European Society of Anaesthesiology.

Objective: Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short-and longterm impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function. Methods: Eight males undergoing prostatectomy under general anesthesia were included. Prior to surgery (baseline), at postoperative days 3 to 4, and after 3 months, patients were examined using [ 11 C]PBR28 brain PET imaging to assess brain immune cell activation. Concurrently, systemic inflammatory biomarkers, ex vivo blood tests on immunoreactivity to lipopolysaccharide (LPS) stimulation, and cognitive function were assessed. Results: Patients showed a global downregulation of gray matter [ 11 C]PBR28 binding of 26 6 26% (mean 6 standard deviation) at 3 to 4 days postoperatively compared to baseline (p 5 0.023), recovering or even increasing after 3 months. LPS-induced release of the proinflammatory marker tumor necrosis factor-a in blood displayed a reduction (41 6 39%) on the 3rd to 4th postoperative day, corresponding to changes in [ 11 C]PBR28 distribution volume. Change in Stroop Color-Word Test performance between postoperative days 3 to 4 and 3 months correlated to change in [ 11 C]PBR28 binding (p 5 0.027). Interpretation: This study translates preclinical data on changes in the brain immune system after surgery to humans, and suggests an interplay between the human brain and the inflammatory response of the peripheral innate immune system. These findings may be related to postsurgical impairments of cognitive function. ANN NEUROL 2017;81:572-582 A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that ultimately reaches and activates the intrinsic immune system of the brain. [1][2][3][4] Triggered by surgery-induced damage-associated molecular patterns (DAMPs), an array of proinflammatory mediators and activated blood-borne immune cells orchestrate a rapid spread of this systemic response to the central nervous system (CNS), with inflammatory markers detectable in human cerebrospinal fluid (CSF) within 12 hours. [4][5][6][7] In surgical rodent models, this periphery-to-brain pathway seems critically dependent on NF-jB and proinflammatory cytokine signaling (eg, tumor necrosis factor-a [TNF-a]) associated with a shortlasting disruption of blood-brain barrier integrity, 2,3,8 migration of peripheral macrophages into the CNS, and subsequent hippocampal neuronal dysfunction and cognitive impairment. 8 In addition to an acute and transient response, often referred to as a syndrome of sickness behavior including fatigue, anorexia, and fever, surgery-induced immune activation may be associated with prolonged impairments in learning,...

Objective Long‐term cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with long‐term changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having long‐term cognitive decline defined as a composite cognitive z score of ≥1.0 compared to patients without long‐term cognitive decline at 3 months postsurgery. Methods Serum and CSF biomarkers of inflammation and blood–brain barrier (BBB) integrity were measured preoperatively and up to 48 hours postoperatively, and cognitive function was assessed preoperatively and at 2 to 5 days and 3 months postoperatively. Results Surgery was associated with a pronounced increase in inflammatory biomarkers in both CSF and blood throughout the 48‐hour study period. A principal component (PC) analysis was performed on 52 inflammatory biomarkers. The 2 first PC (PC1 and PC2) construct outcome variables on CSF biomarkers were significantly associated with long‐term cognitive decline at 3 months, but none of the PC construct serum variables showed a significant association with long‐term cognitive decline at 3 months. Patients both with and patients without long‐term cognitive decline showed early transient increases of the astroglial biomarkers S‐100B and glial fibrillary acidic protein in CSF, and in BBB permeability (CSF/serum albumin ratio). Interpretation Surgery rapidly triggers a temporal neuroinflammatory response closely associated with long‐term cognitive outcome postsurgery. The findings of this explorative study require validation in a larger surgical patient cohort. Ann Neurol 2020;87:370–382

Background: Postoperative neurocognitive decline is a frequent complication in adult patients undergoing major surgery with increased risk for morbidity and mortality. The mechanisms behind cognitive decline after anaesthesia and surgery are not known. We studied the association between CSF and blood biomarkers of neuronal injury or brain amyloidosis and long-term changes in neurocognitive function. Methods: In patients undergoing major orthopaedic surgery (knee or hip replacement), blood and CSF samples were obtained before surgery and then at 4, 8, 24, 32, and 48 h after skin incision through an indwelling spinal catheter. CSF and blood concentrations of total tau (T-tau), neurofilament light, neurone-specific enolase and amyloid b (Ab1-42) were measured. Neurocognitive function was assessed using the International Study of Postoperative Cognitive Dysfunction (ISPOCD) test battery 1e2 weeks before surgery, at discharge from the hospital (2e5 days after surgery), and at 3 months after surgery. Results: CSF and blood concentrations of T-tau, neurone-specific enolase, and Ab1-42 increased after surgery. A similar increase in serum neurofilament light was seen with no overall changes in CSF concentrations. There were no differences between patients having a poor or good late postoperative neurocognitive outcome with respect to these biomarkers of neuronal injury and Ab1-42. Conclusions: The findings of the present explorative study showed that major orthopaedic surgery causes a release of CSF markers of neural injury and brain amyloidosis, suggesting neuronal damage or stress. We were unable to detect an association between the magnitude of biomarker changes and long-term postoperative neurocognitive dysfunction.