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

Abstract

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.

Figure 1

Tryptophan metabolism by the kynurenine pathway. The first and rate-limiting step in the kynurenine pathway is the formation of kynurenine from tryptophan via indoleamine-2,3-dioxygenase (IDO), found ubiquitously, or tryptophan-2,3-dioxygenase (TDO). Kynurenine concentrations within the central nervous system (CNS) are related to peripheral production (42) and transportation into the brain via the large amino acid transporter in the blood brain barrier (50), basolateral secretion of kynurenine by blood brain barrier (BBB) cells (endothelial cells, pericytes) (45), or from local CNS synthesis of kynurenine pathway metabolites (i.e. astrocytes, microglia, perivascular macrophages) (45, 51). These mechanisms are upregulated by cytokines and inflammatory/immune signals, including interferon gamma (INF-γ) (48, 49), interleukins 1 and 12 (IL-1, IL-12) (63, 64), lipopolysaccharide (LPS), and tumor necrosis factor alpha (TNF-α) (65, 66), which are often increased in patients with critical illness. Increased central kynurenine concentrations lead to production of beneficial (kynurenic acid) and neurotoxic kynurenine pathway metabolites. At times of stress and with inflammation, the pathway preferentially produces neurotoxic metabolites including quinolinic acid, 3-hydroxy-kynurenine, anthranilic acid, and picolinic acids (41, 42, 45, 51). An imbalance favoring the production of neurotoxic metabolites leads to neuronal and glial cell injury, excitotoxicity, and apoptosis (, , , –47), which may be clinically manifested as delirium or coma.

Figure 2

Increasing kynurenine levels (μM, micromolar units) are associated with fewer delirium/coma-free days. Interpretative example: Other covariates being equal, patients with a kynurenine concentration at the 75th percentile (kynurenine 21.4 μM in this population) had an average of 1.8 fewer delirium/coma-free days than patients with kynurenine levels at the 25th percentile (5 μM).

Figure 3

Increasing kynurenine/tryptophan ratios are associated with fewer delirium/coma-free days. Interpretative example: Other covariates being equal, patients with a kynurenine/tryptophan ratio at the 75th percentile (0.6 in this population) had an average of 2.1 fewer delirium/coma-free days than patients with a kynurenine/tryptophan ratio at the 25th percentile (0.1).