Background Postoperative delirium (POD) is a common neurocognitive complication following major surgery, particularly in older adults and those undergoing liver resections. Neuroinflammatory mechanisms are considered central to its pathophysiology, yet molecular mediators remain poorly defined. Autoantibodies (aABs) targeting G protein-coupled receptors (GPCRs)—especially those relevant to neurotransmission—may contribute to POD by disrupting neuroimmune homeostasis. This study explored the perioperative dynamics of GPCR-specific aABs and their association with POD incidence.

Methods In this secondary analysis of the PHYDELIO randomized controlled trial (ISRCTN18978802), we evaluated serum aAB levels targeting five GPCRs (M3R, M4R, β2AR, D2R, and 5-HT2AR) in 142 patients undergoing liver surgery. Samples were collected preoperatively and on postoperative days 1, 2, and 7. POD was diagnosed using a comprehensive clinical assessment integrating validated screening tools and chart reviews. Repeated-measures ANOVAs examined time × group interactions, with additional post hoc and nonparametric tests applied as appropriate.

Results Serum levels of four GPCR aABs (M3R, M4R, D2R, and 5-HT2AR) declined significantly following surgery and returned near baseline by day 7. β2AR aAB levels remained stable. Patients who developed POD (45.8%) exhibited consistently lower aAB levels, reaching statistical significance for M3R (p = .029). No significant time × delirium interaction was found for any antibody.

Discussion Major abdominal surgery transiently alters GPCR aAB levels, suggesting perioperative immune modulation or adsorption to tissue following disrupted barriers. Lower M3R aAB concentrations were associated with POD, aligning with proposed cholinergic involvement in its pathogenesis. While only M3R-specific effects reached significance, the consistent trend across aABs supports further investigation into their role as biomarkers or mediators of POD. Future studies should assess their functional activity and potential utility in risk stratification and therapeutic targeting.

Heidecke H works at CellTrend, which develops and sells antibody measurements

PHYDELIO, ISRCTN18978802; EudraCT 2008-007237-47

This secondary analysis did not receive any funding.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical approval was obtained by the Landesamt fuer Gesundheit und Soziales Berlin (Berlin, Germany) ethics committee on 15 January 2009 (ZS EK 11 618/08), and written informed consent was obtained from all participants.

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