Putative Involvement of Cytokine Modulation in the Development of Perioperative Neurocognitive Disorders

Figures & data

Table 1 Cytokine Changes in Cerebrospinal Fluid and Blood Before an Operation

Study	n =	Operation Type	Spinal or General Anaesthetic	Elective or Emergency Surgery	Plasma or Serum Sample Timings	Relevant Analysis	Major Cytokine Findings
Azim et al 2018^Citation90	98	Knee arthroplasty	Spinal	Elective	0, 4–6 and 72 hours after surgery	IL-6, TNF-α, leptin	Pre- and post-operative levels of IL-6, TNF-α and leptin do not predict post-operative pain levels.
Cape et al 2014^Citation63	43	Hip replacement or internal fixation	Spinal	Emergency	Before surgery	IL-1β, Il-1ra, IFN-γ, IGF-1	CSF Il-1ra and IL-1β were higher in patients with POD.
Chuang et al 2005^Citation59	20	Either open reduction and fixation for a broken hip or knee/hip arthroplasty	Spinal	Both	Before surgery	IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IFN-γ, TNF-α	IL-8 is increased in the CSF after peripheral trauma but is not present in the serum. Serum IL-6 levels increase after peripheral trauma, but not in the CSF.
Ji et al 2013^Citation64	83	Hip replacement	General and spinal	Elective	day 0 and day 7	IL-1c, IL-6	Patients with post-operative cognitive dysfunction had higher levels of IL-1β in their CSF before surgery.
Lin 2020^Citation58	447	Hip or knee replacement	Spinal	Elective	Before surgery, 24 hours after surgery	IL-6, TNF-α, cholinergic biomarkers	Levels of CSF IL-6 and TNF-α were elevated before surgery in patients with POD. Levels of plasma IL-6 and TNF-α were increased in plasma before and after surgery in patients with POD.
MacLullich et al 2011^Citation62	36	Hip replacement	Spinal	Emergency	Before surgery	IL-1β, IL-6, IL-8, IL-10, IL-12p70, TNF-α	Patients with POD had higher levels of CSF IL-8.
Neerland et al 2016^Citation45	151	Surgery for a broken hip	Spinal	Emergency	Before surgery	IL-6, sIL-6R, CRP	IL-6 levels in CSF and serum were not associated with POD.
Sajjad et al 2020^Citation60	133	Hip replacement	Spinal	Emergency	Not measured	IL-1β, IL-8, TNF-α	CSF IL-8 levels were higher in patients with POD and patients with depression.
Westhoff et al 2012^Citation43	61	Surgery for a broken hip	General and spinal	Emergency	Before surgery	42 Cytokines in CSF, IL-6 in serum	Pre-operative CSF levels of IL-1ra, IL-6 and Flt-3L were decreased in POD, while in the serum IL-6 levels were increased.

Note: A table summarising studies which have investigated cytokine changes in cerebrospinal fluid before an operation, with additional blood sampling.

Abbreviations: CSF, cerebrospinal fluid; Flt-3L, FMS-like tyrosine kinase 3 ligand; IFN-γ, interferon gamma; IGF-1, insulin-like growth factor 1; IL, interleukin; POD, Post-operative delirium; sIL-6R, soluble IL-6 receptor; TNF-α, tumour necrosis factor alpha.

Table 2 Cytokine Changes in Cerebrospinal Fluid and Blood Before and After an Operation

