Olanzapine versus quetiapine in critically ill patients with hyperactive delirium: Protocol for a multicentre, cluster-randomised, double-crossover, pragmatic clinical trial (CALM-ICU).

Background: Patients in the intensive care unit (ICU) frequently develop hyperactive delirium, which may be accompanied by behaviour that increases clinical risks to themselves as well as other patients and staff. There is a paucity of evidence to inform the urgent enteral administration of antipsychotic drugs to treat such hyperactive delirium and behavioural disturbances. Objective: The aim of this study is to test the efficacy and safety of administering enteral olanzapine when compared to quetiapine in critically ill patients with hyperactive delirium. Design setting participants and interventions: This is a cluster-randomised, double-crossover, clinical trial. Critically ill adult patients admitted to three tertiary Australian intensive care units over a 12-month period will be eligible. Randomisation will occur at the site level, with allocation to open-label olanzapine or quetiapine use over four treatment periods of 3-month duration. Main outcome measure: The primary outcome and days alive and delirium-/coma-free (censored at 14 days post enrolment) will be analysed using median quantile regression accounting for clustering at sites' level and time period and treatment order. Results and conclusion: This trial will compare the effect of enteral olanzapine to quetiapine in critically ill adults with hyperactive delirium on an important indicator of patient outcome.