Fraidakis O, Silverstein JH, Beneken JE, Gravenstein JS. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998;351(9106):857–61.CrossRefPubMedGoogle Scholar
  7. 7.
    Wilmore DW, Kehlet H. Management of patients in fast track surgery. BMJ. 2001;322(7284):473–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Marshall SI, Chung F. Discharge criteria and complications after ambulatory surgery. Anesth Analg. 1999;88(3):508–17.CrossRefPubMedGoogle Scholar
  9. 9.
    Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N, Wolman R, Aggarwal A, Marschall K, Graham SH, Ley C. 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(25):1857–63.CrossRefPubMedGoogle Scholar
  10. 10.
    Ancelin ML, de Roquefeuil G, Ledesert B, Bonnel F, Cheminal JC, Ritchie K. Exposure to anaesthetic agents, cognitive functioning and depressive symptomatology in the elderly. Br J Psychiatry. 2001;178:360–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Hudetz JA, Iqbal Z, Gandhi SD, Patterson KM, Hyde TF, Reddy DM, Hudetz AG, Warltier DC. Postoperative cognitive dysfunction in older patients with a history of alcohol abuse. Anesthesiology. 2007;106(3):423–30.CrossRefPubMedGoogle Scholar
  12. 12.
    Cremer J, Martin M, Redl H, Bahrami S, Abraham C, Graeter T, Haverich A, Schlag G, Borst HG. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg. 1996;61(6):1714–20.CrossRefPubMedGoogle Scholar
  13. 13.
    Deng MC, Dasch B, Erren M, Mollhoff T, Scheld HH. Impact of left ventricular dysfunction on cytokines, hemodynamics, and outcome in bypass grafting. Ann Thorac Surg. 1996;62(1):184–90.CrossRefPubMedGoogle Scholar
  14. 14.
    Hennein HA, Ebba H, Rodriguez JL, Merrick SH, Keith FM, Bronstein MH, Leung JM, Mangano DT, Greenfield LJ, Rankin JS. Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Thorac Cardiovasc Surg. 1994;108(4):626–35.PubMedGoogle Scholar
  15. 15.
    Kalman J, Juhasz A, 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 Int. 2006;48(3):177–80.CrossRefPubMedGoogle Scholar
  16. 16.
    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(3):403–10.CrossRefPubMedGoogle Scholar
  17. 17.
    Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007;21(2):153–60.CrossRefPubMedGoogle Scholar
  18. 18.
    Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr, Heimovitz H, Cohen HJ, Wallace R. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106(5):506–12.CrossRefPubMedGoogle Scholar
  19. 19.
    Weaver JD, Huang MH, Albert M, Harris T, Rowe JW, Seeman TE. Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology. 2002;59(3):371–8.PubMedGoogle Scholar
  20. 20.
    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(1):76–80.PubMedGoogle Scholar
  21. 21.
    Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol. 2002;52(2):168–74.CrossRefPubMedGoogle Scholar
  22. 22.
    Rasmussen LS, Larsen K, Houx P, Skovgaard LT, Hanning CD, Moller JT. The assessment of postoperative cognitive function. Acta Anaesthesiol Scand. 2001;45(3):275–89.CrossRefPubMedGoogle Scholar
  23. 23.
    Hachinski V, Munoz D. Vascular factors in cognitive impairment: where are we now? Ann N Y Acad Sci. 2000;903:1–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Benedict HB, Schretlen D, Groninger L, Brandt J. Hopkins verbal learning test—revised: normative data and analysis of inter-form and test–retest reliability. Clin Neuropsychol. 1998;12(1):43–55.Google Scholar
  25. 25.
    Wilson B, Cockburn J, Baddeley A, Hiorns R. The development and validation of a test battery for detecting and monitoring everyday memory problems. J Clin Exp Neuropsychol. 1989;11(6):855–70.CrossRefPubMedGoogle Scholar
  26. 26.
    Delis DC, Kaplan E, Kramer JH. Delis–Kaplan Executive Function System (D-KEFS). San Antonio: The Psychological Corporation; 2001.Google Scholar
  27. 27.
    Benedict RH, Schretlen D, Groninger L, Dobraski M, Shpritz B. Revision of the Brief Visuospatial Memory Test: Studies of normal performance, reliability, and validity. Psychol Assess. 1996;8(2):145–53.CrossRefGoogle Scholar
  28. 28.
    Wechsler DA. Wechsler adult intelligence scale, 3rd edn. San Antonio: The Psychological Corporation; 1997.Google Scholar
  29. 29.
    Randolph C. Repeatable battery for the assessment of neurological status. San Antonio, TX: Psychological Corporation; 1998.Google Scholar
  30. 30.
    Benton AL, Hamsher K. Multilingual aphasia examination. Iowa City, IA: AJA Associates; 1989.Google Scholar
  31. 31.
