Metabolome Profiling of Yokukansan in Preventing Postoperative Delirium in Elderly Cancer Patients: A Reverse Translational Study.

Aims: Postoperative delirium (PD) is a common and severe complication in older adult patients undergoing invasive cancer resections. This study explored the plasma metabolome associated with PD and evaluated the efficacy of Yokukansan (YKS), a traditional Japanese Kampo medicine, in preventing PD.

Methods: An ancillary study was conducted alongside a double-blind, placebo-controlled randomized clinical trial involving patients 65 years and older, focusing on patients older than 75 years as a primary analysis population. Plasma samples were analyzed using targeted and nontargeted metabolomics. An in vivo study using aged mice assessed the effects of YKS on plasma and brain metabolites.

Results: A total of 83 patients, including 21 patients older than 75 years, were enrolled. Patients with PD had lower levels of several lipid mediators, free fatty acids, and phospholipids. YKS administration led to increased nine phospholipids and four hydrophilic metabolites in patients older than 75 years, including phosphatidylcholine (40:7) and phosphatidylcholine (42:8), which were also altered in delirium patients. In the patients older than 65 years, only two metabolites increased in the YKS administration group. In aged mice, YKS elevated plasma phospholipids, similar to findings in patients older than 75 years, and influenced brain citrulline and creatine, which related to oxidative stress and cognitive function. Correlation analyses revealed associations between plasma and brain metabolite changes.

Conclusion: Our findings suggest that the plasma metabolome provides insight into the pathophysiology of PD and the potential mechanism underlying the preventive effect of YKS against PD.