The pathophysiology of delirium remains elusive though neurotransmitters and their precursor large neutral amino acids (LNAAs) may play a role. This pilot study investigated whether alterations of tryptophan (Trp), phenylalanine (Phe), and tyrosine (Tyr), plasma levels were associated with a higher risk of transitioning to delirium in critically ill patients.
Plasma LNAA concentrations were determined on days 1 and 3 in mechanically ventilated (MV) patients from the MENDS randomized controlled trial (dexmedetomidine vs. lorazepam sedation). Three independent variables were calculated by dividing the plasma concentrations of Trp, Phe, and Tyr by the sum of all other LNAA concentrations. Delirium was assessed daily using the Confusion Assessment Method in ICU (CAM-ICU). Markov regression models were used to analyze the independent associations between plasma LNAA ratios and transition to delirium after adjusting for important covariates.
The 97 patients included in the analysis had a high severity of illness (median APACHE II, 28; IQR, 24 to 32). Patients with either high or very low tryptophan to LNAA ratios (p=0.0003), and tyrosine to LNAA ratios (p=0.02) were at increased risk of transitioning to delirium, after adjusting for potential confounders. Phenylalanine levels were not associated with transition to delirium (p=0.27). Older age and exposure to fentanyl were also associated with a higher probability of transitioning to delirium.
In this pilot study, plasma tryptophan/LNAA (via serotonin or tryptophan metabolites) and tyrosine/LNAA ratios (via dopamine or its downstream neurotransmitter norepinephrine) were associated with transition to delirium in MV patients, suggesting that alterations of amino acids may be important in the pathogenesis of ICU delirium. Future studies studying the role of amino acid precursors of neurotransmitters are warranted in critically ill patients.