123 7 DELIRIUM | PART THREE Introduction Delirium is a common, complex neuropsychiatric disorder with a high prevalence among hospitalized patients with advanced cancer [1, 2]. This medical condition is characterized by changes in attention, awareness and cognition, which develop over a short period of time, and tend to fluctuate in severity during the course of a day [3]. Delirium is associated with high morbidity and also increased mortality [4, 5]; it causes significant distress in patients and their caregivers, and interferes with symptom assessment and decision making [6, 7]. Therefore, early recognition and adequate management of delirium is of utmost importance in the care of hospitalized patients with advanced cancer. New guidelines recommend that the use of pharmacological interventions in the management of delirium should be limited to patients with distressing symptoms (such as agitation, anxiety, or perceptual disturbances), or if there are safety concerns where the patient is a potential risk to themselves or others [8, 9]. In general, haloperidol, a typical or first-generation antipsychotic, is recommended as the first line pharmacological option [10, 11]. A recently performed systematic review and meta-analysis of 15 randomized clinical trials suggested that atypical or second-generation antipsychotics, including olanzapine, have a benefit with regard to efficacy and safety compared to haloperidol [12]. Pooled atypical antipsychotics were associated with a shorter time to response (TTR; standard mean difference [SMD], -0.27) and a lower incidence (risk ratio [RR], 0.3) of extrapyramidal symptoms (EPS). However, most of the included studies were single center with small sample sizes, heterogeneous study populations, and at risk of bias. Recently, a Cochrane systematic review included nine trials with 727 participants, assessing antipsychotics for delirium treatment in non-ICU patients [9]. Seven trials included a comparison of a typical to an atypical antipsychotic drug or placebo, including three studies, evaluating patients with advanced cancer [13-15]. Pooled analysis showed no significant difference in delirium severity (SMD-0.17, 95% CI:-0.4-0.02; seven studies; 542 participants), overall delirium resolution (RR 1.1, 95% CI: 0.8-1.5; five studies; 349participants), overallmortality (RR1.7, 95%CI: 0.8-3.5; four studies; 342participants, or increased risk of EPS (RR 12.2, 95%CI: 0.55-270; two studies; 198 participants) with atypical antipsychotics compared to typical antipsychotics. There was no evidence to support or refute the suggestion that antipsychotics shorten the course of delirium in hospitalized patients. However, the results were assessed as (very) low evidence (downgraded due to risk of bias, inconsistency, and/or imprecision). Moreover, important clinical endpoints, like duration of delirium, health-related quality of life, and cardiac arrhythmia were not reported for any trial comparing typical vs. atypical antipsychotics. Taken together, the efficacy and safety of pharmacological interventions for the treatment of delirium in patients with cancer is controversial. Effective and safe strategies for the management of delirium remain an unmet clinical need. Atypical antipsychotics may be an effective and safe alternative to haloperidol. Therefore, we conducted a multicenter, phase III randomized clinical trial (RCT) to compare the efficacy and tolerability of ageadjusted and titratable doses of olanzapine vs. haloperidol for the treatment of delirium in hospitalized patients with advanced cancer.
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