Hui 2017.

Methods	Randomised clinical trial, single‐site, placebo‐controlled, double‐blind, parallel groups Study duration: from baseline assessment until discharge or death Location: USA
Participants	Total: 90 patients randomised and started on standardised haloperidol regimen. 58 developed an agitation episode and received study medication Setting: acute palliative care unit in a cancer centre Mean age years (range): lorazepam plus haloperidol 66 years (43 to 90); placebo plus haloperidol 64 years (30 to 88) Gender no. (% female): lorazepam plus haloperidol 11 (38%); placebo plus haloperidol 16 (55%) Diagnosis (%): 100% cancer Delirium severity: baseline delirium severity was assessed by the Memorial Delirium Assessment Scale (MDAS). Scores can range from 0 to 30 with higher scores indicating greater severity. Median and IQR scores were: 30.0 (23.0 to 30) in the lorazepam and haloperidol group; and 28.0 (19.0 to 30.0) in the placebo and haloperidol group. Participants had moderate to severe delirium. Performance status: 89.6% of participants in the lorazepam and haloperidol group, and 93% in the placebo and haloperidol group had Karnofsky Performance Status (KPS) scores of 30 or lower and were considered severely disabled and in need to hospitalisation. KPS scores range from 0 (dead) to 100 (normal) Inclusion criteria: adult patients who were 18 years or older with a diagnosis of advanced cancer. All had a diagnosis of delirium using DSM‐IV‐TR criteria; and a history of agitation with a Richmond Agitation‐Sedation Scale (RASS) score of 1 or more over the previous 24 hours despite receiving scheduled haloperidol of 1 mg to 8 mg per day. Between February 2014 and August 2014 study medication was started as a form of rescue medication for agitation, if RASS score was 2 or more. In September 2014, the RASS score threshold was reduced to 1 or more to allow any patient with agitation proceed to the blinded phase. Exclusion criteria: dementia, use of benzodiazepines or chlorpromazine within the previous 48 hours; contraindications to neuroleptics or contraindications to benzodiazepines
Interventions	Intervention: lorazepam plus haloperidol. n = 29 Enrolled patients were immediately started on a standardised open‐label regimen of haloperidol (2 mg) every 4 hours intravenously. If they met the need for rescue medication for agitation they were randomised to receive either of the study medications. In the intervention arm, once the participant met the agitation threshold for rescue medication, a single dose of 3 mg of lorazepam in 25 ml of 0.9% normal saline solution was infused intravenously over 1.5 minutes Comparison: placebo plus haloperidol. n = 29 Once the participant met the threshold for rescue medication, a single dose of identically appearing placebo was infused intravenously over 1.5 minutes Timing of treatment: medication was administered once the participant reached the threshold for rescue medication based on their RASS score (RASS threshold was 1 or more) Treatment duration: single administration
Outcomes	Primary outcome: Change in agitation as assessed by RASS score change from baseline to 8 hours after study medication administration. The RASS score is 10‐point numeric rating scale that ranges from −5 (unarousable) to 4 (very agitated or combative) Secondary outcomes: Delirium severity assessed by the MDAS Use of additional rescue agents Palliative symptoms assessed by the Edmonton Symptom Assessment System Comfort (perceived by caregivers and nurses) Delirium recall Communication capacity Adverse effects assessed using the Udvalg for Kliniske Undersøgelser (UKU) assessment Discharge outcomes Overall survival
Notes	Study funder: this study was supported by grant R21CA186000‐01A1 from the National Cancer Institute (Drs Hui, Bruera, Hess, and Breitbart); a Mentored Research Scholar Grant in Applied and Clinical Research (MRSG‐14‐1418‐01‐CCE) from the American Cancer Society (Dr Hui) and the Andrew Sabin Family Fellowship Award (Dr Hui) from the Andrew Sabin Family Foundation; grant P30CA016672 from the National Institutes of Health Cancer Center (Drs Diba and Hess and Ms Liu); and grant R01CA200867 from the National Institutes of Health (Dr Delgado‐Guay) Conflicts of interest disclosure: none reported Trial registration – ClinicalTrials.gov Identifier: NCT01949662
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Web‐based simple randomisation was used to assign patients to the 2 treatment groups.
Allocation concealment (selection bias)	Low risk	Allocation was concealed by using a secured website 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	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.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Blinded physicians and nurses were involved in the identification of potential patients, administration of study medications and documentation of study outcomes". Hui 2017, p1048.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Reasons for attrition are described. 3 participants lost to follow‐up in both the intervention and comparison groups. In the intervention group 1 died and 2 were discharged; in the comparison group 3 died.
Selective reporting (reporting bias)	Low risk	Protocol available; primary and secondary outcomes reported correspond with those identified in the protocol.
Sample size	High risk	Fewer than 50 participants per arm