Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery

Jan Hirsch, Susana Vacas, Niccolo Terrando, Miao Yuan, Laura P Sands, Joel Kramer, Kevin Bozic, Mervyn M Maze, Jacqueline M Leung, Jan Hirsch, Susana Vacas, Niccolo Terrando, Miao Yuan, Laura P Sands, Joel Kramer, Kevin Bozic, Mervyn M Maze, Jacqueline M Leung

Abstract

Background: Postoperative delirium is prevalent in older patients and associated with worse outcomes. Recent data in animal studies demonstrate increases in inflammatory markers in plasma and cerebrospinal fluid (CSF) even after aseptic surgery, suggesting that inflammation of the central nervous system may be part of the pathogenesis of postoperative cognitive changes. We investigated the hypothesis that neuroinflammation was an important cause for postoperative delirium and cognitive dysfunction after major non-cardiac surgery.

Methods: After Institutional Review Board approval and informed consent, we recruited patients undergoing major knee surgery who received spinal anesthesia and femoral nerve block with intravenous sedation. All patients had an indwelling spinal catheter placed at the time of spinal anesthesia that was left in place for up to 24 h. Plasma and CSF samples were collected preoperatively and at 3, 6, and 18 h postoperatively. Cytokine levels were measured using ELISA and Luminex. Postoperative delirium was determined using the confusion assessment method, and cognitive dysfunction was measured using validated cognitive tests (word list, verbal fluency test, digit symbol test).

Results: Ten patients with complete datasets were included. One patient developed postoperative delirium, and six patients developed postoperative cognitive dysfunction. Postoperatively, at different time points, statistically significant changes compared to baseline were present in IL-5, IL-6, I-8, IL-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, IL-6/IL-10, and receptor for advanced glycation end products in plasma and in IFN-γ, IL-6, IL-8, IL-10, MCP-1, MIP-1α, MIP-1β, IL-8/IL-10, and TNF-α in CSF.

Conclusions: Substantial pro- and anti-inflammatory activity in the central neural system after surgery was found. If confirmed by larger studies, persistent changes in cytokine levels may serve as biomarkers for novel clinical trials.

Keywords: Blood-brain barrier; Delirium; Immune response; Surgery.

Figures

Fig. 1
Fig. 1
Time course of inflammatory markers MCP-1, interleukins 6 and 8, and tumor necrosis factor α over the perioperative period shows increased CSF levels in some patients. Of these, NIP 6 is the patient who developed postoperative delirium, NIP 3, 5, 8, and 9 developed POCD. Conversely, NIP 4 and 10 had no increase in these cytokines while developing POCD
Fig. 2
Fig. 2
Left Column: Calculated difference between postoperative measurements and baseline measurements for plasma IL-5 and IL-8, plotted separately for patients with and without postoperative delirium and POCD. There was a significant difference in the sub-analyses at baseline vs. 18 h for IL-5 in the subjects with postoperative delirium or POCD and baseline vs. 6 and 18 h for IL-8 (see Table 2) in both groups. Right Column: The measured concentrations for both cytokines, as well plotted separately, for patients with and without POCD/delirium

