Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery

Abstract

BackgroundPostoperative 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.MethodsAfter 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).ResultsTen 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.ConclusionsSubstantial 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0681-9) contains supplementary material, which is available to authorized users.

Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice

“…Perioperative PLX5622 treatment protects mice with DIO from surgery induced memory loss ( ‡ ‡ P < 0.005 vs. DIO alone at day 7). (C and D) Analysis of LXA 4 and IL-6 levels, showing that DIO paradoxically lowers plasma LXA 4 levels that otherwise rise by 3 days after surgery in healthy control mice (C) and potentiates the postoperative (day 3) rise in hippocampal IL-6 levels seen in control mice (D). (E and F) Corresponding measurements from plasma (LXA 4 ) and hippocampus (IL-6), showing that perioperative PLX5622 treatment abolishes the impact of surgery on circulating LXA 4 levels in mice with DIO (E) and prevents hippocampal IL-6 levels from rising in mice with DIO (F).…”

“…When tissue healing occurs, SPMs (36) such as LXA 4 help to systemically end the initial inflammatory response at the site of insult and potentially within the brain. LCR rats do not adequately resolve postoperative inflammation and develop cognitive decline that persists for months (37).…”

“…Efforts to identify causes of, and treatments for, POCD have focused on the innate immune response to the aseptic trauma of surgery and consequent neuroinflammation (3,4). Neuroinflammation may be a common precursor of cognitive decline, as it is also implicated in more chronic forms of neurodegeneration (5).…”

The immune response of the human brain to abdominal surgery

“…[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, memory, and concentration termed postoperative cognitive dysfunction.…”

Minimizing Stress Response and Cognitive Dysfunction in Orthopedic Surgery: The Prospects of Epidural Anesthesia

“…immune suppression by itself [1][2][3] . The surgical stress response begins with initial changes in the neuroendocrine balance, and it can also result from alterations in homeostasis.…”