Randomization and masking, study procedures and interventions
delirium, acute pain, hallucinations, agitation, coma
ADVERSE EFFECTS, COMA
Randomization was computer-generated using a block design of eight patients per block (4 haloperidol and 4 placebo in random order), stratified by participating center [The study drug was administered intravenously, starting with 2.5 mg three times daily (for patients ≥ 80 years 1 mg), and increased up to 5 mg three times daily (for patients ≥ 80 years 2.5 mg) if delirium persisted in the next 8-h shift. The first dose was administered immediately after randomization or at the subsequent regular medication prescription in the electronic patient system (every 8 h). When delirium had resolved (or was not assessable due to coma) for 24 h, study drug was decreased (from 5 to 2.5 mg for patients < 80 years or from 2.5 to 1 mg for patients ≥ 80 years) or stopped (if at a dose of 2.5 mg for patients < 80 years or 1 mg for patients ≥ 80 years). The study drug was restarted if delirium re-occurred within the 14-day intervention period and the patient remained at the ICU. At the discretion of the ICU clinical team, and after consultation with the research team when necessary, doses could be lowered (or held) when safety concerns presumably related to haloperidol were suspected (i.e., drug associated adverse effects, as described in Additional file Open-label haloperidol during the 14-day intervention period was strongly discouraged. If agitation did not resolve after potential causes (e.g., acute pain) were identified and treated, it could be treated with an alpha-2 agonist (e.g., dexmedetomidine, clonidine) or GABA agonist (e.g., propofol, benzodiazepine). Patients appearing to be in distress (e.g., from hallucinations) could be treated with a low-dose atypical antipsychotic. Standard clinical practice was followed according to clinical protocols, based on the clinical practice guidelines from the Society of Critical Care Medicine that were implemented in a previous multi-center implementation study [