References

    1. Fong TG, Tulebaev SR, Inouye SK. Delirium in elderly adults: diagnosis, prevention and treatment. Nat Rev Neurol. 2009;5:210–20. doi: 10.1038/nrneurol.2009.24.
    1. Deiner S, Silverstein JH. Postoperative delirium and cognitive dysfunction. Br J Anaesth. 2009;103(Suppl 1):i41–6. doi: 10.1093/bja/aep291.
    1. Terrando N, Brzezinski M, Degos V, et al. Perioperative cognitive decline in the aging population. Mayo Clin Proc. 2011;86:885–93. doi: 10.4065/mcp.2011.0332.
    1. Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology. 2008;108:18–30. doi: 10.1097/01.anes.0000296071.19434.1e.
    1. 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;351:857–61. doi: 10.1016/S0140-6736(97)07382-0.
    1. Johnson T, Monk T, Rasmussen LS, et al. Postoperative cognitive dysfunction in middle-aged patients. Anesthesiology. 2002;96:1351–7. doi: 10.1097/00000542-200206000-00014.
    1. Ehlenbach WJ, Hough CL, Crane PK, et al. Association between acute care and critical illness hospitalization and cognitive function in older adults. JAMA. 2010;303:763–70. doi: 10.1001/jama.2010.167.
    1. Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004;32:955–62. doi: 10.1097/01.CCM.0000119429.16055.92.
    1. Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS. Long-term consequences of postoperative cognitive dysfunction. Anesthesiology. 2009;110:548–55. doi: 10.1097/ALN.0b013e318195b569.
    1. Kobbe P, Vodovotz Y, Kaczorowski DJ, Mollen KP, Billiar TR, Pape HC. Patterns of cytokine release and evolution of remote organ dysfunction after bilateral femur fracture. Shock. 2008;30:43–7. doi: 10.1097/SHK.0b013e31815d190b.
    1. Terrando N, Yang T, Ryu JK, et al. Stimulation of the alpha7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice. Mol Med. 2014;20:667–75.
    1. Cibelli M, Fidalgo AR, Terrando N, et al. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol. 2010;68:360–8. doi: 10.1002/ana.22082.
    1. Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci U S A. 2010;107:20518–22. doi: 10.1073/pnas.1014557107.
    1. Terrando N, Eriksson LI, Ryu JK, et al. Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol. 2011;70:986–95. doi: 10.1002/ana.22664.
    1. Lehnardt S, Massillon L, Follett P, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A. 2003;100:8514–9. doi: 10.1073/pnas.1432609100.
    1. Vacas S, Degos V, Tracey KJ, et al. High-mobility group box 1 protein initiates postoperative cognitive decline by engaging bone marrow-derived macrophages. Anesthesiology. 2014;120(5):1160–67.
    1. Rosczyk HA, Sparkman NL, Johnson RW. Neuroinflammation and cognitive function in aged mice following minor surgery. Exp Gerontol. 2008;43:840–6. doi: 10.1016/j.exger.2008.06.004.
    1. Degos V, Maze M, Vacas S, et al. Bone fracture exacerbates murine ischemic cerebral injury. Anesthesiology. 2013;118:1362–72. doi: 10.1097/ALN.0b013e31828c23f8.
    1. Beloosesky Y, Hendel D, Weiss A, et al. Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. J Gerontol A Biol Sci Med Sci. 2007;62:420–6. doi: 10.1093/gerona/62.4.420.
    1. MacLullich AM, Edelshain BT, Hall RJ, et al. Cerebrospinal fluid interleukin-8 levels are higher in people with hip fracture with perioperative delirium than in controls. J Am Geriatr Soc. 2011;59:1151–3. doi: 10.1111/j.1532-5415.2011.03428.x.
    1. Chuang D, Power SE, Dunbar PR, Hill AG. Central nervous system interleukin-8 production following neck of femur fracture. ANZ J Surg. 2005;75:813–6. doi: 10.1111/j.1445-2197.2005.03530.x.
    1. Anckarsater R, Vasic N, Jideus L, et al. Cerebrospinal fluid protein reactions during non-neurological surgery. Acta Neurol Scand. 2007;115:254–9. doi: 10.1111/j.1600-0404.2006.00741.x.
    1. Bromander S, Anckarsater R, Kristiansson M, et al. Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study. J Neuroinflammation. 2012;9:242. doi: 10.1186/1742-2094-9-242.
    1. Tang JX, Baranov D, Hammond M, Shaw LM, Eckenhoff MF, Eckenhoff RG. Human Alzheimer and inflammation biomarkers after anesthesia and surgery. Anesthesiology. 2011;115:727–32. doi: 10.1097/ALN.0b013e31822e9306.