Study	n =	Operation Type	Spinal or General Anaesthetic	Elective or Emergency Surgery	Intervention	Biofluid Sample Timings	Relevant Analysis	Major Cytokine Findings
Bromander et al 2012^Citation48	35	Knee arthroplasty	Spinal	Elective	Nil	0, 3 hours and the first morning after surgery	IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, TNF-α	Post-operative cytokine increases in the CNS were greater than in serum, particularly in IL-8.
Buvanendran et al 2006^Citation75	30	Hip arthroplasty	Spinal	Elective	RCT with rofecoxib	0, 1, 3, 9, 24 and 30 hours after surgery	IL-1β, IL-6, IL-8, TNF-α	CSF levels of IL-6 increased after surgery, which was attenuated by preoperative rofecoxib.
Danielson et al 2018^Citation79	30	Open aortic valve surgery for aortic stenosis	General and spinal	Elective	RCT with methylprednisolone	24 hours before and 24 hours after surgery	IL-6, IL-8, TNF-α	Methylprednisolone before surgery decreased the levels of IL-6 and IL-8 in the serum and decreased IL-8 in the CSF.
Danielson et al 2020^Citation67	27	Knee or hip replacement	Spinal	Elective	Nil	0, 4, 8, 24, 32 and 48 hours after surgery	IL-6, IL-8, CXCL6, CCL3, CCL8	Higher CSF levels of IL-6, IL-8, CCL3, CCL8, and CXCL6 were found at 48 hours after surgery in patients with long-term cognitive decline.
Fertleman et al 2022^Citation65	11	Surgery for a broken hip	Spinal	Emergency	Nil	0, after surgery and day 1 after surgery	IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, TNF-α	Cytokine rises were greater in CSF than plasma, with the largest increase in IL-8.
Hirsch et al 2016^Citation61	10	Major knee surgery	Spinal	Elective	Nil	0, 3, 6 and 18 hours after surgery	14 cytokines	Increases in pro-inflammatory cytokines were found in patients’ plasma and CSF after surgery. The changes in MCP, MIP-1α and MIP-1β were greater in CSF than serum.
Lindblom et al 2018^Citation44	23	Complex surgery of the thoracic aorta	General and spinal	Both	Nil	Before surgery, 8 am day 1 and 8 am day 2 after surgery	92 proteins with neurological relevance	IL-6 levels in CSF and serum are increased in post-operative spinal cord injury, IL-6 serum levels are increased in POD.
Nader et al 2001^Citation78	15	Lower limb revascularisation	Spinal	Unclear	Non-RCT with clonidine	0, post-operative samples taken but time points unclear	TNF-α	Clonidine decreases plasma and CSF levels of TNF-α after surgery.
Reinsfelt et al 2012^Citation52	10	Aortic valve bypass surgery	General and spinal	Elective	Nil	24 hours before surgery and 24 hours after surgery	Il-6, Il-8, S-100B	After aortic valve replacement there was a 3.5-fold increase in CSF IL-6 (p<0.001) and a 12-fold increase in IL-8 (p<0.05).
Reinsfelt et al 2013^Citation66	10	Aortic valve bypass surgery	General and spinal	Elective	Nil	24 hours before and 24 hours after surgery	IL-6, IL-8, TNF‐α	Using the cohort from Reinsfelt et al 2012^53, showed that TNF-α levels increased in the CSF but not in the serum.
Renner et al 2011^Citation76	11	Hip arthroplasty	Spinal	Elective	RCT with etoricoxib	0, 1.5, 2, 4, 8, 12, 24, 26, 32 and 48 hours after surgery	IL-6, PGE2	Preoperative administration of etoricoxib lead to a reduction in serum IL-6 and pain levels, but no reduction was seen in CSF IL-6.
Vasunilashorn et al 2021^Citation68	29	Knee or hip total arthroplasty	Spinal	Elective	Nil	Before surgery and 1-month after surgery	IL-6, CHI3L1, CRP	In serum samples there was a significant increase in IL-6 at 1 month.
Wang et al 2013^Citation91	36	Aortic aneurysm surgery ± cardiopulmonary bypass	Spinal	Elective	Nil	Pre-incision, wound closure and every 4 hours for up to 5 days after surgery	IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, IFN-γ and TNF-α	Plasma IL-6 levels were higher in the patient group which underwent cardiopulmonary bypass.

Note: A table summarising studies which have investigated cytokine changes in cerebrospinal fluid and blood both before and after an operation.

Abbreviations: CCL, chemokine ligand; CHI3L1, chitinase 3-like protein; CNS, central nervous system; CSF, cerebrospinal fluid; CXCL, chemokine ligand; IFN-γ, interferon gamma; IL, interleukin; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; PGE, prostaglandin; POD, post-operative delirium; RCT, randomised controlled trial; S-100B, S100 calcium-binding protein B; TNF-α, tumour necrosis factor alpha.

Azim S, Nicholson J, Rebecchi MJ, et al. Interleukin-6 and leptin levels are associated with preoperative pain severity in patients with osteoarthritis but not with acute pain after total knee arthroplasty. The Knee. 2018;25(1):25–33. doi:10.1016/j.knee.2017.12.001

 PubMed Web of Science ®Google Scholar

Cape E, Hall RJ, van Munster BC, et al. Cerebrospinal fluid markers of neuroinflammation in delirium: a role for interleukin-1β in delirium after Hip fracture. J Psychosom Res. 2014;77(3):219–225. doi:10.1016/j.jpsychores.2014.06.014

 PubMed Web of Science ®Google Scholar

Chuang D, Power SE, Dunbar PR, Hill AG. Central nervous system interleukin-8 production following neck of femur fracture. ANZ J Surg. 2005;75(9):813–816. doi:10.1111/j.1445-2197.2005.03530.x

 PubMed Web of Science ®Google Scholar

Ji MH, Yuan HM, Zhang GF, et al. Changes in plasma and cerebrospinal fluid biomarkers in aged patients with early postoperative cognitive dysfunction following total Hip-replacement surgery. J Anesth. 2013;27(2):236–242. doi:10.1007/s00540-012-1506-3

 PubMed Web of Science ®Google Scholar

Lin X, Tang J, Liu C, et al. Cerebrospinal fluid cholinergic biomarkers are associated with postoperative delirium in elderly patients undergoing Total Hip/knee replacement: a prospective cohort study. BMC Anesthesiol. 2020;20(1):1–11. doi:10.1186/s12871-020-01166-9

 PubMed Web of Science ®Google Scholar

MacLullich AMJ, 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(6):1151–1153. doi:10.1111/j.1532-5415.2011.03428.x

