This phase II/IIII trial studies how well haloperidol and lorazepam work in controlling symptoms of persistent agitated delirium in patients with cancer that has spread to other places in the body undergoing palliative care. Haloperidol and lorazepam may help in controlling symptoms of agitated delirium in patients with cancer and may lessen any distress that their caregivers may be experiencing.

Primary Objectives:

I. To compare the effect of neuroleptic dose escalation, benzodiazepine rotation, combination therapy, and neuroleptic withdrawal on the change in the Richmond Agitation Sedation Scale (RASS) score over 24 hours in patients admitted to an acute palliative care unit (APCU) who do not respond to low-dose haloperidol

Secondary Objectives:

I. To compare the effects of neuroleptic dose escalation, benzodiazepine rotation, combination therapy, and neuroleptic withdrawal on (1) rescue medication use; (2) the proportion of patients in the target RASS range (defined as RASS between -2 and 0) as well as the proportion of patients achieving treatment response (defined as RASS reduction of ≥ 1.5 points); (3) perceived comfort as assessed by caregivers and bedside nurses; (4) delirium-related distress in caregivers and nurses (Delirium Experience Questionnaire); (5) achievement of the proxy comfort goal; (6) symptom expression (Edmonton Symptom Assessment Scale [ESAS]); (7) delirium severity (Memorial Delirium Assessment Scale [MDAS]); (8) adverse effects; and (9) quality of end-of-life care.

II. To identify novel predictive markers of response to haloperidol and lorazepam.

OUTLINE: Patients are randomized to 1 of 4 groups.

GROUP I: Patients receive haloperidol intravenously (IV) over 3-15 minutes every 4 hours and then every hour as needed and placebo IV every 4 hours and then every hour as needed until discharge from palliative care unit.

GROUP II: Patients receive lorazepam IV over 3-15 minutes every 4 hours and then every hour as needed and placebo IV every 4 hours and then every hour as needed until discharge from palliative care unit.

GROUP III: Patients receive haloperidol IV over 3-15 minutes every 4 hours and then every hour as needed and lorazepam IV over 3-15 minutes every 4 hours and then every hour as needed until discharge from palliative care unit.

GROUP IV: Patients receive two different placebos IV every 4 hours. Patients then receive placebo IV and lorazepam IV over 3-15 minutes every hour as needed until discharge from palliative care unit.

Inclusion Criteria:

1. [Patients] Diagnosis of advanced cancer (defined as locally advanced, metastatic recurrent, or incurable disease)
2. [Patients] Admitted to the acute palliative care unit‡
3. [Patients] Delirium as per DSM-5 criteria
4. [Patients] Hyperactive or mixed delirium with RASS ≥1* in the past 24 h despite efforts to treat potential underlying causes
5. [Patients] On scheduled haloperidol for delirium (≤8 mg in the past 24 h) or required ≥4 mg of rescue haloperidol for agitation in the past 24 h
6. [Patients] Age 18 years or older
7. [Caregivers] Patient's spouse, adult child, sibling, parent, other relative, or significant other (partner as defined by patient)
8. [Caregivers] Age 18 years or older

Exclusion Criteria:

1. [Patients] History of myasthenia gravis or acute narrow angle glaucoma
2. [Patients] History of neuroleptic malignant syndrome or active seizure disorder (with seizure episode within the past week)
3. [Patients] History of Parkinson's disease, Alzheimer's or Lewy body dementia
4. [Patients] History of prolonged QTc or QTcF interval (>500 ms)† if documented by most recent ECG within the past month
5. [Patients] History of hypersensitivity to haloperidol or lorazepam
6. [Patients] On scheduled lorazepam within the past 48 h