    1. Buvanendran A, Kroin JS, Berger RA, et al. Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology. 2006;104:403–10. doi: 10.1097/00000542-200603000-00005.
    1. Anckarsater R, Anckarsater H, Bromander S, Blennow K, Wass C, Zetterberg H. Non-neurological surgery and cerebrospinal fluid biomarkers for neuronal and astroglial integrity. J Neural Transm. 2014;121:649–53. doi: 10.1007/s00702-013-1156-0.
    1. Tateno F, Sakakibara R, Kishi M, Ogawa E. Bupivacaine-induced chemical meningitis. J Neurol. 2010;257:1327–9. doi: 10.1007/s00415-010-5522-7.
    1. Santos MC, de Albuquerque BC, Monte RL, Filho GG, Alecrim M. Outbreak of chemical meningitis following spinal anesthesia caused by chemically related bupivacaine. Infect Control Hosp Epidemiol. 2009;30:922–4. doi: 10.1086/599358.
    1. Sinclair R, Eriksson AS, Gretzer C, Cassuto J, Thomsen P. Inhibitory effects of amide local anaesthetics on stimulus-induced human leukocyte metabolic activation, LTB4 release and IL-1 secretion in vitro. Acta Anaesthesiol Scand. 1993;37:159–65. doi: 10.1111/j.1399-6576.1993.tb03693.x.
    1. Huang YH, Tsai PS, Huang CJ. Bupivacaine inhibits COX-2 expression, PGE2, and cytokine production in endotoxin-activated macrophages. Acta Anaesthesiol Scand. 2008;52:530–5. doi: 10.1111/j.1399-6576.2008.01590.x.
    1. Block L, Jorneberg P, Bjorklund U, Westerlund A, Biber B, Hansson E. Ultralow concentrations of bupivacaine exert anti-inflammatory effects on inflammation-reactive astrocytes. Eur J Neurosci. 2013;38:3669–78. doi: 10.1111/ejn.12364.
    1. Bijur PE, Latimer CT, Gallagher EJ. Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department. Acad Emerg Med. 2003;10:390–2. doi: 10.1111/j.1553-2712.2003.tb01355.x.
    1. Youngblom E, DePalma G, Sands L, Leung J. The temporal relationship between early postoperative delirium and postoperative cognitive dysfunction in older patients: a prospective cohort study. Can J Anaesth. 2014;61:1084–92. doi: 10.1007/s12630-014-0242-6.
    1. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990;113:941–8. doi: 10.7326/0003-4819-113-12-941.
    1. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166:1338–44. doi: 10.1164/rccm.2107138.
    1. Teng EL, Wimer C, Roberts E, et al. Alzheimer's dementia: performance on parallel forms of the dementia assessment battery. J Clin Exp Neuropsychol. 1989;11:899–912. doi: 10.1080/01688638908400943.
    1. Wechsler D. Wechsler adult intelligence scale—revised, Harcourt Brace Jovanovich [for] Psychological Cor. 1981.
    1. Wang Y, Sands LP, Vaurio L, Mullen EA, Leung JM. The effects of postoperative pain and its management on postoperative cognitive dysfunction. Am J Geriatr Psychiatry. 2007;15:50–9. doi: 10.1097/01.JGP.0000229792.31009.da.
    1. Kackar RN, Harville DA. Approximations for standard errors of estimators of fixed and random effects in mixed linear models. J Am Stat Assoc. 1984;79:853–62.
    1. Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum likelihood. Biometrics. 1997;53:983–97. doi: 10.2307/2533558.
    1. Vacas S, Degos V, Tracey KJ, Maze M. High-mobility group box 1 protein initiates postoperative cognitive decline by engaging bone marrow-derived macrophages. Anesthesiology. 2014;120:1160–7. doi: 10.1097/ALN.0000000000000045.
    1. Hauser CJ, Sursal T, Rodriguez EK, Appleton PT, Zhang Q, Itagaki K. Mitochondrial damage associated molecular patterns from femoral reamings activate neutrophils through formyl peptide receptors and P44/42 MAP kinase. J Orthop Trauma. 2010;24:534–8. doi: 10.1097/BOT.0b013e3181ec4991.
    1. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7. doi: 10.1038/nature08780.
    1. Peng L, Xu L, Ouyang W. Role of peripheral inflammatory markers in postoperative cognitive dysfunction (POCD): a meta-analysis. PLoS One. 2013;8 doi: 10.1371/journal.pone.0079624.
