Association of Tryptophan and NAD+ Metabolites with Brain and Skeletal Muscle Function in Critical Care Patients and Survivors

Background: Patients who survive Intensive Care Unit (ICU) acquired delirium will likely experience new or worsened physical, mental, and/or cognitive impairments (termed Post-Intensive Care Syndrome (PICS)). Although advances in critical care treatments have reduced mortality rates among older adult ICU survivors, roughly 67% suffer PICS. The most vulnerable to long-term physical and cognitive impairments are older adults or those who exhibit accelerated aging because of pre-existing physical frailty or cognitive frailty. Yet, identification of at-risk patients during admittance is likely difficult because of the 1) homogeneity in the clinical presentation of patients with pre-existing age-related physical frailty and critical illness compared to those suffering from only critical illness and 2) many patients arrive severely debilitated making administration of physical function or other volitional assessments difficult. Therefore, it is essential that new biomarkers to guide early diagnosis, prognosis, and disease monitoring are identified. To this point, tryptophan derivatives, particularly kynurenines and nicotinamide family (e.g., NAD+), have been shown to mediate the relationship between chronic inflammation and physical impairment or signal accelerated aging, respectively. However, it remains unknown if similar associations exist in ICU patients and the prognostic utility of elevated neurotoxic tryptophan metabolites relative to neuroprotective tryptophan metabolites to predict adverse health outcomes while in the ICU. Methods: A secondary analysis of pooled data from three randomized control trials was used to investigate the following aims. To address Aims 1 and 2, blood samples from patients with ICU acquired delirium were analyzed for kynurenine and salvage pathway metabolites. To address Aim 3, blood samples from patients who survived an ICU stay, experienced ICU delirium, and completed both objective and subjective physical function assessments within in month of ICU discharge and before the COVID-19 pandemic. Results: Delirium duration was significantly (p< 0.05) associated with elevated circulating kynurenine and lower NAD+. Delirium severity was significantly associated with elevated circulating lower NAD+ but not kynurenine. Post-ICU physical function performance was significantly associated with elevated circulating kynurenine but not NAD+. Conclusion: Elevated concentration of frailty biomarkers are associated with delirium severity and duration in the ICU and post-ICU physical function.