Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery

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.

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

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