Young 2017.

Methods	RCT
Participants	Sample size: 100 (experimental 51, control 49 (48 analysed)) Sex (male %): experimental 67%, control 65% Age: experimental 60, control 61 Country: New Zealand Setting: mechanically ventilated adults admitted to a multidisciplinary ICU Disease severity score: APACHE II score median 22.1 Inclusion criteria People at least 18 years of age who require invasive mechanical ventilation in the ICU and are expected to be receiving mechanical ventilation beyond the next calendar day Exclusion criteria Greater than 2 hours of invasive mechanical ventilation or non‐invasive ventilation, or both, in an ICU during this hospital admission (includes time ventilated in another hospital’s ICU) In the view of the treating clinician, hyperoxia is clinically indicated for reasons including (but not limited to) carbon monoxide poisoning or a requirement for hyperbaric oxygen therapy In the view of the treating clinician, avoidance of hyperoxia is clinically indicated for reasons including (but not limited to) COPD, paraquat poisoning, previous exposure to bleomycin, or chronic hypercapnic respiratory failure Pregnancy Death is deemed to be inevitable as a result of the current acute illness, and either the treating clinician, the participant, or the substitute decision‐maker is not committed to full active treatment Adults with a life expectancy of less than 90 days due to a chronic or underlying medical condition Admitted following a drug overdose (including alcohol intoxication) Long‐term dependence on invasive ventilation prior to this acute illness Confirmed or suspected diagnosis of any of the following: Guillain‐Barré syndrome, cervical cord injury above C5, muscular dystrophy, or motor neuron disease Enrolment not considered to be in the patient’s best interest Enrolled in any other trial of targeted oxygen therapy Previously enrolled in the ICU‐ROX study
Interventions	Experimental: no specific measures taken to avoid high FiO2 or SpO2, FiO2< 0.30 discouraged (thus we could not categorize the experimental group as using either a low or high target). Participants assigned to the ‘higher group’ received ‘standard care’ both whilst ventilated and after extubation with no specific measures taken to avoid high FiO2 or high SpO2. The use of upper alarm limits for SpO2 in the higher group was prohibited, as upper alarm limits for SpO2 were not used as part of standard care. The lower limit alarm for SpO2 was set at 90% (or lower if clinically appropriate). If the PaO2 or SaO2 was lower than the acceptable limit, inspired oxygen might be increased if clinically appropriate, irrespective of the SpO2 reading. The use of an FiO2 of less than 0.3 whilst ventilated was discouraged. Control: target SaO2/SpO2 91% to 96%. When a participant was allocated to conservative oxygen therapy, the inspired oxygen concentration was decreased to room air as rapidly as possible provided that the SpO2 measured by peripheral pulse oximetry was greater than the acceptable lower limit. SpO2 levels of greater than 96% were strictly avoided, and an upper SpO2 alarm limit of 97% applied whenever supplemental oxygen was administered in the ICU to minimize the risk of hyperoxaemia. After extubation, in the conservative oxygen group, the upper monitored alarm limit of acceptable SpO2 of 97% was applied whenever supplemental oxygen was being administered. In the event that the SpO2 exceeded the acceptable upper limit, downward titration of supplemental oxygen was undertaken as a high priority and supplemental oxygen was discontinued as soon possible. The lower limit alarm for SpO2 was set at 90% (or lower if clinically appropriate). If the PaO2 or SaO2 was lower than the acceptable limit, inspired oxygen might be increased if clinically appropriate, irrespective of the SpO2 reading. Categorized by us as using a low target in the control group Co‐intervention: there were no restrictions on concomitant treatments provided to participants. If an increase in FiO2 for procedures performed in the ICU included (but were not limited to) bronchoscopy, suctioning, tracheostomy, or preparation for extubation, this was permitted in both groups. Duration: until death or discharge from the ICU, or day 28 postrandomization
Outcomes	*Outcomes that will be reported in the final trial report: Ventilator‐free days All‐cause mortality (day 90 and day 180) Duration of survival Quality of life Functional outcome assessed by the extended Glasgow Outcome Scale Proportion of participants in paid employment at baseline who are unemployed at 180 days Cognitive function
Notes	*The trial report included data from a pilot phase of the ICU‐ROX trial. It included the first 100 patients of an overall sample of 1000, which was to examine the feasibility. Only feasibility outcomes were reported, and outcomes prespecified in protocol will be reported in final trial report including 1000 participants, thus no relevant outcomes were reported. Email sent 6 December 2018 to Dr Young and reply was received. The trial was supported by public funds.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Encrypted web‐based system
Allocation concealment (selection bias)	Low risk	Central randomization
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not described; however, blinding of outcome assessment was clarified by email
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 5% were lost to follow‐up.
Selective reporting (reporting bias)	Low risk	The trial was registered prior to randomization (ACTRN12615000957594). Only feasibility outcomes were reported, and outcomes prespecified in the protocol will be reported in the final trial report including 1000 participants. However, mortality is reported in total (30.3%), but is not specified according to treatment group.
Other bias	Low risk	The trial appeared to be free of other issues that could put it at risk of bias.

APACHE II: Acute Physiology, Age, Chronic Health Evaluation II; ARDS: acute respiratory distress syndrome; AUC: area under the curve; C5: cervical spine vertebral level 5; COPD: chronic obstructive pulmonary disease; CPC: cerebral performance category; CPR: cardiopulmonary resuscitation; EEG: electroencephalogram; FiO₂: fraction of inspired oxygen; GCS: Glasgow Coma Scale; H₂O: dihydrogen monoxide (water); ICU: intensive care unit; MAP: mean arterial pressure; mRS: modified ranking scale; MV: mechanical ventilation; NIRS: cerebral near‐infrared spectroscopy; NIHSS: National Institutes of Health Stroke Scale; NSE: neuron‐specific enolase; OHCA: out‐of‐hospital cardiac arrest; PaCO₂: partial pressure of arterial carbon dioxide; PaO₂: partial pressure of arterial oxygen; PEEP: positive end‐expiratory pressure; PaO₂/FiO₂ ratio: ratio of arterial oxygen partial pressure to fractional inspired oxygen; RCT: randomized controlled trial; ROSC: return of spontaneous circulation; SaO₂: arterial oxygen saturation of haemoglobin; SAPS: simplified acute physiology score; SOFA: sequential organ failure assessment; SpO₂: peripheral oxygen saturation; TBI: traumatic brain injury; TnT: cardiac troponin; TTM: targeted temperature management; VF: ventricular fibrillation; VT: ventricular tachycardia