Hui 2017.

Methods	Design: randomised, single‐centre Blinding: double‐blind Duration: the timing of the primary outcome was eight hours from when the blinded study medication was administered. Setting: inpatient palliative care unit, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Participants	Diagnosis: cancer (including head and neck, breast, gastrointestinal, genitourinary, gynaecological, haematological, respiratory). Most participants had metastatic cancer stage (n = 46), others locally advanced (n = 1) and recurrent or persistent (n = 11). N = 58 (90 randomised patients*, 58 received the study medication) Age: mean 65 years old (range 30 to 90) Sex: 27 female, 31 male Race/ethnicity: 44 white, 8 black, 2 Hispanic, 4 'other' Inclusion criteria: adult patients who were 18 years or older with a diagnosis of advanced cancer in the acute palliative care unit, and having a diagnosis of delirium according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM‐IV‐TR), and had a history of agitation according to a Richmond Agitation‐Sedation Scale (RASS) score of two or more higher in the past 24 hours, despite receiving scheduled haloperidol of 1 mg to 8 mg per day (patients with hyperactive or mixed delirium) Exclusion criteria: patients with dementia; use of benzodiazepines or chlorpromazine within the past 48 hours; contraindications to neuroleptics; contraindications to benzodiazepines
Interventions	1. Lorazepam + haloperidol (n = 29): lorazepam (3 mg) given in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode 2. Placebo + haloperidol (n = 29): placebo given in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode All enroled participants immediately initiated a standardised open‐label regimen with haloperidol (2 mg) every 4 hours intravenously and another 2 mg every hour as needed for agitation. Once the participant met the threshold with RASS score two or higher, a single dose of 3 mg of lorazepam in 25 mL of 0.9% normal saline solution or identically appearing placebo (25 mL of 0.9% normal saline) was infused intravenously over 1.5 minutes. Participants in both groups then received 2 mg of haloperidol intravenously afterwards. "All patients had at least two days of delirium with documentation of agitation before starting the study intervention. The use of other medications and withholding of scheduled haloperidol were permissible as per standard of practice according to the clinical judgment of the attending physician and bedside nurse."
Outcomes	The severity of delirium assessed with Memorial Delirium Assessment Scale (MDAS, range, 0 to 30; higher scores indicates greater severity); Length of hospital admission: duration of stay in acute palliative care unit; Mortality from all causes; Discharged (alive from the acute palliative care unit); Individual side effects: adverse symptoms measured using the Edmonton Symptom Assessment System (ESAS range, 0 to 10; higher scores indicate greater severity); adverse effects related to use of benzodiazepines and antipsychotics measured using Udvalg for Kliniske Undersøgelser assessment (range 0 to 3; higher scores indicate greater severity); Unable to use (not predefined in this review protocol) RASS (Richmond Agitation‐Sedation Scale) score, a validated 10‐point numeric rating scale that ranges from ‐5: unarousable to 4: combative); the use of any additional psychotropic agents during the first 8 hours after study medication administration and then daily until discharge; patient comfort perceived by caregivers and bedside nurses daily (5‐point Likert scale ranging from "strongly agree" to "strongly disagree"); the recalled frequency of 6 delirium symptoms; the communication capacity perceived by caregivers and bedside nurses assessed daily; overall survival from the time of study medication administration
Notes	"Because of the nature of the study population, 32 patients died or were discharged before requiring the study medication." Enrolment: occurred from February 11, 2014, to Jun 30, 2016. Data collection was completed in October 2016. Consent: it was stated that "written surrogate consent was obtained from the medical power of attorney or legal representative of included participants".
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	1:1 ratio using web‐based simple randomisation
Allocation concealment (selection bias)	Low risk	Quote: "Allocation was concealed by using a secured web site that was only accessible to the study pharmacist, who then assigned patients to the study intervention."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Research staff conducting the study assessments, bedside nurses, attending physicians, patients, and caregivers were blinded to the allocation of the study medication and study outcomes throughout the entire study. To ensure proper blinding, a separate clinical nurse administered the study medication instead of the bedside nurse who conducted the RASS score assessments."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	As above
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data available for n = 58 (n = 29 in each group from originally n = 90 randomised). Because of the nature of the study population, many participants died or were discharged before requiring the study medication. For these 58 participants in the primary analysis, six participants (6/58, 10.3%; three in each group) were lost to follow‐up prior to completion of 8 hours of study medication administration.
Selective reporting (reporting bias)	Low risk	Results were reported for all stated outcomes. Authors detailed protocol changes relating to study objectives, eligibility criteria and statistical analysis. These have been provided fully in the supplementary section of their published paper.
Other bias	Low risk	Funding: This study was supported by grant R21CA186000‐01A1 from the National Cancer Institute; a Mentored Research Scholar Grant in Applied and Clinical Research (MRSG‐14‐1418‐01‐CCE) from the American Cancer Society and the Andrew Sabin Family Foundation; grant P30CA016672 from the National Institutes of Health Cancer Center; and grant R01CA200867 from the National Institutes of Health. It was stated that "the funding sources were not involved in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, and approval of the manuscript, and the decision to submit for publication". Declarations of interest: Quote: "All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported."

^{AIDS: Acquired Immune Deficiency Syndrome
 DRS: Delirium Rating Scale
 DSM‐III‐R: Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revision
 DSM‐IV‐TR: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
 ESAS: Edmonton Symptom Asessment System
 ESRS: Extrapyramidal Symptom Rating Scale
 MDAS: Memorial Delirium Assessment Scale
 RASS: Richmond Agitation‐Sedation Scale}