Effect 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

Department of Intensive Care Medicine, University Medical Centre, Utrecht, Netherlands.
The Lancet (Impact Factor: 45.22). 11/2010; 376(9755):1829-37. DOI: 10.1016/S0140-6736(10)61855-7
Source: PubMed


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.
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, number NCT00704301.
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).
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.
ZonMw, the Netherlands Brain Foundation, and Novartis.

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Available from: Michael A Kuiper, Oct 13, 2015
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    • "In this single-center retrospective cohort study, patients were selected from three prospective studies conducted at the ICU of the University Medical Centre Utrecht (UMCU) between March 2009 and May 2012. These three prospective studies included: the control group of the randomized clinical trial on Rivastigmine [17], The ICU Environment Study [18] and the Epidemiology of ICU Delirium Study (unpublished data, but study results were presented at the European Delirium Association 7th annual meeting, 2012, Bielefeld, Germany). All three studies were approved by the UMCU medical ethics committee. "
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    ABSTRACT: Delirium is an acute disturbance of consciousness and cognition. It is a common disorder in the intensive care unit (ICU) and associated with impaired long-term outcome. Despite its frequency and impact, delirium is poorly recognized by ICU-physicians and -nurses using delirium screening tools. A completely new approach to detect delirium is to use monitoring of physiological alterations. Temperature variability, a measure for temperature regulation, could be an interesting component to monitor delirium, but whether temperature regulation is different during ICU delirium has not yet been investigated. The aim of this study was to investigate whether ICU delirium is related to temperature variability. Furthermore, we investigated whether ICU delirium is related to absolute body temperature. We included patients who experienced both delirium and delirium free days during ICU stay, based on the Confusion Assessment method for the ICU conducted by a research- physician or -nurse, in combination with inspection of medical records. We excluded patients with conditions affecting thermal regulation or therapies affecting body temperature. Daily temperature variability was determined by computing the mean absolute second derivative of the temperature signal. Temperature variability (primary outcome) and absolute body temperature (secondary outcome) were compared between delirium- and non-delirium days with a linear mixed model and adjusted for daily mean Richmond Agitation and Sedation Scale scores and daily maximum Sequential Organ Failure Assessment scores. Temperature variability was increased during delirium-days compared to days without delirium (βunadjusted=0.007, 95% confidence interval (CI)=0.004 to 0.011, p<0.001). Adjustment for confounders did not alter this result (βadjusted=0.005, 95% CI=0.002 to 0.008, p<0.001). Delirium was not associated with absolute body temperature (βunadjusted=-0.03, 95% CI=-0.17 to 0.10, p=0.61). This did not change after adjusting for confounders (βadjusted=-0.03, 95% CI=-0.17 to 0.10, p=0.63). Our study suggests that temperature variability is increased during ICU delirium.
    PLoS ONE 10/2013; 8(10):e78923. DOI:10.1371/journal.pone.0078923 · 3.23 Impact Factor
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    • "It also has been hypothesized that reduced cholinergic inhibition of microglia is involved in delirium [15]. However, administration of rivastigmine, a pharmacological agent that may restore cholinergic control of microglia, did not decrease duration of delirium and might have increased mortality of critically ill patients with delirium [43]. Data from studies performed in critically ill patients receiving prolonged mechanical ventilation also suggest that use of GABA-agonists, such as benzodiazepines, is associated with an increased risk of brain dysfunction [44]. "
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    ABSTRACT: Sepsis often is characterized by an acute brain dysfunction, which is associated with increased morbidity and mortality. Its pathophysiology is highly complex, resulting from both inflammatory and noninflammatory processes, which may induce significant alterations in vulnerable areas of the brain. Important mechanisms include excessive microglial activation, impaired cerebral perfusion, blood--brain-barrier dysfunction, and altered neurotransmission. Systemic insults, such as prolonged inflammation, severe hypoxemia, and persistent hyperglycemia also may contribute to aggravate sepsis-induced brain dysfunction or injury. The diagnosis brain dysfunction in sepsis relies essentially on neurological examination and neurological tests, such as EEG and neuroimaging. A brain MRI should be considered in case of persistent brain dysfunction after control of sepsis and exclusion of major confounding factors. Recent MRI studies suggest that septic shock can be associated with acute cerebrovascular lesions and white matter abnormalities. Currently, the management of brain dysfunction mainly consists of control of sepsis and prevention of all aggravating factors, including metabolic disturbances, drug overdoses, anticholinergic medications, withdrawal syndromes, and Wernicke's encephalopathy. Modulation of microglial activation, prevention of blood--brain-barrier alterations, and use of antioxidants represent relevant therapeutic targets that may impact significantly on neurologic outcomes. In the future, investigations in patients with sepsis should be undertaken to reduce the duration of brain dysfunction and to study the impact of this reduction on important health outcomes, including functional and cognitive status in survivors.
    Annals of Intensive Care 05/2013; 3(1):15. DOI:10.1186/2110-5820-3-15 · 3.31 Impact Factor
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    • "Rivastigmine use in the critically ill is specifically discouraged in the guidelines: “We do not recommend administering rivastigmine to reduce the duration of delirium in ICU patients (-1B).” Although tested in only one study, when rivastigmine was compared with placebo in critically ill patients the investigation was halted because of perceived futility and potential harm by the DSMB (Data Safety Monitoring Board) [96]; rivastigmine-treated patients were found to have more severe and longer delirium, with a trend toward a higher mortality rate. Delirium in association to alcohol withdrawal was not covered in these guidelines because of space considerations; this topic is reviewed in a separate publication [95]. "
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    ABSTRACT: The recently published Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit differ from earlier guidelines in the following ways: literature searches were performed in eight databases by a professional librarian; psychometric validation of assessment scales was considered in their recommendation; discrepancies in recommendation votes by guideline panel members are available in online supplements; and all recommendations were made exclusively on the basis of evidence available until December of 2010. Pain recognition and management remains challenging in the critically ill. Patient outcomes improve with routine pain assessment, use of co-analgesics and administration as well as dose adjustment of opiates to patient needs. Thoracic epidurals help ease patients undergoing abdominal aortic surgery. Little data exists to guide clinicians as to the type or dose of co-analgesics; no opiate choice is associated with better patient outcomes. Lighter or no sedation is beneficial, and interruption is desirable in patients who require deep sedation for specific pathologic states. Delirium screening is probably useful; no treatment modality can be unequivocally recommended, and the benefit of prophylaxis is established only for early mobilization. The details of these recommendations, as well as more recent publications that complement the guidelines, are provided in this commentary.
    Annals of Intensive Care 04/2013; 3(1):9. DOI:10.1186/2110-5820-3-9 · 3.31 Impact Factor
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