Intensive Care Unit Delirium in Surgical Patients is Associated with Upregulation in Tryptophan Metabolism

INTRODUCTION: In intensive care unit (ICU) patients, delirium is frequent, occurs early in ICU admission, and is associated with poor outcomes. Risk models based on clinical factors have shown variable performance in terms of predictive ability. Identification of a candidate biomarker that associates with delirium may lead to a better understanding of disease mechanism, validation biomarker studies, and the ability to develop targeted interventions for prevention and treatment of delirium. This study analyzed metabolite concentrations early in the course of ICU admission to assess the association with delirium onset. METHODS: Within 24 hours of ICU admission, blood samples for global and targeted metabolomics analyses in adult, surgical ICU patients were prospectively collected. Metabolites were determined using mass spectrometry (MS) / ultra-high pressure liquid chromatography (UHPLC) and analyzed in patients with delirium and a group of controls matched on age, sex, and admission Sequential Organ Function Assessment (SOFA) score. RESULTS: Patients in the study (n=65 per group) were a mean age of 59 years, had a median SOFA score of 6, and were most commonly admitted to the ICU following major trauma. In the delirium group, median (interquartile range [IQR]) onset of delirium was 3 (1 - 6) days, and the most common delirium subtype was mixed (56%). Kynurenic acid was significantly increased, and tryptophan concentration was significantly decreased in the delirium group (p=0.04). The ratio of kynurenine to tryptophan concentration was significantly higher in the delirium group (p=0.005). CONCLUSIONS: Evidence of upregulation was found in the tryptophan metabolic pathway in delirious patients as tryptophan concentrations were lower, tryptophan metabolites were higher, and ratio of kynurenine/tryptophan was increased. These findings suggest a role of increased inflammation, and accumulation of neurotoxic metabolites in the pathogenesis of ICU delirium. Future studies should target this pathway to validate metabolites in the tryptophan pathway as risk biomarkers in patients with ICU delirium.