Relationships of Preoperative and 24-Hour Postoperative Plasma and Cerebrospinal Fluid Cytokines with Postoperative Delirium

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Abstract
Background: Postoperative delirium is a common syndrome of acute changes in attention, cognition, and consciousness that may result from inflammation and/or neuroinflammation, but few studies have distinguished the relationships of preoperative and 24-hour postoperative systemic inflammation (i.e. in blood) versus neuroinflammation (i.e. in cerebrospinal fluid, or CSF) in postoperative delirium. Methods: We measured CSF and plasma cytokine levels before and 24-hours after non-cardiac/non-neurologic surgery in 199 patients age ≥ 60 years who were enrolled in two prospective cohort studies. Delirium was assessed with the confusion assessment method (CAM), 3-minute diagnostic interview for CAM-defined delirium, or the CAM for the Intensive Care Unit (CAM-ICU) in patients who remained intubated postoperatively and validated chart review. Cytokines were measured with immunoassays for IL-6, IL-7, IL-8, IL-10, IL-16, TARC, MCP-1, and IP-10. Associations of CSF and plasma cytokine levels with postoperative delirium were assessed with univariable and multivariable logistic regression analyses with Holm correction for family-wise error. Results: Surgery was associated with significant changes in nearly all measured CSF and plasma cytokines (p < 0.05) except plasma IL-16 and MCP-1. In multivariable analyses adjusted for preoperative Mini-Mental Status Exam (MMSE) score and surgery duration, higher preoperative CSF IL-6 (OR 1.80, 95% CI 1.18–2.75, Holm p=0.049) and CSF IL-8 (OR 1.94, 95% CI 1.22–3.06, Holm p = 0.040) levels were independently associated with postoperative delirium. Higher 24-hour postoperative CSF IL-10 was nominally associated with delirium (OR 1.57, 95% CI 1.06–2.33, p = 0.026) in a multivariable regression controlling for MMSE and surgery duration, but this association did not remain significant after multiple-comparison correction (Holm p = 0.21). No other preoperative or 24-hour postoperative CSF or plasma cytokine levels were associated with delirium (p > 0.05). Conclusions: Surgery elicited robust postoperative changes in CSF and plasma cytokines, but 24-hour postoperative cytokine elevations were not significantly associated with postoperative delirium after multiple-comparison correction. In contrast, elevated preoperative CSF IL-6 and IL-8 levels were associated with postoperative delirium independent of baseline cognitive status and surgery duration. Thus, our findings support an important role for preoperative neuroinflammation in postoperative delirium in older elective surgery patients.
Funding Information
  • Foundation for Anesthesia Education and Research Research Fellowship Grant
  • National Institutes of Health (K23-AG084898)
  • National Institutes of Health (R03-AG067976)
  • National Institutes of Health (P30-AG072958)
  • National Institutes of Health (R01-AG073598)
  • National Institutes of Health (R01-AG057525)
  • National Institutes of Health (R01-AG074185)
  • National Institutes of Health (R01-AG076903)
  • National Institutes of Health (R01-AG073598)
  • National Institutes of Health (P30-AG072958)
  • National Institutes of Health (P30-AG028716)
  • National Institutes of Health (R01-AG074185)
  • National Institutes of Health (K76-AG057022)
  • Foundation for Anesthesia Education and Research GEMSSTAR grant
  • International Anesthesia Research Society Mentored Research Award
  • National Institutes of Health (R01-AG076903)
  • National Institutes of Health (R01-AG073598)
  • National Institutes of Health (R03-AG05918)

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