The association between cerebrospinal fluid interleukin-6, soluble interleukin-6 receptor, and interleukin-6 trans-signalling binary complex with postoperative delirium: an observational cohort study

Background Postoperative delirium causes significant morbidity and mortality. Delirium is associated with the presence of plasma and CSF biomarkers, including interleukin-6 (IL-6). When IL-6 binds to the non-membrane-bound soluble IL-6 receptor (sIL-6R), the resultant binary complex, IL-6·sIL-6R, triggers pro-inflammatory processes called trans-signalling. While murine models implicate central IL-6 trans-signalling in perioperative cognitive dysfunction, there are few clinical reports addressing its role in delirium. The primary aim was to investigate whether postoperative changes in CSF IL-6, sIL-6R and IL-6·sIL-6R complexes were associated with the incidence and severity of postoperative delirium. We also explored whether CSF sIL-6R was related to peripheral inflammation and blood–brain barrier permeability. Methods We performed an exploratory analysis of data from an ongoing observational cohort study on perioperative delirium in patients undergoing major surgery, with delirium incidence (3-Minute Diagnostic Confusion Assessment Method or Confusion Assessment Method for the Intensive Care Unit) and severity (Delirium Rating Scale-Revised-98), plasma, and CSF samples collected on postoperative days 1–7. Biomarkers were analysed using enzyme-linked immunosorbent assay. Results In the 24 patients included undergoing major surgery (median age 67 yr, interquartile range 61–73), 13 participants had paired pre- and postoperative CSF IL-6 and sIL-6R data. The peak postoperative change in log CSF sIL-6R was significantly correlated with delirium incidence ( P =0.03) and peak delirium severity ( ρ =0.68, P =0.02). The peak postoperative change in log CSF IL-6·sIL-6R, a surrogate of trans-signalling, was associated with peak delirium severity ( ρ =0.70, P =0.01). CSF soluble sgp130, the natural inhibitor of the trans-signalling pathway, did not correlate with delirium. CSF sIL-6R was also significantly correlated with peripheral inflammation (plasma IL-6 and IL-8) and blood–brain barrier permeability (CSF:plasma albumin ratio and plasma S100B). Conclusions Interleukin-6 trans-signalling may be implicated in postoperative delirium, which raises the future possibility of targeted immunomodulatory therapy in susceptible individuals to prevent and/or reverse postoperative co gnitive decline. Clinical trial registration NCT02926417.