Association between cholinesterase activity and critical illness brain dysfunction

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.

Precision‐based approaches to delirium in critical illness: A narrative review

“…There is a vast array of biomarker literature in post‐operative and critical care delirium. Biomarkers that have been reported in a critical care population including neurofilament light protein (NfL), serum C‐reactive protein (CRP), interleukin (IL)‐1, IL‐6, IL‐8, and IL‐10, plasma tau, neuron‐specific enolase (NSE), and most recently acetylcholinesterase, which was reported by Hughes et al in 2022 10,45 …”

“…Based on their findings, the authors concluded that NfL measurement within the first 3 days of admission may be useful to identify those patients with worse clinical outcomes and serve as a valuable tool for investigating future delirium interventions. In 2022, Hughes et al 45 reported a landmark delirium biomarker study where they hypothesized that higher acetylcholinesterase (AChE) activity would be an indication of delirium presence in ICU. The authors enrolled 272 ICU patients and compared AChE activity in patients with delirium versus normal mental state.…”

“…Rivastigmine, a cholinesterase inhibitor, had been assessed in a RCT as a potential treatment for delirium based on the impaired cholinergic neurotransmission hypothesis for delirium, but ultimately was found to increase not only the duration of delirium, but mortality as well, leading to the abandonment of further investigation 68 . This is less surprising given the current emphasis on the anticholinergic burden and its association with delirium and dementia 45 …”

Reexamining cholinesterase inhibitors for the prevention and treatment of delirium in high-risk populations

“…Reexamining cholinesterase inhibitors for the prevention and treatment of delirium in high-risk populations Ori J. Lieberman 1* , Vanja C. Douglas 1 and Sara C. LaHue 1,2 We read with interest the article Hughes et al recently published in Critical Care describing the correlation between circulating levels of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity in critically ill adults and their risk of delirium or coma [1]. The implementation of a point-of-care testing paradigm for serum AChE and BChE activity raises the possibility of identifying a population at high risk of developing delirium for future clinical trials.…”

“…Designing such a clinical trial would necessitate identifying a population at high risk for developing delirium. At ICU admission, the use of rapid point-of-care testing for the measurement of serum AChE and BChE activity, such as that reported by Hughes et al [1], or selection of those with co-existing cognitive impairment [15], could be used to further enrich a population with a cholinergic deficit. Randomization to AChEi initiation or placebo could then occur and in-hospital and post-discharge outcomes would be collected.…”