Dysfunction of the blood-brain barrier in postoperative delirium patients, referring to the axonal damage biomarker phosphorylated neurofilament heavy subunit

Autoři: Kazuhito Mietani aff001;  Masahiko Sumitani aff002;  Toru Ogata aff003;  Nobutake Shimojo aff004;  Reo Inoue aff001;  Hiroaki Abe aff002;  Gaku Kawamura aff001;  Yoshitsugu Yamada aff001
Působiště autorů: Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan aff001;  Department of Pain and Palliative Medicine, The University of Tokyo Hospital, Tokyo, Japan aff002;  Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Saitama, Japan aff003;  Department of Emergency and Critical Care Medicine, Tsukuba University Hospital, Ibaraki, Japan aff004
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0222721



Delirium is the most common postoperative complication of the central nervous system (CNS) that can trigger long-term cognitive impairment. Its underlying mechanism is not fully understood, but the dysfunction of the blood-brain barrier (BBB) has been implicated. The serum levels of the axonal damage biomarker, phosphorylated neurofilament heavy subunit (pNF-H) increase in moderate to severe delirium patients, indicating that postoperative delirium can induce irreversible CNS damage. Here, we investigated the relationship among postoperative delirium, CNS damage and BBB dysfunction, using pNF-H as reference.


Blood samples were collected from 117 patients within 3 postoperative days. These patients were clinically diagnosed with postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit. We measured intercellular adhesion molecule-1, platelet and endothelial cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin as biomarkers for BBB disruption, pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6), and pNF-H. We conducted logistic regression analysis including all participants to identify independent biomarkers contributing to serum pNF-H detection. Next, by multiple regression analysis with a stepwise method we sought to determine which biomarkers influence serum pNF-H levels, in pNF-H positive patients.


Of the 117 subjects, 41 were clinically diagnosed with postoperative delirium, and 30 were positive for serum pNF-H. Sensitivity and specificity of serum pNF-H detection in the patients with postoperative delirium were 56% and 90%, respectively. P-selectin was the only independent variable to associate with pNF-H detection (P < 0.0001) in all 117 patients. In pNF-H positive patients, only PECAM-1 was associated with serum pNF-H levels (P = 0.02).


Serum pNF-H could be an objective delirium biomarker, superior to conventional tools in clinical settings. In reference to pNF-H, P-selectin may be involved in the development of delirium-related CNS damage and PECAM-1 may contribute to the progression of delirium- related CNS damage.

Klíčová slova:

Biomarkers – Central nervous system – Cytokines – Endothelial cells – Immune cells – Regression analysis – Surgical and invasive medical procedures – Cell adhesion


1. Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH: Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med 2009; 180: 1092–7 doi: 10.1164/rccm.200904-0537OC 19745202

2. Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, et al: The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 2001; 27: 1892–1900 doi: 10.1007/s00134-001-1132-2 11797025

3. Milbrandt EB, Deppen S, Harrison PL, Shintani AK, Speroff T, Stiles RA, 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 15071384

4. Franco K, Litaker D, Locala J, Bronson D: The Cost of Delirium in the Surgical Patient. Psychosomatics 2001; 42: 68–73 11161124

5. van Eijk MM, van Marum RJ, Klijn IA, de Wit N, Kesecioglu J, Slooter AJ: Comparison of delirium assessment tools in a mixed intensive care unit. Crit Care Med 2009; 37: 1881–5 doi: 10.1097/CCM.0b013e3181a00118 19384206

6. Gunther ML, Morandi A, Krauskopf E, Pandharipande P, Girard TD, Jackson JC, et al: The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study. Crit Care Med 2012; 40: 2022–32 doi: 10.1097/CCM.0b013e318250acc0 22710202

7. Kline RP, Pirraglia E, Cheng H, Santi SD, Li Y, Haile M, et al: Surgery and Brain Atrophy in Cognitively Normal Elderly Subjects and Subjects Diagnosed with Mild Cognitive Impairment. Anesthesiology 2012; 116: 603–12 doi: 10.1097/ALN.0b013e318246ec0b 22293721

