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-6sIL-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-6sIL-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 (=0.68,P=0.02).The peak postoperative change in log CSF IL-6sIL-6R, a surrogate of trans-signalling, was associated with peak delirium severity (=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.