Haloperidol and Lorazepam in Controlling Symptoms of Persistent Agitated Delirium in Patients With Advanced Cancer Undergoing Palliative Care

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
as needed and placebo IV every 4 hours and as needed until discharge from palliative care
unit.

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

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

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

Inclusion Criteria:

- PATIENTS: Diagnosis of advanced cancer (defined as locally advanced, metastatic
recurrent, or incurable disease)

- PATIENTS: Admitted to the acute palliative care unit

- PATIENTS: Delirium as per Diagnostic and Statistical Manual of Mental Disorders
(DSM)-5 criteria

- PATIENTS: Hyperactive or mixed delirium with RASS >= 1 in the past 24 hours (h)
despite efforts to treat potential underlying causes

- 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

- CAREGIVERS: Patient's spouse, adult child, sibling, parent, other relative, or
significant other (partner as defined by patient)

- CAREGIVERS: At the patient's bedside at least 4 h/day

Exclusion Criteria:

- PATIENTS: History of myasthenia gravis, acute narrow angle glaucoma, or hepatic
encephalopathy

- PATIENTS: History of neuroleptic malignant syndrome or active seizure disorder (with
seizure episode within the past week)

- PATIENTS: History of Parkinson's disease or dementia

- PATIENTS: History of prolonged corrected QT (QTc) interval (> 500 ms) if documented by
electrocardiogram (ECG) within the past month

- PATIENTS: History of hypersensitivity to haloperidol or lorazepam

- PATIENTS: On scheduled lorazepam within the past 48 hours