Fast track — ArticlesEffect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial
Introduction
Delirium is an acute neuropsychiatric syndrome, characterised by disturbances of attention and other cognitive functions.1 Delirium is very common in patients in intensive care units, with reported frequencies up to 80%,2, 3 and is associated with increased complications, length of hospital stay, and mortality.3, 4, 5 Antipsychotics and benzodiazepines have become the standard drug treatment for delirium in critically ill patients,6 although few placebo-controlled trials have been done for antipsychotics7, 8 and none for benzodiazepines.9 Furthermore, haloperidol might lead to extrapyramidal side-effects and ventricular arrhythmia,10 whereas benzodiazepines might even induce delirium.11
Several lines of evidence suggest that impaired cholinergic neurotransmission has an important role in the development of delirium.12 Serum anticholinergic activity was found to be increased in patients with delirium,13 and drugs with anticholinergic effects can cause delirium, particularly in elderly patients.14 Persistent delirium can be treated successfully with cholinesterase inhibitors, such as rivastigmine, and in case series of elderly patients, low-dose rivastigmine (ie, 3–6 mg daily) was sufficient to resolve symptoms of delirium, usually within 48–72 h.15, 16 Rivastigmine is an inhibitor of acetylcholinesterase and butyrylcholinesterase, and has been approved for the symptomatic treatment of Alzheimer's disease, Parkinson's disease dementia, and Lewy-body dementia.17 On the basis of these considerations, we postulated that rivastigmine added to usual care would reduce the duration of delirium in critically ill patients.
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Patients
Patients were enrolled from six hospitals in the Netherlands and treated between November, 2008, and January, 2010. In the six participating intensive care units, patients were assessed daily by trained nurses with the confusion assessment method for the intensive care unit (CAM-ICU)18 to identify occurrence of delirium, which was confirmed daily by research nurses. If the treating physician in the intensive care unit had any doubts about the delirium diagnosis, a psychiatrist, geriatrician, or
Results
The DSMB recommended that the trial be halted after the fourth interim analysis and inclusion of 109 patients (figure 1). Five patients were withdrawn from the study by their families (one on rivastigmine and four on placebo), leading to a modified intention-to-treat analysis of 54 patients on rivastigmine and 50 on placebo. Data were censored for 16 patients who died and 19 patients who were discharged from hospital while still delirious. Mortality during treatment with the study drug seemed
Discussion
We have shown that in critically ill patients, rivastigmine did not decrease duration of delirium when it was added to standard treatment with haloperidol (panel). Furthermore, rivastigmine was associated with a more severe type of delirium, longer stay in the intensive care unit, and higher mortality than was placebo, although the difference in mortality between treatment groups was not significant. The DSMB advised that the trial should be halted prematurely because of increased mortality in
References (34)
- et al.
Systemic infection and delirium: when cytokines and acetylcholine collide
Lancet
(2010) - et al.
Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study
Lancet
(2000) - et al.
A new method of classifying prognostic comorbidity in longitudinal studies: development and validation
J Chronic Dis
(1987) - et al.
Drug treatment of delirium: past, present and future
J Psychosom Res
(2008) - et al.
Donepezil in the prevention and treatment of post-surgical delirium
Am J Geriatr Psychiatry
(2005) Diagnostic and statistical manual of mental disorders
(2000)- et al.
Incidence, risk factors and consequences of ICU delirium
Intensive Care Med
(2007) - et al.
Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit
JAMA
(2004) - et al.
Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients
Crit Care
(2005) - et al.
The impact of delirium on the survival of mechanically ventilated patients
Crit Care Med
(2004)
American Psychiatric Association
Am J Psychiatry
Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study
Crit Care Med
Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial
Crit Care Med
Benzodiazepines for delirium
Cochrane Database Syst Rev
Haloperidol: a quarter century of experience
J Clin Psychiatry
Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients
Anesthesiology
Association of elevated plasma anticholinergic activity with delirium in surgical patients
Am J Psychiatry
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