Shehabi 2013.

Methods	Multicentre (6), randomized controlled trial, unblinded parallel group, feasibility and safety study Setting: tertiary and regional hospital Country: Australia and New Zealand Groups: Early goal directed sedation vs. standard sedation Period: July 2011 to December 2011
Participants	Sample size: n = 37 (21/16) Included Intubated within the previous 12 hours Expected to need mechanical ventilation for longer than 24 hours Required immediate and ongoing sedation Excluded ≧ 18 years of age Pregnancy proven or suspected Primary neurological injury A diagnosis likely to result in prolonged weakness Drug overdose Burn injury Acute liver failure Dementia Psychiatric illness Need for ongoing neuromuscular blockade Palliative care, or treatment limitations Inability to communicate in English A mean blood pressure < 55 mmHg A heart rate < 55/minute A high‐grade AV block in the absence of a functioning pacemaker Missing: none lost to follow up
Interventions	Intervention: early goal‐directed sedation (EGDS) was based on an algorithm including a dexmedetomidine infusion at a starting dose of 1 μg/kg/hour without a loading dose. Bolus administration of dexmedetomidine was strictly prohibited owing to the risk of severe bradycardia and sinus arrest. If required, sedation could be supplemented with propofol. Sedatives were administered to achieve the desired level of light sedation whenever possible. Dexmedetomidine was titrated to the desired level of sedation by the bedside nurses. Propofol could be used as a supplement. Clonidine, remifentanil or benzodiazepines were only to be administered for management of convulsions, palliations, procedural anaesthesia or refractory agitation. Control: standard sedation (type of drug, way of administration, time for cessation and level of sedation) was at the discretion of the treating clinician.
Outcomes	Primary Main feasibility outcomes were time to randomization and time spent in the light sedation range (–2 to 1) of the Richmond Agitation Sedation Scale (RASS) in the 48 hours after randomization Secondary Proportion of patients treated with dexmedetomidine, propofol and midazolam The number of days given and the cumulative dose of sedative, analgesic, and antipsychotic agents received The proportion of RASS assessments in the deep sedation (–3 to –5) and agitation (> 1) RASS range The proportion of patients with delirium (identified by the CAM‐ICU The number of days spent alive and free of delirium Number of patients extubated and alive within 7 days of randomization The number of ventilator‐free days at 28 days Mortality at discharge from hospital and 90 days after randomization Other feasibility outcomes included the average recruitment rate. Safety outcomes included device removal and self‐extubation, the use of physical restraints, major serious adverse events, vasopressor therapy, and haemodynamic instability. Measured by: CAM‐ICU Adverse events: 2 reported in the EGDS group (self‐extubation and removal of devices); none in control group.
Notes	Conclusion: delivery of EGDS sedation was feasible, appeared safe, achieved early light sedation, minimized benzodiazepine and propofol use, and decreased the need for physical restraints. An equal proportion of patients (38%) experienced 1 or more positive CAM‐ICU assessments. Funding: Hospira provided the study drug dexmedetomidine at no cost to study sites. Hospira and its employees had no input into the design, protocol, study conduct, data collection, data analysis, manuscript preparation, review or submission. Conflict of interest Supported, in part, by an unrestricted Grant‐In‐Aid from Hospira, Lake Forest, IL. Dr Shehabi: unrestricted Grant‐In‐Aid research grants from Hospira Inc. (Lake Forest, IL); research grants from Roche Diagnostics and Thermofisher Scientific; competitive research funding grants from National Health and Medical Research Council, Australia. Dr Shehabi's research department has received payment for article preparation for being part of SEDCOM delirium manuscript review 2009; and speakers’ honoraria and consulting fee from Hospira and Roche Diagnostics. He was on an advisory boards for Hospira and GSK and has received payment from GSK for the development of educational material approved by College of Intensive Care Medicine of ANZ. Dr Reade has received a consulting fee and research grants from Hospira Dr McArthur has received grant support, travel reimbursements, and provisions for writing assistance from Hospira Australia Dr Seppelt was on an advisory board in Intensive Care supported by Hospira; has received competitive research funding grants from National Health and Medical Research Council, Australia; and has received payment for the development of educational presentations from Asklepios Medical Education. Dr Webb has consulted for Alix Healthcare Services Consulting, Ibis Biosciences, Astra Zeneca, Jansen Cilag, and has received grant support from Fresenius Kabi. In the online report ACTRN 12611000166976 it is stated that Hospira Pty Ltd gave a unrestricted grant of USD 100,000 Study number: ACTRN 12611000166976 Contact with authors: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Concealed envelopes: unclear whether they were opaque and were opened sequentially, and only after the envelope was irreversibly assigned to the participant
Allocation concealment (selection bias)	High risk	Block randomization in a very small sample could have increased the possibility of foreseeing the next allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	Flowchart accounts for all patients throughout the study
Selective reporting (reporting bias)	Unclear risk	The online protocol ACTRN 12611000166976 does not include information on outcome measures, therefore this cannot be assessed
Other bias	Unclear risk	Unknown other biases
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding of patients, clinicians, study personnel
Blinding of outcome assessment (detection bias) All outcomes	High risk	Unblinded outcome assessor