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Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients

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Abstract

Aim

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.

Methods

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 plasma concentrations of Trp, Phe, and Tyr by the sum of all other LNAA concentrations. Delirium was assessed daily using the confusion assessment method for the intensive care unit (CAM-ICU). Markov regression models were used to analyze independent associations between plasma LNAA ratios and transition to delirium after adjusting for covariates.

Results

The 97 patients included in the analysis had a high severity of illness (median APACHE II, 28; IQR, 24–32). After adjusting for confounders, only high or very low tryptophan/LNAA ratios (p = 0.0003), and tyrosine/LNAA ratios (p = 0.02) were associated with increased risk of transitioning to delirium, while phenylalanine levels were not (p = 0.27). Older age, higher APACHE II scores and increasing fentanyl exposure were also associated with higher probabilities of transitioning to delirium.

Conclusions

In this pilot study, plasma tryptophan/LNAA and tyrosine/LNAA ratios 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 evaluating the role of amino acid precursors of neurotransmitters are warranted in critically ill patients.

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Acknowledgments

Dr. Pandharipande has received research grants and honoraria from Hospira Inc. Dr. Ely has received research grants and honoraria from Hospira, Inc., Pfizer, Eli Lilly, GSK, and a research grant from Aspect Medical Systems. Dr. Girard has received honoraria from Hospira, Inc. The other authors report no financial disclosures. Dr. Pandharipande is supported by the VA Clinical Science Research and Development Service (VA Career Development Award), the ASCCA-FAER-Abbot Physician Scientist Award, and the Vanderbilt Physician Scientist Development Award. Dr. Girard is supported by the Hartford Geriatrics Health Outcomes Research Scholars Award Program and the Vanderbilt Physician Scientist Development Program. Dr. Ely is supported by the VA Clinical Science Research and Development Service (VA Merit Review Award) and the National Institutes of Health (AG0727201). The amino acid analysis was supported by the Vanderbilt CTSA grant 1 UL1 RR024975 from NCRR/NIH.

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Authors and Affiliations

  1. Division of Critical Care Medicine, Department of Anesthesiology, Vanderbilt Medical Center, 526 MAB, 1211 21st Avenue South, Nashville, TN, 37212, USA

    P. P. Pandharipande

  2. Center for Health Services Research, Vanderbilt Medical Center, Nashville, TN, USA

    A. Morandi, T. D. Girard, A. K. Shintani & E. Wesley Ely

  3. Department of Internal Medicine and Geriatrics, Poliambulanza Hospital, Brescia, Italy

    A. Morandi

  4. Geriatric Research Group, Brescia, Italy

    A. Morandi

  5. Vanderbilt University School of Medicine, Nashville, TN, USA

    J. R. Adams

  6. Division of Allergy/Pulmonary/Critical Care Medicine, Vanderbilt Medical Center, Nashville, TN, USA

    T. D. Girard & E. Wesley Ely

  7. Department of Biostatistics, Vanderbilt Medical Center, Nashville, TN, USA

    J. L. Thompson & A. K. Shintani

  8. VA Tennessee Valley Health System and Geriatric Research, Education and Clinical Center (GRECC), Nashville, TN, USA

    P. P. Pandharipande, T. D. Girard & E. Wesley Ely

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  1. P. P. Pandharipande
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Correspondence to P. P. Pandharipande.

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Pandharipande, P.P., Morandi, A., Adams, J.R. et al. Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients. Intensive Care Med 35, 1886–1892 (2009). https://doi.org/10.1007/s00134-009-1573-6

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  • DOI: https://doi.org/10.1007/s00134-009-1573-6

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