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Higher acetylcholinesterase activity associated with delirium during critical illness

Rod Tucker
12 December, 2022  

A higher cholinesterase activity in critically ill patients increases the risk of delirium but does not lead to cognitive impairment over time

Increased acetylcholinesterase activity in critically ill patients is associated with an increased risk of being delirious but this does lead to subsequent cognitive impairment following discharge from hospital according to the findings of a prospective study by US researchers.

Delirium is defined as a disturbance of consciousness and cognition that develops over a short period of time (hours to days) and fluctuates over time. Furthermore, it is a common manifestation of acute brain dysfunction in critically ill patients with prevalence as high as 75%. However, more troublesome is the finding from a meta-analysis of 24 studies, which showed how delirium was significantly associated with long-term cognitive decline in both surgical and nonsurgical patients. The causes of delirium remain uncertain although several pro-inflammatory markers have been found to be elevated in critical ill patients with delirium. A widely held hypothesis has proposed that this inflammatory response seen in critically ill patients is regulated by the cholinergic system, resulting from a deficit of acetylcholine (ACh). The cholinesterase enzyme, acetylcholinesterase (AChE), is found primarily found in synapses and red blood cell membranes and cleaves ACh in the synaptic cleft, terminating the transmission of a stimulus. Although the primary neurotransmitter of the cholinergic system is acetylcholine, this cannot be measured directly in clinical settings but the activity of two enzymes, AChE and butyrylcholinesterase (BChE) can be assessed with a decreased activity of the latter, seen in patients with systemic inflammation.

Researchers therefore set out to establish whether there was an association between acute brain dysfunction (i.e., delirium and coma) during critical illness and the activity of these two enzymes as well as if enzyme activity levels were predictive of long-term cognitive impairment, disability, and health-related quality of life in survivors of critical illness. Blood samples were taken on days 1 (study enrolment), 3, 5 and 7 while in the hospital to measure the activity of both enzymes. In addition, patients were assessed for delirium and/or coma twice daily until discharged from the intensive care unit IICU) and then once daily after ICU discharge.

Cholinesterase activity, delirium and cognitive impairment

A total of 272 patients with a median age of 56 (56% male) and a median Sequential Organ Failure Assessment score at enrolment of 8, were included in the analysis. Overall, 15% of the cohort died within the hospital and 23% within 90 days of enrolment.

Measurement showed that a higher AChE enzyme activity level was associated with a higher odd of delirious status on the same day (p = 0.045), but not comatose mental status (p = 0.13). When examining delirium, patients with AChE activity at the 75th percentile compared to those with values at the 25th percentile example, had 64% increased odds of developing delirium (odds ratio, OR = 1.64, 95% CI 1.11 – 2.43, p = 0.045). However, when AChE levels were normalised per gram of haemoglobin (since AChE is found in synapses and on red blood cell membranes), this relationship was no longer significant (OR = 1.20, 95% CI 0.95 – 1.52, P = 0.21).

A further finding was how patients in the 75th percentile of BChE activity, had 44% higher odds of having more days alive without delirium or coma, i.e., indicating less brain dysfunction (OR = 1.44, 95% CI 1.06 – 1.94, p = 0.05). Finally, there was no significant association between any of the cholinesterase enzymes with cognitive impairment, disability, or quality of life after discharge.

The authors concluded that plasma cholinesterase activity was predictive of acute brain dysfunction during critical illness but not long-term impairments. They suggested that future studies need to examine whether cholinergic modulation in selected patients identified by plasma cholinesterase activity, could reduce acute brain dysfunction.

Citation
Hughes CG et al. Association between cholinesterase activity and critical illness brain dysfunction. Crit Care 202