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The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness*

Adams Wilson, Jessica R. MD; Morandi, Alessandro MD, MPH; Girard, Timothy D. MD, MSCI; Thompson, Jennifer L. MPH; Boomershine, Chad S. MD, PhD; Shintani, Ayumi K. MPH, PhD; Ely, E. Wesley MD, MPH; Pandharipande, Pratik P. MD, MSCI

doi: 10.1097/CCM.0b013e318236f62d
Clinical Investigations

Objectives: Plasma tryptophan levels are associated with delirium in critically ill patients. Although tryptophan has been linked to the pathogenesis of other neurocognitive diseases through metabolism to neurotoxins via the kynurenine pathway, a role for kynurenine pathway activity in intensive care unit brain dysfunction (delirium and coma) remains unknown. This study examined the association between kynurenine pathway activity as determined by plasma kynurenine concentrations and kynurenine/tryptophan ratios and presence or absence of acute brain dysfunction (defined as delirium/coma-free days) in intensive care unit patients.

Design, Setting, and Patients: This was a prospective cohort study that utilized patient data and blood samples from the Maximizing Efficacy of Targeted Sedation and Reducing Neurologic Dysfunction trial, which compared sedation with dexmedetomidine vs. lorazepam in mechanically ventilated patients.

Measurements and Main Results: Baseline plasma kynurenine and tryptophan concentrations were measured using high-performance liquid chromatography with or without tandem mass spectrometry. Delirium was assessed daily using the Confusion Assessment Method for the Intensive Care Unit. Linear regression examined associations between kynurenine pathway activity and delirium/coma-free days after adjusting for sedative exposure, age, and severity of illness. Among 84 patients studied, median age was 60 yrs and Acute Physiology and Chronic Health Evaluation II score was 28.5. Elevated plasma kynurenine and kynurenine/tryptophan ratio were both independently associated with significantly fewer delirium/coma-free days (i.e., fewer days without acute brain dysfunction). Specifically, patients with plasma kynurenine or kynurenine/tryptophan ratios at the 75th percentile of our population had an average of 1.8 (95% confidence interval 0.6–3.1) and 2.1 (95% confidence interval 1.0–3.2) fewer delirium/coma-free days than those patients with values at the 25th percentile (p = .006 and p < .001, respectively).

Conclusions: Increased kynurenine pathway activation, assessed by plasma kynurenine and kynurenine/tryptophan ratio, was associated with fewer days alive and without acute brain dysfunction in intensive care unit patients. Future studies are warranted to clarify this relationship and investigate potential therapeutic interventions.

From the Vanderbilt University School of Medicine (JRAD), Nashville, TN; Department of Medicine (AM, TDG, EWE), Division of Allergy, Pulmonary, and Critical Care Medicine, Center for Health Service Research, and Center for Quality of Aging (AM), Vanderbilt University School of Medicine, Nashville, TN; Department of Biostatistics (JLT, AKS), Department of Medicine (CSB), Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Anesthesia Service (PPP), Tennessee Valley Health Care System (Nashville); and Department of Anesthesiology, Division of Critical Care Medicine, Vanderbilt Medical Center and the Geriatric Research (EWE, TDG), Education and Clinical Center (GRECC) Service, Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN.

* See also p. 1001.

Dr. Girard is supported by the National Institutes of Health (AG034257). Dr. Ely is supported by the VA Clinical Science Research and Development Service (VA Merit Review Award) and the National Institutes of Health (AG027472). Drs. Girard and Ely are both supported by the Veterans Affairs Tennessee Valley Geriatric Research, Education and Clinical Center (GRECC). Dr. Boomershine is supported by the National Institutes of Health (U01GM092691, K08DK080219-02S1, and K08DK080219) and Pfizer (GA9002FP). The tryptophan metabolites analysis was supported by the Vanderbilt CTSA grant UL1 RR024975 from NCRR/NIH. Dr. Boomershine has received honoraria from Amgen, AstraZeneca, Pfizer, Eli Lilly, Forest Pharmaceuticals, Takeda Pharmaceuticals North America, and URL Pharma, and a research grant from Pfizer Inc. Dr. Pandharipande was supported by the VA Clinical Science Research and Development Service (VA Career Development Award). The ASCCA-FAER-Abbot Physician Scientist Award funded the Maximizing Efficacy of Targeted Sedation and Reducing Neurologic Dysfunction study. Dr. Girard has received honoraria from Hospira. Dr. Ely has received a research grant and honoraria from Hospira, Pfizer, Eli Lilly, GSK, and a research grant from Aspect Medical Systems. Dr. Pandharipande has received a research grant from Hospira and honoraria from Hospira, GSK, and Orion Pharma. The remaining authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: pratik.pandharipande@vanderbilt.edu

© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins