Postoperative delirium is a severe complication associated with poor overall and especially neurocognitive prognosis after anesthesia and surgery. As a systemic phenomenon, peripheral immune response to surgical trauma may play a central role. Although analysis of differential gene expression in peripheral immune cells could provide insights into immune dysregulation in postoperative delirium (POD), no such analysis has been conducted yet in a sufficiently sized prospective cohort.

We performed gene expression analysis in N=599 cognitively healthy male and female patients ≥65 years who provided blood samples for microarray-based transcriptomics before major elective surgery and on the first postoperative day. Patients were followed up for delirium until the seventh postoperative day. We identified differentially expressed genes in POD using a multivariable linear regression framework adjusted for sex, age, body mass index, preoperative physical status, duration of anesthesia and operative procedure.

Preoperative gene expression was not significantly different in patients who were later diagnosed with POD. However, we identified a total of 1063 unique significantly associated genes which differed in baseline-corrected mRNA abundance among POD patients after surgery (n=394 positively, n=681 inversely). This set was significantly enriched for genes related to cellular and humoral immune response, RNA metabolism and platelet function.

Post-, but not preoperative gene expression in peripheral immune cells has been found to be altered in patients with POD. Whereas most enriched pathways were related to immune response and acute phase reaction, few molecular alterations were found, which may reflect nervous system alterations and need further clarification.

HIGHLIGHTS

Postoperative delirium (POD) is a common severe complication in older surgical patients

Systemic inflammation has been considered a major hallmark of POD

We describe immune cell gene expression in a large prospective cohort of surgical patients

POD is associated with postoperative, but no preoperative alteration in gene expression

Differentially expressed genes are involved in immune, platelet, but also neuronal function

Florian Lammers-Lietz, MD, received personal fees from PI Health Solutions GmbH during the conduct of the study. Claudia Spies, MD, PhD, received grants from the European Commission during the conduct of the study. During the past 36 months, Prof. Spies received grants from Deutsche Forschungsgemeinschaft, Deutsches Zentrum fuer Luft- und Raumfahrt e.V., Einstein Stiftung Berlin, Federal Joint Committee (GBA Innovationsfond), inner university grants, Projekttraeger im DLR, Stifterverband, Federal Ministry for Economic Affairs and Climate Action, pay-ments by the Georg Thieme Verlag, sponsoring from Dr. F. Koehler Chemie GmbH, Sintetica GmbH, Federal Joint Committee (GBA Innovationsfond), Max-Planck-Gesellschaft zur Foerderung der Wissenschaften e.V., Stifterverband fuer die deutsche Wissenschaft, Philipps Electronics Nederland BV, Federal Ministry of Education and Research, Robert-Koch-Institut and the European Commission. Prof. Spies is involved in patents 5753 627.7 (issued), PCT/EP 2015/067731 (issued), 3 174 588 (issued), 10 2014 215 211.9, 10 2018 114 364.8, 10 2018 110 275.5, 50 2015 010 534.8, 50 2015 010 347.7, 10 2014 215 212.7. She is part of the DSMB of Prothor (unpaid) and received advisory payments from Takeda. She participates in or is member of the Association of the Scientific Medical Societies in Germany (AWMF), European and German Society of Anesthesiology and Intensive Care Medicine (DGAI and ESAIC), European Society of Intensive Care Medicine (ESICM), Berlin Medical Society, Deutsche Forschungsgemeinschaft and the German National Academy of Sciences (Leopoldina) without receiving payments. Maik Pietzner reveived funding from the European Union unrelated to the BioCog study or the work presented in this manuscript. None of the other authors declare any conflict of interest.

NCT02265263

The BioCog Project was funded by the European Union Seventh Framework Program [FP7/2007-2013] under grant agreement no 602461

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