Association between cholinesterase activity and critical illness brain dysfunction

Christopher G Hughes; Christina S Boncyk; Benjamin Fedeles; Pratik P Pandharipande; Wencong Chen; Mayur B Patel; Nathan E Brummel; James C Jackson; Rameela Raman; E Wesley Ely; Timothy D Girard

doi:10.1186/s13054-022-04260-1

Association between cholinesterase activity and critical illness brain dysfunction

Crit Care. 2022 Dec 6;26(1):377. doi: 10.1186/s13054-022-04260-1.

Authors

Christopher G Hughes¹, Christina S Boncyk², Benjamin Fedeles^{3

4}, Pratik P Pandharipande⁵, Wencong Chen^{6

7}, Mayur B Patel^{8

9}, Nathan E Brummel¹⁰, James C Jackson^{11

12}, Rameela Raman^{6

7}, E Wesley Ely^{11

12}, Timothy D Girard¹³

Affiliations

¹ Department of Anesthesiology, Division of Anesthesiology Critical Care Medicine and Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, 1211 21st Ave. South, 422 MAB, Nashville, TN, 37212, USA. christopher.hughes@vumc.org.
² Department of Anesthesiology, Division of Anesthesiology Critical Care Medicine and Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, 1211 21st Ave. South, 422 MAB, Nashville, TN, 37212, USA.
³ United States Air Force, Washington, USA.
⁴ Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁵ Departments of Anesthesiology and Surgery, Division of Anesthesiology Critical Care Medicine and Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁷ Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Department of Surgery, Division of Acute Care Surgery and Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Nashville Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN, USA.
¹⁰ Division of Allergy, Critical Care and Sleep Medicine, Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
¹¹ Department of Medicine, Division of Pulmonary and Critical Care Medicine and Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Geriatric Research, Education and Clinical Center Service, Nashville Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN, USA.
¹³ Department of Critical Care Medicine and Clinical Research, Investigation, and Systems Modeling of Acute Illnesses Center, University of Pittsburgh, Pittsburgh, PA, USA.

Abstract

Background: Delirium is a frequent manifestation of acute brain dysfunction and is associated with cognitive impairment. The hypothesized mechanism of brain dysfunction during critical illness is centered on neuroinflammation, regulated in part by the cholinergic system. Point-of-care serum cholinesterase enzyme activity measurements serve as a real-time index of cholinergic activity. We hypothesized that cholinesterase activity during critical illness would be associated with delirium in the intensive care unit (ICU) and cognitive impairment after discharge.

Methods: We enrolled adults with respiratory failure and/or shock and measured plasma acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity on days 1, 3, 5, and 7 after enrollment. AChE values were also normalized per gram of hemoglobin (AChE/Hgb). We assessed for coma and delirium twice daily using the Richmond Agitation Sedation Scale and the Confusion Assessment Method for the ICU to evaluate daily mental status (delirium, coma, normal) and days alive without delirium or coma. Cognitive impairment, disability, and health-related quality of life were assessed at up to 6 months post-discharge. We used multivariable regression to determine whether AChE, AChE/Hgb, and BChE activity were associated with outcomes after adjusting for relevant covariates.

Results: We included 272 critically ill patients who were a median (IQR) age 56 (39-67) years and had a median Sequential Organ Failure Assessment score at enrollment of 8 (5-11). Higher daily AChE levels were associated with increased odds of being delirious versus normal mental status on the same day (Odds Ratio [95% Confidence Interval] 1.64 [1.11, 2.43]; P = 0.045). AChE/Hgb and BChE activity levels were not associated with delirious mental status. Lower enrollment BChE was associated with fewer days alive without delirium or coma (P = 0.048). AChE, AChE/Hgb, and BChE levels were not significantly associated with cognitive impairment, disability, or quality of life after discharge.

Conclusion: Cholinesterase activity during critical illness is associated with delirium but not with outcomes after discharge, findings that may reflect mechanisms of acute brain organ dysfunction.

Trial registration: NCT03098472. Registered 31 March 2017.

Keywords: Acetylcholinesterase; Butyrylcholinesterase; Cognitive impairment; Critical illness; Delirium.

MeSH terms

Acetylcholinesterase
Aftercare
Brain
Butyrylcholinesterase*
Critical Illness*
Humans
Middle Aged
Patient Discharge
Quality of Life

Substances

Butyrylcholinesterase
Acetylcholinesterase

Associated data

ClinicalTrials.gov/NCT03098472