Page 2013.

Methods	Single‐centre, double‐blind, placebo‐controlled randomized trial Setting: general mixed medical‐surgical ICU Country: UK Groups: haloperidol vs. placebo Period: November 2010 to September 2012
Participants	Sample size: 142 (71/70) Included Critically ill patients ( ≧ 18 years ) demanding mechanical ventilation within 72 hours of admission Excluded Allergy to haloperidol Moderate to severe dementia Parkinson's disease Structural brain damage Chronic anti‐psychotic use Corrected QTc interval (QTc) > 500 ms History of torsade de pointes [abnormal heart rhythm] History of neuroleptic malignant syndrome Family history of dystonic reactions to drugs Pregnancy Moribund Not expected to survive 48 hours' predicted ICU stay < 48 hours undergone elective surgery Involved in a clinical medicinal product trial within 30 days Missing: 2 that are accounted for: 1 lost to follow up and 1 discontinued intervention
Interventions	Interventions: receive haloperidol 2.5 mg every 8 hours Control: 0.9% saline placebo intravenously every 8 hours irrespective of coma or delirium status
Outcomes	Primary Delirium‐ and coma‐free days in the first 14 days after randomization measured by CAM‐ICU. Secondary Delirium‐ and coma‐free days to day 28 Ventilator‐free days to day 28 28‐day mortality LOS in ICU LOS in hospital Prolonged QTc Extrapyramidal effects Adverse events attributed to study drug Measured by: CAM‐ICU Adverse events: oversedation was found in 11 patients in the haloperidol group, 6 patients in the placebo group, serious adverse events were 3 reported incidents in the intervention group (fast atrial fibrillation with hypotension (n = 1), readmission to ICU with sepsis (n = 1), failed extubation (n = 1)) and 5 in placebo group (apnoea post treatment for agitation (n = 1), readmission to ICU with sepsis (n = 1), failed extubation (n = 3).
Notes	Conclusion: early treatment with haloperidol did not alter the prevalence or duration of delirium or coma, with an average duration of delirium of 5 days in both groups. Haloperidol did not have effect on any secondary outcomes. Funding: National Institute for Health Research, UK Intensive Care Foundation Conflict of interest: VJP has received honoraria from Orion; EWE from Hospira, Orion and Abbott; and DFM and GDP are co‐directors of Research for the UK Intensive Care Foundation. The rest have no conflicts of interest. A health evaluation and cost effectiveness were presented later in a conference proceeding (Page 2015), based on data originating from this study. Study number: ISRCTN83567338 Confrerence proceedings: 2 Contact with authors: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization by an independent nurse in a 1:1 ratio with permuted block sizes of 4 and 6
Allocation concealment (selection bias)	Low risk	A centralized, secure web‐based randomization service was used
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis. All patients were analysed in their randomized group irrespective of treatment actually received. Numbers and reasons for dropouts and withdrawals are described in the trial profile 142 patients randomized/141 contributed outcome data
Selective reporting (reporting bias)	Low risk	Authors have reported outcomes described in the online protocol
Other bias	Unclear risk	Unknown other biases
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and personnel were blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinded data monitoring. Statisticians were not masked to allocation