    1. Terrando N, Monaco C, Feldmann M, Maze M. Unraveling the interactions between postoperative infection, surgery, and inflammation in post-operative cognitive dysfunction. Helsinki, Finland: European Journal of Anaesthesiology, Euroanesthesia; 2010. pp. 1–2.
    1. Degos V, Vacas S, Han Z, et al. Depletion of bone marrow-derived macrophages perturbs the innate immune response to surgery and reduces postoperative memory dysfunction. Anesthesiology. 2013;118:527–36. doi: 10.1097/ALN.0b013e3182834d94.
    1. van Rossum D, Hanisch UK. Microglia. Metab Brain Dis. 2004;19:393–411. doi: 10.1023/B:MEBR.0000043984.73063.d8.
    1. Vacas S, Degos V, Feng X, Maze M. The neuroinflammatory response of postoperative cognitive decline. Br Med Bull. 2013;106:161–78. doi: 10.1093/bmb/ldt006.
    1. Niederkorn JY. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat Immunol. 2006;7:354–9. doi: 10.1038/ni1328.
    1. Baune BT, Ponath G, Golledge J, et al. Association between IL-8 cytokine and cognitive performance in an elderly general population—the MEMO study. Neurobiol Aging. 2008;29:937–44. doi: 10.1016/j.neurobiolaging.2006.12.003.
    1. Beloeil H, Asehnoune K, Moine P, Benhamou D, Mazoit JX. Bupivacaine's action on the carrageenan-induced inflammatory response in mice: cytokine production by leukocytes after ex-vivo stimulation. Anesth Analg. 2005;100:1081–6. doi: 10.1213/01.ANE.0000146964.05212.65.
    1. Lai LT, Trooboff S, Morgan MK, Harvey RJ. The risk of meningitis following expanded endoscopic endonasal skull base surgery: a systematic review. J Neurol Surg B Skull Base. 2014;75:18–26.
    1. Soler ZM, Schlosser RJ. Spontaneous cerebrospinal fluid leak and management of intracranial pressure. Adv Otorhinolaryngol. 2013;74:92–103.
    1. Felisati G, Bianchi A, Lozza P, Portaleone S. Italian multicentre study on intrathecal fluorescein for craniosinusal fistulae. Acta Otorhinolaryngol Ital. 2008;28:159–63.
    1. Cape E, Hall RJ, van Munster BC, et al. Cerebrospinal fluid markers of neuroinflammation in delirium: a role for interleukin-1beta in delirium after hip fracture. J Psychosom Res. 2014;77:219–25. doi: 10.1016/j.jpsychores.2014.06.014.
    1. Trzepacz PT. The delirium rating scale. Its use in consultation-liaison research. Psychosomatics. 1999;40:193–204. doi: 10.1016/S0033-3182(99)71235-1.
    1. Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology. 2007;68:666–9. doi: 10.1212/01.wnl.0000256043.50901.e3.
    1. Ozkan D, Akkaya T, Yalcindag A, et al. Propofol sedation in total knee replacement : effects on oxidative stress and ischemia-reperfusion damage. Anaesthesist. 2013;62:537–42. doi: 10.1007/s00101-013-2192-8.
    1. Hughes SF, Hendricks BD, Edwards DR, Bastawrous SS, Middleton JF. Lower limb orthopaedic surgery results in changes to coagulation and non-specific inflammatory biomarkers, including selective clinical outcome measures. Eur J Med Res. 2013;18:40. doi: 10.1186/2047-783X-18-40.
    1. Hirota K, Hashimoto H, Tsubo T, Ishihara H, Matsuki A. Quantification and comparison of pulmonary emboli formation after pneumatic tourniquet release in patients undergoing reconstruction of anterior cruciate ligament and total knee arthroplasty. Anesth Analg. 2002;94:1633–8.
    1. Wakai A, Wang JH, Winter DC, Street JT, O'Sullivan RG, Redmond HP. Tourniquet-induced systemic inflammatory response in extremity surgery. J Trauma. 2001;51:922–6. doi: 10.1097/00005373-200111000-00016.
    1. Parmet JL, Berman AT, Horrow JC, Harding S, Rosenberg H. Thromboembolism coincident with tourniquet deflation during total knee arthroplasty. Lancet. 1993;341:1057–8. doi: 10.1016/0140-6736(93)92414-O.
    1. Cheng K, Giebaly D, Campbell A, Rumley A, Lowe G. Systemic effects of polymethylmethycrylate in total knee replacement: a prospective case-control study. Bone Joint Res. 2014;3:108–16. doi: 10.1302/2046-3758.34.2000230.
    1. He HJ, Wang Y, Le Y, et al. Surgery upregulates high mobility group box-1 and disrupts the blood-brain barrier causing cognitive dysfunction in aged rats. CNS Neurosci Ther. 2012;18:994–1002. doi: 10.1111/cns.12018.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