    Bohnen N, Twijnstra A, Jolles J. Performance in the Stroop color word test in relationship to the persistence of symptoms following mild head injury. Acta Neurol Scand. 1992;85(2):116–21.CrossRefPubMedGoogle Scholar
  32. 32.
    Franke A, Lante W, Fackeldey V, Becker HP, Kurig E, Zoller LG, Weinhold C, Markewitz A. Pro-inflammatory cytokines after different kinds of cardio-thoracic surgical procedures: is what we see what we know? Eur J Cardiothorac Surg. 2005;28(4):569–75.CrossRefPubMedGoogle Scholar
  33. 33.
    Bartoc C, Frumento RJ, Jalbout M, Bennett-Guerrero E, Du E, Nishanian E. A randomized, double-blind, placebo-controlled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients. J Cardiothorac Vasc Anesth. 2006;20(2):217–22.CrossRefPubMedGoogle Scholar
  34. 34.
    Roytblat L, Talmor D, Rachinsky M, Greemberg L, Pekar A, Appelbaum A, Gurman GM, Shapira Y, Duvdenani A. Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg. 1998;87(2):266–71.CrossRefPubMedGoogle Scholar
  35. 35.
    Hudetz JA, Iqbal Z, Gandhi SD, Patterson KM, Byrne AJ, Hudetz AG, Pagel PS, Warltier DC. Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol Scand. 2009;53(7):864–72.CrossRefPubMedGoogle Scholar
  36. 36.
    Newman SP. Analysis and interpretation of neuropsychologic tests in cardiac surgery. Ann Thorac Surg. 1995;59(5):1351–5.CrossRefPubMedGoogle Scholar
  37. 37.
    Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology. 2002;97(1):215–52.CrossRefPubMedGoogle Scholar
  38. 38.
    Xu J, Wen Y, Cibelli M, Ma D, Maze M. Postoperative cognitive dysfunction: a role for cytokine-mediated inflammation in the hippocampus. Anesthesiology. 2006;105:A1175.Google Scholar
  39. 39.
    van der Mast RC. Postoperative delirium. Dement Geriatr Cogn Disord. 1999;10(5):401–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Shalaby MR, Waage A, Aarden L, Espevik T. Endotoxin, tumor necrosis factor-alpha and interleukin 1 induce interleukin 6 production in vivo. Clin Immunol Immunopathol. 1989;53(3):488–98.CrossRefPubMedGoogle Scholar
  41. 41.
    Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med. 1993;119(8):771–8.PubMedGoogle Scholar
  42. 42.
    Cruickshank AM, Fraser WD, Burns HJ, Van Damme J, Shenkin A. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci (Lond). 1990;79(2):161–5.Google Scholar
  43. 43.
    Li JJ, Fang CH. C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases. Med Hypotheses. 2004;62(4):499–506.CrossRefPubMedGoogle Scholar
  44. 44.
    Dijkstra JB, Houx PJ, Jolles J. Cognition after major surgery in the elderly: test performance and complaints. Br J Anaesth. 1999;82(6):867–74.PubMedGoogle Scholar
  45. 45.
    Johnson T, Monk T, Rasmussen LS, Abildstrom H, Houx P, Korttila K, Kuipers HM, Hanning CD, Siersma VD, Kristensen D, Canet J, Ibanaz MT, Moller JT. Postoperative cognitive dysfunction in middle-aged patients. Anesthesiology. 2002;96(6):1351–7.CrossRefPubMedGoogle Scholar
  46. 46.
    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(1):18–30.CrossRefPubMedGoogle Scholar
  47. 47.
    Gunning-Dixon FM, Raz N. Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study. Neuropsychologia. 2003;41(14):1929–41.CrossRefPubMedGoogle Scholar
  48. 48.
    Ihara H, Berrios GE, London M. Group and case study of the dysexecutive syndrome in alcoholism without amnesia. J Neurol Neurosurg Psychiatry. 2000;68(6):731–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Teunissen CE, van Boxtel MP, Bosma H, Bosmans E, Delanghe J, De Bruijn C, Wauters A, Maes M, Jolles J, Steinbusch HW, de Vente J. Inflammation markers in relation to cognition in a healthy aging population. J Neuroimmunol. 2003;134(1-2):142–50.CrossRefPubMedGoogle Scholar
  50. 50.
    Vernaglione L, Cristofano C, Muscogiuri P, Chimienti S. Does atorvastatin influence serum C-reactive protein levels in patients on long-term hemodialysis? Am J Kidney Dis. 2004;43(3):471–8.CrossRefPubMedGoogle Scholar
  51. 51.
    American Heart Association. Heart Disease and Stroke Statistics: 2004 Update. Dallas: American Heart Association; 2003.Google Scholar

Copyright information

© Japanese Society of Anesthesiologists 2010

Authors and Affiliations

  • Judith A. Hudetz
    • 1
    • 2
  • Sweeta D. Gandhi
    • 1
    • 2
  • Zafar Iqbal
    • 1
    • 2
  • Kathleen M. Patterson
    • 1
    • 2
  • Paul S. Pagel
    • 1
    • 2
  1. 1.Department of AnesthesiologyClement J. Zablocki Veterans Administration Medical CenterMilwaukeeUSA
  2. 2.Department of AnesthesiologyMedical College of WisconsinMilwaukeeUSA

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