8. Inoue R, Sumitani M, Ogata T, Chikuda H, Matsubara T, Kato S, et al: Direct evidence of central nervous system axonal damage in patients with postoperative delirium: A preliminary study of pNF-H as a promising serum biomarker. Neuroscience Letters 2017; 653: 39–44 28504118

9. Ueno T, Ohori Y, Ito J, Hoshikawa S, Yamamoto S, Nakamura K, et al: Hyperphosphorylated neurofilament NF-H as a biomarker of the efficacy of minocycline therapy for spinal cord injury. Spinal Cord 2011; 49: 333–6 doi: 10.1038/sc.2010.116 20805831

10. Shaw G, Yang C, Ellis R, Anderson K, Mickle JP, Scheff S, et al: Hyperphosphorylated neurofilament NF-H is a serum biomarker of axonal injury. Biochem Biophys Res Commun 2005; 336: 1268–77 doi: 10.1016/j.bbrc.2005.08.252 16176808

11. Saxena S, Maze M: Impact on the brain of the inflammatory response to surgery. Presse Med 2018; 47: e73–81

12. Barr J, Fraser GL, Puntillo K, Wesley Ely E, Gélinas C, Dasta JF, et al: Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41: 263–306 doi: 10.1097/CCM.0b013e3182783b72 23269131

13. de Rooij SE, van Munster BC, Korevaar JC, Levi M: Cytokines and acute phase response in delirium. J Psychosom Res 2007; 62: 521–5 doi: 10.1016/j.jpsychores.2006.11.013 17467406

14. Hughes CG, Pandharipande PP, Thompson JL, Chandrasekhar R, Ware LB, Ely EW, et al: Endothelial activation and blood-brain barrier injury as risk factors for delirium in critically ill patients. Crit Care Med 2016; 44: e809–17 doi: 10.1097/CCM.0000000000001739 27088157

15. Tomasi CD, Vuolo F, Generoso J, Soares M, Barichello T, Quevedo J, et al: Biomarkers of Delirium in a Low-Risk Community-Acquired Pneumonia-Induced Sepsis. Molecular Neurobiology 2017; 54: 722–26 doi: 10.1007/s12035-016-9708-6 26768428

16. Rengel KF, Pandharipande PP, Hughes CG: Postoperative delirium. Presse Med. 2018; 47: e53–64 doi: 10.1016/j.lpm.2018.03.012 29680484

17. Terrando N, Monaco C, Ma D, Foxwell BMJ, Feldmann M, Maze M: Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline. PNAS 2010; 107: 20518–22 doi: 10.1073/pnas.1014557107 21041647

18. Pasternak LR: Preanesthesia evaluation of the surgical patient. ASA Refresher Courses in Anesthesiology 1996; 24: 205–19

19. Schrijver EJ, de Vries OJ, Verburg A, de Graaf K, Bet PM, van de Ven PM, et al: Efficacy and safety of haloperidol prophylaxis for delirium prevention in older medical and surgical at-risk patients acutely admitted to hospital through the emergency department: study protocol of a multicenter, randomised, double-blind, placebo-controlled clinical trial. BMC Geriatrics 2014; 14: 96 doi: 10.1186/1471-2318-14-96 25168927

20. Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, et al: Evaluation of delirium in critically ill patients: Validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001; 29: 1370–9 doi: 10.1097/00003246-200107000-00012 11445689

21. Hayakawa K, Okazaki R, Ishii K, Ueno T, Izawa N, Tanaka Y, et al: Phosphorylated neurofilament subunit NF-H as a biomarker for evaluating the severity of spinal cord injury patients, a pilot study. Spinal Cord 2012; 50: 493–6 doi: 10.1038/sc.2011.184 22270191

22. Hughes CG, Pandharipande PP, Thompson JL, Chandrasekhar R, Ware LB, Ely EW, et al: Endothelial activation and blood-brain barrier injury as risk factors for delirium in critically ill patients. Crit Care Med 2016; 44: e809–17 doi: 10.1097/CCM.0000000000001739 27088157

