Cytokines and Postoperative Delirium in Older Patients Undergoing Major Elective Surgery

Sarinnapha M. Vasunilashorn, Long Ngo, Sharon K. Inouye, Towia A. Libermann, Richard N. Jones, David C. Alsop, Jamey Guess, Sandra Jastrzebski, Janet E. McElhaney, George A. Kuchel, Edward R. Marcantonio

A proinflammatory state has been associated with several age-associated conditions; however, the inflammatory mechanisms of delirium remain poorly characterized. Using the Successful Aging after Elective Surgery Study of adults age ≥70 undergoing major noncardiac surgery, 12 cytokines were measured at four timepoints: preoperative, postanesthesia care unit, postoperative day 2 (POD2) and 30 days later (POD1M). We conducted a nested, longitudinal matched (on age, sex, surgery type, baseline cognition, vascular comorbidity, and Apolipoprotein E genotype) case-control study: delirium cases and no-delirium controls were selected from the overall cohort (N = 566; 24% delirium). Analyses were independently conducted in discovery, replication, and pooled cohorts (39, 36, 75 matched pairs, respectively). Nonparametric signed-rank tests evaluating differences in cytokine levels between matched pairs were used to identify delirium-associated cytokines. In the discovery and replication cohorts, matching variables were similar in cases and controls. Compared to controls, cases had (*p < .05, **p < .01) significantly higher interleukin-6 on POD2 in the discovery, replication, and pooled cohorts (median difference [pg/mL] 50.44**, 20.17*, 39.35**, respectively). In the pooled cohort, cases were higher than controls for interleukin-2 (0.99*, 0.77*, 1.07**, 0.73* at preoperative, postanesthesia care unit, POD2, POD1M, respectively), vascular endothelial growth factor (4.10* at POD2), and tumor necrosis factor-alpha (3.10* at POD1M), while cases had lower interleukin-12 at POD1M (-4.24*). In this large, well-characterized cohort assessed at multiple timepoints, we observed an inflammatory signature of delirium involving elevated interleukin-6 at POD2, which may be an important disease marker for delirium. We also observed preliminary evidence for involvement of other cytokines.