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Abstract INTRODUCTION:
Delirium is a condition characterized by fluctuating changes in cognitive function, attention, memory, and consciousness. Delirium is not known to be caused by one specific factor; rather, it is the balance between predisposing factors such as age, cognitive impairment, and comorbidities, as well as precipitating factors such as polypharmacy, infection, and surgery. Therefore, the rates of delirium in older adults who undergo anesthesia and surgery are especially high, with rates varying depending on the type of surgery that is performed. For example, patients who undergo hip fracture repair surgery develop post-operative delirium up to 53% of the time(1). Despite its frequency, delirium is often missed and underdiagnosed in clinical settings, leading to greater risk for injuries, mortality and prolonged hospitalization with persistent symptoms after hospital discharge. Current strategies for detecting delirium rely on subjective measures, where nurses and clinicians must observe changes in the cognitive function of their patients, with delirium assessed via the Confusion Assessment Method (CAM). Alternatively, urinary biomarkers for early detection of delirium may offer a more objective and less biased approach for risk assessment and/or diagnosis of vulnerable patients.
OBJECTIVE:
This project aims to apply metabolomics to identify a panel of urinary biomarkers that enable the prognosis and/or diagnosis of delirium onset in older patients following hip surgery using capillary electrophoresis-mass spectrometry (CE-MS).
METHODS:
In this pilot study, 56 urine samples from 9 patients (8 females, 1 male; mean age: 89; 2 total CAM+ patients) who underwent hip fracture repair surgery were collected over a period of 1 month along with the administration of a CAM assessment. The urine samples were analyzed using multisegment injection-CE-MS (MSI-CE-MS) to measure polar/ionic metabolites in both positive and negative mode. A targeted metabolomic approach was used using an authenticated list of known urinary metabolites, where their integrated peaks were normalized to an internal standard and hydration status adjusted for creatinine. After removing redundant, unreliable, and spurious signals, the data was analyzed using a partial least-squares-discriminant analysis (PLS-DA) model to rank urinary metabolites associated with CAM-positive delirium patients. Also, a receiver operating characteristic (ROC) curve was applied to identify a urinary metabolite ratio that differentiated delirium from delirium-free patients after hip surgery.
RESULTS:
The PLS-DA model showed that there was good separation between CAM-positive and CAM-negative patients. Two high ranking urinary metabolites (VIP score > 1.8) in this model were putatively identified as uric acid and phenylalanine. A ratiometric ROC curve using uric acid and phenylalanine was determined to provide the optimal discrimination between CAM-positive delirium patients to CAM-negative controls with an area under the curve (AUC) of 0.947 (p < 0.001).
DISCUSSION:
Changes in large neutral amino acids has often been implicated in the pathophysiology of delirium. For example, phenylalanine has been shown to be increased in serum in patients who developed post-operative delirium(2). In our urine samples, we observed a similar trend, with phenylalanine increased in CAM-positive patients. Additionally, lower uric acid in serum has been shown to be a risk factor for post-operative delirium in older patients(3). Similarly, our results also showed that lower uric acid correlated with a CAM-positive assessment. To further support these results, a ROC curve highlighted that a ratio of these two metabolites showed good discrimination between patients who developed delirium and patients who did not develop delirium.
In conclusion, the results from this pilot study indicate that a panel of urinary metabolites may serve as non-invasive biomarkers for the diagnosis of delirium in older patients following hip surgery. To further validate these preliminary findings, a multi-centre clinical study is currently underway to recruit a larger patient population with repeat urine samples collected during hospitalization to allow for greater study power.
REFERENCES:
(1) Cerejeira, J.; Mukaetova-Ladinska, E. B. A Clinical Update on Delirium: From Early Recognition to Effective Management. Nurs. Res. Pract. 2011, 2011, 1–12. https://doi.org/10.1155/2011/875196.
(2) Guo, Y.; Zhang, Y.; Jia, P.; Wang, W.; Zhou, Q.; Sun, L.; Zhao, A.; Zhang, X.; Wang, X.; Li, Y.; Zhang, J.; Jiang, W. Preoperative Serum Metabolites Are Associated With Postoperative Delirium in Elderly Hip-Fracture Patients. J. Gerontol. Ser. A 2017, 72 (12), 1689–1696. https://doi.org/10.1093/gerona/glx001.
(3) Xu, L.; Lyu, W.; Wei, P.; Zheng, Q.; Li, C.; Zhang, Z.; Li, J. Lower Preoperative Serum Uric Acid Level May Be a Risk Factor for Postoperative Delirium in Older Patients Undergoing Hip Fracture Surgery: A Matched Retrospective Case-Control Study. BMC Anesthesiol. 2022, 22 (1). https://doi.org/10.1186/s12871-022-01824-0. |
= Discovery stage. (53.14%, 2025)
= Translation stage. (22.33%, 2025)
= Clinically available. (24.53%, 2025)
