Table 1 Definition of study objectives

Survival days in 28 days

Number of days that patients survive in 28 days. All patients will be classified as either ‘alive at study day 28’ or, if dead, ‘dead at study day 28’ on an intention-to-treat basis.

Delirium diagnosis

Patients are diagnosed as delirious when they have at least one positive CAM-ICU screening during their complete ICU stay. Patients who were not delirious during their ICU-stay are considered as non-delirious patients.

Delirium-and-coma-free days in 28 days

Number of days that the patient is alive and not delirious and not in coma over 28 days starting from the day of inclusion. A delirium-and-coma-free day is defined as a negative CAM-ICU screening with a Richmond Agitation Sedation Score (RASS) greater than (more alert than) -3/-4/-5 during a day. In case a delirious patient is discharged to the ward, a delirium-free day is defined as a delirium observation scale score [30] of less than 3 during a complete day.

Duration of mechanical ventilation

Time in days that the patient is on the mechanical ventilator. If the patient is ventilated mechanically several times during one ICU admission, then the ventilator times are added. Both invasive and non-invasive ventilation will be registered. Ventilator-free days (in 28 days) will be calculated.

Incidence of re-intubation

Patients who need to be intubated within 28 days from randomization, following a previous extubation, irrespective of the reason for re-intubation, are counted as incident case for re-intubation.

Incidence of ICU readmission

Patients who need to be readmitted to the ICU during within 28 days from randomization, irrespective of the reason for readmission, are counted as incident cases for ICU readmission.

Side effects

Drowsiness, agitation, QTc-time prolongation (using 12-leads ECG or monitor strip with Bazett’s formula) and development of extra pyramidal symptoms such as tandem gait, dystonia, tremor, myoclonus, tics, rigidity, akathisia [31], determined daily by physical examination by the intensivist.

Serious adverse event

Any untoward medical occurrence or effect at any dose that results in one of the following outcomes and is not classified as a clinical outcome of delirium or the underlying disease using the description above:

- death that is not related to the underlying disease or sequel of the underlying disease, or death that is considered by the investigator to be related to study drug

- prolonged inpatient hospitalization or re-hospitalization

- a life-threatening experience (that is, immediate risk of dying)

- persistent or significant disability/incapacity

- congenital anomaly/birth defect

- considered significant by the investigator for any other reason

Sudden unexpected serious adverse reactions

Unexpected adverse reactions are adverse reactions, of which the nature, or severity, is not consistent with the applicable product information. Adverse reactions are all untoward and unintended responses to an investigational product related to any dose administered.