Deprescribing in the Pharmacologic Management of Delirium

A Randomized Trial in the Intensive Care Unit

Noll L. Campbell, PharmD, MS; Anthony J. Perkins, MS; Babar A. Khan, MD, MS; Sujuan Gao, PhD; Mark O. Farber, MD; Sikandar Khan, MD, MS; Sophia Wang, MD; Malaz A. Boustani, MD, MPH


J Am Geriatr Soc. 2019;67(4):695-702. 

In This Article

Abstract and Introduction


Objective: Benzodiazepines and anticholinergics are risk factors for delirium in the intensive care unit (ICU). We tested the impact of a deprescribing intervention on short-term delirium outcomes.

Design: Multisite randomized clinical trial.

Setting: ICUs of three large hospitals.

Participants: Two hundred adults aged 18 years or older and admitted to an ICU with delirium, according to the Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the ICU (CAM-ICU). Participants had a contraindication to haloperidol (seizure disorder or prolonged QT interval) or preference against haloperidol as a treatment for delirium, and were excluded for serious mental illness, stroke, pregnancy, or alcohol withdrawal. Participants were randomized to a deprescribing intervention or usual care. The intervention included electronic alerts combined with pharmacist support to deprescribe anticholinergics and benzodiazepines.

Measurements: Primary outcomes were delirium duration measured by the CAM-ICU and severity measured by the Delirium Rating Scale Revised-98 (DRS-R-98) and the CAM-ICU-7; secondary outcomes included adverse events and mortality.

Results: Participants had a mean age of 61.8 (SD = 14.3) years, 59% were female, and 52% were African American, with no significant differences in baseline characteristics between groups. No differences between groups were identified in the number exposed to anticholinergics (P = .219) or benzodiazepines (P = .566), the median total anticholinergic score (P = .282), or the median total benzodiazepine dose in lorazepam equivalents (P = .501). Neither median delirium/coma-free days (P = .361) nor median change in delirium severity scores (P = .582 for DRS-R-98; P = .333 for CAM-ICU-7) were different between groups. No differences in adverse events or mortality were identified.

Conclusions: When added to state-of-the-art clinical services, this deprescribing intervention had no impact on medication use in ICU participants. Given the age of the population, results of clinical outcomes may not be easily extrapolated to older adults. Nonetheless, improved approaches for deprescribing or preventing anticholinergics and benzodiazepines should be developed to determine the impact on delirium outcomes.


Deprescribing interventions are hypothesized to reduce the future risk of drug-induced adverse events.[1,2] We previously tested the impact of a deprescribing intervention in an electronic medical record (EMR) system to reduce exposure to anticholinergics among older adults with delirium or dementia in a general medical ward.[3] In hospitalized patients, anticholinergics and benzodiazepines worsen neurotransmitter imbalances of cholinergic deficiency and dopaminergic and γ-aminobutyric acid excess, leading to higher risk of delirium.[4–8] While our initial EMR-based deprescribing intervention did not reduce new orders for anticholinergics, it modestly increased discontinuation orders; however, no impact on clinical outcomes was identified.[3]

Feedback from providers exposed to the EMR-based intervention suggested the intervention failed to change prescribing habits due to a noninterruptive nature of the alert and lack of human decision support.[3] Based on this feedback, we enhanced the electronic deprescribing intervention by designing an interruptive alert that offered recommendations for alternative (nonanticholinergic) medications with easy-to-order keystrokes and a pharmacist supporting the intervention through direct clinical support to medical and surgical teams.[9]

Delirium in critically ill adults has been associated with longer hospital stays, higher mortality, and higher rates of long-term cognitive impairment.[10–18] Because no medication is US Food and Drug Administration approved for the treatment of delirium, we developed a multicomponent approach to delirium treatment in the intensive care unit (ICU) based on the neurotransmitter models described above, called the pharmacologic management of delirium (PMD).[8,9,19] PMD includes deprescribing anticholinergics and benzodiazepines and prescribing low-dose haloperidol for 7 days. However, some patients in the ICU possess contraindications to haloperidol, such as prolonged QT intervals or seizure disorder, or have personal preference against using haloperidol for an off-label indication. Therefore, we performed two parallel, pragmatic randomized trials of the PMD intervention, one that employed all three components of the intervention (PMD)[19] and this trial that employed only the deprescribing interventions (de-PMD). Our hypothesis for both trials was that participants receiving the intervention would have (1) higher number of days without delirium or coma and (2) lower delirium severity.