 PubMed Web of Science ®Google Scholar

Neerland BE, Hall RJ, Seljeflot I, et al. Associations between delirium and preoperative cerebrospinal fluid C-Reactive Protein, Interleukin-6, and Interleukin-6 receptor in individuals with acute hip fracture. J Am Geriatr Soc. 2016;64(7):1456–1463. doi:10.1111/jgs.14238

 PubMed Web of Science ®Google Scholar

Sajjad MU, Blennow K, Knapskog AB, et al. Cerebrospinal fluid levels of Interleukin-8 in delirium, dementia, and cognitively healthy patients. J Alzheimers Dis. 2020;73(4):1363–1372. doi:10.3233/JAD-190941

 PubMed Web of Science ®Google Scholar

Westhoff D, Hoogland IC, Van De Beek D, et al. Preoperative cytokine levels in CSF do not predict post-surgical delirium. Shock. 2012;37:37–38.

 Web of Science ®Google Scholar

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(1):242. doi:10.1186/1742-2094-9-242

 PubMed Web of Science ®Google Scholar

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(3):403–410. doi:10.1097/00000542-200603000-00005

 PubMed Web of Science ®Google Scholar

Danielson M, Reinsfelt B, Westerlind A, Zetterberg H, Blennow K, Ricksten S-E. Effects of methylprednisolone on blood-brain barrier and cerebral inflammation in cardiac surgery-a randomized trial. J Neuroinflammation. 2018;15(1):283. doi:10.1186/s12974-018-1318-y

 PubMed Web of Science ®Google Scholar

Danielson M, Wiklund A, Granath F, et al. Neuroinflammatory markers associate with cognitive decline after major surgery: findings of an explorative study. Ann Neurol. 2020;87(3):370–382. doi:10.1002/ana.25678

 PubMed Web of Science ®Google Scholar

Fertleman M, Pereira C, Dani M, Harris BHL, Di Giovannantonio M, Taylor-Robinson SD. Cytokine changes in cerebrospinal fluid and plasma after emergency orthopaedic surgery. Sci Rep. 2022;12(1):2221. doi:10.1038/s41598-022-06034-9

 PubMed Web of Science ®Google Scholar

Hirsch J, Vacas S, Terrando N, et al. Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery. J Neuroinflammation. 2016;13(1):211. doi:10.1186/s12974-016-0681-9

 PubMed Web of Science ®Google Scholar

Lindblom RPF, Shen Q, Axén S, Landegren U, Kamali-Moghaddam M, Thelin S. Protein profiling in serum and cerebrospinal fluid following complex surgery on the thoracic aorta identifies biological markers of neurologic injury. J Cardiovasc Transl Res. 2018;11(6):503–516. doi:10.1007/s12265-018-9835-8

 PubMed Web of Science ®Google Scholar

Nader ND, Ignatowski TA, Kurek CJ, Knight PR, Spengler RN. Clonidine suppresses plasma and cerebrospinal fluid concentrations of TNF-α during the perioperative period. Anesth Analg. 2001;93(2):363–369. doi:10.1213/00000539-200108000-00026

 PubMed Web of Science ®Google Scholar

Reinsfelt B, Ricksten S-E, Zetterberg H, Blennow K, Freden-Lindqvist J, Westerlind A. Cerebrospinal fluid markers of brain injury, inflammation, and blood-brain barrier dysfunction in cardiac surgery. Ann Thorac Surg. 2012;94(2):549–555. doi:10.1016/j.athoracsur.2012.04.044

 PubMed Web of Science ®Google Scholar

Reinsfelt B, Westerlind A, Blennow K, Zetterberg H, Ricksten S-E. Open-heart surgery increases cerebrospinal fluid levels of Alzheimer-associated amyloid beta. Acta Anaesthesiol Scand. 2013;57(1):82–88. doi:10.1111/j.1399-6576.2012.02769.x

 PubMed Web of Science ®Google Scholar

Renner B, Brune K, Zacher J, Walter G, Strauss J. Preoperative administration of etoricoxib in patients undergoing Hip replacement causes inhibition of inflammatory mediators and better pain relief. Naunyn Schmiedebergs Arch Pharmacol. 2011;383:83. doi:10.1007/s00210-011-0617-y

 Web of Science ®Google Scholar

Vasunilashorn SM, Ngo LH, Dillon ST, et al. Plasma and cerebrospinal fluid inflammation and the blood-brain barrier in older surgical patients: the Role of Inflammation after Surgery for Elders (RISE) study. J Neuroinflammation. 2021;18(1):1–10. doi:10.1186/s12974-021-02145-8

 PubMed Web of Science ®Google Scholar

Wang Y, Landry K, Issa M, et al. Surgery-induced inflammation reduces morphine distribution into cerebrospinal fluid. FASEB J. 2013;27. Available from: http://www.fasebj.org/cgi/content/meeting_abstract/27/1_MeetingAbstracts/668.2?sid=bb3a5aa8-6cd0-4e69-abb1-4b007ff25888.

 Web of Science ®Google Scholar