Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients

Background: Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients.
Methods: Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT00704301.
Findings: Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7-14·2) than in the placebo group (3·0 days, IQR 1·0-9·3; p=0·06).
Interpretation: Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. Funding: ZonMw, the Netherlands Brain Foundation, and Novartis.