Anticholinergic drug exposure at intensive care unit admission affects the occurrence of delirium. A prospective cohort study

  • Ariël M. Vondeling
    Corresponding author at: Department of Geriatric Medicine, Diakonessenhuis Utrecht, Bosboomstraat 1 3582 KE, Utrecht, the Netherlands.
    Department of Geriatric Medicine, Diakonessenhuis Utrecht, the Netherlands

    Department of Geriatric Medicine and Expertise Centre Pharmacotherapy in Old Persons (EPHOR), University Medical Centre Utrecht, Utrecht University, the Netherlands
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  • Wilma Knol
    Department of Geriatric Medicine and Expertise Centre Pharmacotherapy in Old Persons (EPHOR), University Medical Centre Utrecht, Utrecht University, the Netherlands
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  • Toine C.G. Egberts
    Department of Clinical Pharmacy, University Medical Center Utrecht & Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
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  • Arjen J.C. Slooter
    Department of Intensive Care Medicine and UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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      • Exposure to drugs with anticholinergic effects before ICU admission increases the risk of developing delirium.
      • The effect is more pronounced in the first days of the ICU admission.
      • Advanced age and septic shock increases the risk for delirium in ICU patients.
      • The ADS scale can be effectively used to measure anticholinergic load in ICU patients.



      Anticholinergic drugs may increase the risk of delirium in non-critically ill patients, but it is unclear whether exposure to these drugs is also a risk factor for Intensive Care Unit (ICU) delirium. In this study the hypothesis was tested that anticholinergic drug exposure at ICU admission increases the risk to develop delirium during ICU stay, particularly in patients with advanced age and severe sepsis.


      A prospective cohort study was performed in the mixed 32-bed medical-surgical ICU of the University Medical Center Utrecht, the Netherlands in the period from January 2011 till June 2013. Included were nonneurological patients that were consecutively admitted for more than 24 hours. The presence of delirium was evaluated each day using a validated algorithm based on the Confusion Assessment Method for the ICU (CAM-ICU), the initiation of delirium treatment as well as chart review by researchers. Anticholinergic drug exposure at ICU admission was assessed using the Anticholinergic Drug Scale (ADS). To evaluate the association between anticholinergic drug exposure at ICU admission and the risk of developing delirium, we performed multivariable competing risk Cox proportional hazard analysis corrected for confounding factors.


      Approximately half (47%, n=513) of the 1090 included patients developed delirium during ICU admission. The absolute risk for delirium development increased with more anticholinergic drug exposure: 42% in patients with ADS score=0, 49% in patients with ADS score=1, and 53% in patients with ADS higher than 1. Taking competing events (death and discharge) and potential confounding factors into account, the subdistribution hazard ratio (SHR) was 1.13 (95% CI: 0.91-1.40) for ADS score=1 point and 1.35 (95% CI: 1.09-1.68) for ADS ≥2 compared with an ADS score=0 (no anticholinergic drug exposure). The effect was strongest during the first days of ICU admittance and was strongest in patients above 65 year without severe sepsis and/or septic shock (SHR 2.15, 95% CI 1.43-3.25).


      Anticholinergic drug exposure at ICU admission increases the risk of delirium in critically ill patients. This effect was most pronounced in patients older than 65 years without severe sepsis and/or septic shock, and declining over time.



      ACH (Acetylcholine), ADS (Anticholinergic Drug Scale), APACHE IV (Acute Physiology and Chronic Health Evaluation), ARS (Anticholinergic Risk Scale), CAM-ICU (Confusion Assessment Method – ICU), ICU (Intensive Care Unit), IQR (InterQuartile Range), SD (Standard Deviation), CSHR (Cause-Specific Hazard Ratio), SHR (Subdistribution Hazard Rratio), SOFA (Sequential Organ Failure Assessment)
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