124 PART THREE | DELIRIUM Patients and methods Study design This multicenter, randomized controlled, phase III trial (NCT01539733) was conducted at five sites (1 university cancer center, 2 teaching hospitals, 2 high-care hospices) in the Netherlands between January 2011 and July 2016. At the time of their admission, patients and/or their legal representatives were asked for written informed consent to participate in this study in case the patient was diagnosed with delirium during hospitalization. The method for concealment of allocation was by enclosing assignments in sequentially numbered, opaque, sealed envelopes provided by an independent third party (university medical center pharmacist). The envelopes were opened sequentially, and only after the envelope had been irreversibly assigned to the participant. The study staff assessing the effect of antipsychotic treatment was blinded to the participant’s treatment group for the entire duration of the study. The clinical staff administering the study medication and the patient being treated, were not blinded. The study was conducted according to Good Clinical Practice guidelines, the Declaration of Helsinki and local laws, and was approved by the institutional review boards of each participating study site. Patients Eligible patients were ≥18 years of age with advanced cancer, who were admitted to a medical oncology ward or high-care hospice facility, who spoke the Dutch language fluently, and were diagnosed with delirium. Exclusion criteria included diagnosis of glaucoma, Parkinson’s disease, dementia, psychiatric disorders interfering with delirium assessment, history of neuroleptic malignant syndrome or convulsions, delirium due to substance withdrawal, or cardiac conduction abnormalities (prolonged QTc interval of >500 msec on the electrocardiogram [ECG]). Patients being treated with other neuroleptic medication or lithium were also excluded from entering the study, because of the high probability of interactions (QTc prolongation, EPS, tardive dyskinesia, neuroleptic malignant syndrome etc.). Procedures Newly admitted patients were screened for delirium by the attending nurse using the Delirium Observation Scale (DOS) on set days (Mondays and Thursdays) during each nursing shift (day, evening, night), or whenever delirium was suspected by the nursing or medical staff. The DOS is a 13-item scale based on the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) criteria for delirium, designed to be completed by a nurse [16]. The DOS is an accurate screening scale for delirium in patients with advanced cancer [17]. The range of the total DOS score is 0-13; a total score of ≥3 indicates delirium. Patients with DOS score ≥3 were assessed on Delirium Rating Scale-R-98 (DRS-R-98) by a blinded assessor to confirm the diagnosis of delirium. The DRS-R-98 has 16- items, 13 of which assess the severity of symptoms, and 3 items are of diagnostic significance [18]. The rating is applicable to the preceding 24 h. Each severity item’s rating levels are anchored with descriptions appropriate to that particular symptom. The severity ratings range from 0 (no impairment) to 3 (severe impairment), and a severity score of ≥15.25, or a total score of ≥17.75 is indicative of delirium; higher
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