125 7 DELIRIUM | PART THREE scores indicate higher severity of delirium. Delirium is considered cleared, if the severity score is <15.25 with a decline of at least 4.5 points (d = 0.8) in the total score [18]. Site initiation involved training of the clinical and study staff for standardized assessment of DOS and DRS-R-98 scores (performed by M.V. and E.N.). Once delirium was diagnosed, potential precipitating factors for delirium, including changes in dose or type of opioids (<48 hours before diagnosis of delirium), dehydration, infection, intracranial malignancy, infection, and metabolic imbalances were identified and scored (yes or no) by a comprehensive assessment. Delirium was categorized according to motor subtype (hypoactive, hyperactive or mixed), based on DRS-R-98 items 7 (motor agitation) and item 8 (motor retardation). We also determined the predominance of certain “psychomotor features” by clinical observation. The hypoactive subtype is characterized by reduced alertness, sedation, and reduction of motor activity. The hyperactive form is associated with hypervigilance, overt psychotic features (e.g., hallucinations, delusions), andagitation. Themixed subtypehas overlapping features of the hypoactive and hyperactive subtypes. All patients received tailored interventions targeted at the underlying causes of delirium, and appropriate non-pharmacological measures were taken according to clinical practice guidelines [8, 10, 11]. Subsequently, all patients were randomized in a 1:1 ratio to receive haloperidol orally (PO) or subcutaneously (SC), or olanzapine PO or intramuscularly (IM). Dosing of antipsychotics was age adjusted and based on clinical practice guidelines [10, 11]. Patients <75 years of age assigned to haloperidol started with a loading dose of 1 mg. DOS scores were determined every 40 minutes thereafter. If the DOS score was ≥3, subsequent doses were increased by 1 mg up to a maximum dose of 20 mg PO or 10 mg SC on day 1 (Supplemental Table 1). Patients <75 years of age assigned to olanzapine started with a loading dose of 5 mg. DOS scores were determined every 2 h thereafter. If the DOS score was ≥3, subsequent doses were increased to a maximum dose of 20 mg PO or IM (Supplemental table 2). The loading, titration, and maximum doses of both haloperidol and olanzapine were halved for patients ≥75 years of age. If the DOS score was <3, resolution of delirium was confirmed by DRS-R-98 assessment. Maintenance dose of haloperidol or olanzapine was one half of the total dose of the study drug administered during the first 24 h after initiation, and divided in 1 or 2 doses. On days 2, 3, 4 and 7, DRS-R-98 assessment was repeated. If the DRS-R-98 severity score was ≥15.25, maintenance doses of haloperidol and olanzapine were adjusted (Supplementary Table 1 and 2). Treatment with antipsychotics was discontinued if the maximum daily dose of the study drug was reached without resolution of delirium, or if serious (grade ≥3) treatmentrelated adverse events (TRAEs) occurred. TRAEs, including somnolence, dizziness, and EPS (including tremors and muscle stiffness) were monitored and graded daily according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [19] by the study staff. ECG was performed before initiation of the study drug, and on day 2. If QTc prolongation (>500 msec) occurred, treatment with the study drug was also discontinued. Administration of the benzodiazepine receptor agonist lorazepam PO or intravenously (IV) was allowed, if the patient was deemed to require immediate intervention for
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