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

Abstract

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 collected prospectively. Metabolites were determined using mass spectrometry/ultra-high-pressure liquid chromatography 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 (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 onset of delirium was 3 (interquartile range 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 because tryptophan concentrations were lower, tryptophan metabolites were higher, and the kynurenine-to-tryptophan ratio 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.

Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients

“…In a study of 84 intensive care unit (ICU) patients, elevated plasma kynurenine and KTR were associated with more days in delirium/coma (14). A more recent study of 130 ICU patients found significantly higher KTR in patients with delirium (n=65) (15). The only other study of the KP in hip fracture patients found higher KTR in plasma in patients with delirium before surgery (16).…”

“…Similarly, IDO-deficient mice were protected from cognitive dysfunction following endotoxin injection (6). Clinical studies have identified an increased Kyn:Trp ratio (KTR) in blood, a potential marker of IDO activity that usually increases during inflammation, to be associated with delirium (14)(15)(16). However, to the best of our knowledge, no studies have been conducted on KP metabolites in cerebrospinal fluid (CSF), and the potentially neuroactive metabolites have not been measured, thus leaving unanswered the key question of the potential for engagement of neuroactive kynurenine metabolites with their targets in delirium.…”

NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders

“…It is also possible that systemic infection may impair higher brain functions through the uptake of kyrurenine across the blood brain barrier (42). For example, the pervasive cognitive deficits in delirium might arise from high levels of kyrurenine crossing into the brain during systemic infection (43), and that the residual "brain fog" from infections such as COVID19 (44)(45)(46), which also leads to systemic kynurenine production, may also involve sustained blockade of NMDAR in higher cortical circuits by kynurenic acid. As there are pharmacological tools to reduce kynurenine production that may relieve NMDAR blockade, these are important areas for future research.…”

<strong>Pyridoxal 5'-phosphate to mitigate immune dysregulation and coagulopathy in COVID-19</strong>

“…Callouts illustrate how systemic dysregulation come together to exacerbate organ damage when PLP is deficient. In the brain, seizures refractory to antiepileptic medications may occur in critically ill patients with low PLP, as PLP is required for the biosynthesis of γaminobutyric acid (GABA), 53,54 a major inhibitory neurotransmitter; stokes may occur due to clot formation and emboli; and delirium is exacerbated in ICU patients by the accumulation of neurotoxic kynurenine metabolites, 55 including neuroinflammatory 3hydroxykynurenine and excitotoxic quinolinic acid. 40,43 In the lung, viral cytopathology is exacerbated by cytokine-and ROS-mediated tissue damage, and gas exchange is compromised by edema and vascular constriction.…”