23. Tomasi CD, Vuolo F, Generoso J, Soares M, Barichello T, Quevedo J, et al: Biomarkers of Delirium in a Low-Risk Community-Acquired Pneumonia-Induced Sepsis. Mol Neurobiol 2017; 54: 722–6 doi: 10.1007/s12035-016-9708-6 26768428

24. Nourshargh S, Alon R: Leukocyte migration into inflamed tissues. Immunity 2014; 41: 694–707 doi: 10.1016/j.immuni.2014.10.008 25517612

25. Scott DW, Patel RP: Endothelial heterogeneity and adhesion molecules N-glycosylation: implications in leukocyte trafficking in inflammation. Glycobiology 2013; 23: 622–33 doi: 10.1093/glycob/cwt014 23445551

26. Vainer B, Nielsen OH: Changed colonic profile of P-selectin, platelet-endothelial cell adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), ICAM-2, and ICAM-3 in inflammatory bowel disease. Clin Exp Immunol 2000; 121: 242–7 doi: 10.1046/j.1365-2249.2000.01296.x 10931137

27. Park OK, Lee CH, Hwang IK, Yoo KY, Choi JH, Won MH: Effects of repeated restraint stress on platelet endothelial cell adhesion molecule-1 immunoreactivity and protein levels in the gerbil hippocampus after transient cerebral ischemia. Anat Cell Biol 2010; 43: 54–63 doi: 10.5115/acb.2010.43.1.54 21190005

28. Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, et al: Long-term cognitive impairment after critical illness. N Engl J Med 2013; 369: 1306–16 doi: 10.1056/NEJMoa1301372 24088092

29. Kline RP, Pirraglia E, Cheng H, De Santi S, Li Y, Haile M, et al: Surgery and brain atrophy in cognitively normal elderly subjects and subjects diagnosed with mild cognitive impairment. Anesthesiology 2012; 116: 603–12 doi: 10.1097/ALN.0b013e318246ec0b 22293721

30. Shi Q, Warren L, Saposnik G, Macdermid JC: Confusion assessment method: a systematic review and meta-analysis of diagnostic accuracy. Neuropsychiatric Disease and Treatment 2013; 9: 1359–70 doi: 10.2147/NDT.S49520 24092976

31. Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, et al: Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001; 286: 2703–10 doi: 10.1001/jama.286.21.2703 11730446

32. Van Munster BC, Korse CM, de Rooij SE, Bonfrer JM, Zwinderman AH, Korevaar JC: Markers of cerebral damage during delirium in elderly patients with hip fracture. BMC Neurol 2009; 27: 9–21

33. Žurek J, Fedora M, The usefulness of S100B, NSE, GFAP, NF-H, secretagogin and Hsp70 as a predictive biomarker of outcome in children with traumatic brain injury. Acta Neurochir 2012; 154: 93–103 doi: 10.1007/s00701-011-1175-2 21976236

34. Robinson TN, Raeburn CD, Tran ZV, Brenner LA, Moss M: Motor subtypes of postoperative delirium in older adults. Arch Surg 2011; 146: 295–300 doi: 10.1001/archsurg.2011.14 21422360

35. Peterson JF, Pun BT, Dittus RS, Thomason JW, Jackson JC, Shintani AK, et al: Delirium and its motoric subtypes: a study of 614 critically ill patients. J am Geriatr Soc. 2006; 54: 479–84 doi: 10.1111/j.1532-5415.2005.00621.x 16551316

36. Matsushige T, Inoue H, Fukunaga S, Hasegawa S, Okuda M, Ichiyama T: Serum neurofilament concentrations in children with prolonged febrile seizures. J Neurol Sci 2012; 321: 39–42 doi: 10.1016/j.jns.2012.07.043 22863291

37. Hu YY, He SS, Wang XC, Duan QH, Khatoon S, Iqbal K, et al: Elevated levels of phosphorylated neurofilament proteins in cerebrospinal fluid of Alzheimer disease patients. Neurosci Lett 2002; 320: 156–60 doi: 10.1016/s0304-3940(02)00047-2 11852185

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2019 Číslo 10
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