Asfar 2017.

Methods	RCT 2‐by‐2 factorial trial randomizing to 4 groups. 2 groups were included in our analysis.
Participants	Sample size: 442 randomized (219 experimental, 223 control) Sex (male): experimental 63%, control 65% Age (mean): experimental 67.8, control 66.3 Country: France Setting: multidisciplinary ICU Disease severity score: SAPS III median 71 Inclusion criteria Patients aged 18 years and older if they were mechanically ventilated and exhibited septic shock refractory to fluid resuscitation as defined by an absence of response to 20 mL/kg of crystalloids or colloids and requiring vasopressor (norepinephrine or epinephrine, at a minimum infusion rate of 0.1 μg/kg per min); they also had to have been assessed within 6 hours after the initiation of vasopressors. Septic shock was defined by the presence of 2 or more diagnostic criteria of systemic inflammatory response syndrome, proven or suspected infection, and sudden dysfunction of at least 1 organ. Exclusion criteria Severe hypoxaemia defined as PaO2: FiO2 ratio of less than 100 mmHg for a minimum positive end‐expiratory pressure of 5 cm H2O Plasma sodium concentration of less than 130 mmol/L or more than 145 mmol/L Intracranial hypertension Patient admitted for cardiac arrest Overt cardiac failure Under legal guardianship No affiliation with the French healthcare system Pregnancy Recent participation in another biomedical study or another interventional study with mortality as the primary endpoint An investigator’s decision not to resuscitate
Interventions	Experimental: hyperoxia group (mechanical ventilation with FiO2 of 1.0 for 24 hours after inclusion; thereafter FiO2 as in the normoxia group). Categorized by us as using a high target in the experimental group. Control: target SaO2 of 88% to 95% using mechanical ventilation Co‐intervention: not specified Duration: 24 hours
Outcomes	Primary outcome Death from any cause at day 28 after inclusion Secondary outcomes 90‐day mortality Daily SOFA from inclusion to day 7 19 days alive and free from organ dysfunction at day 28 Length of stay in the ICU Alive at day 28 without organ support was defined as days alive without vasopressor infusion, mechanical ventilation, or renal replacement treatment Safety data (as specified in protocol (NCT01722422) Outcomes not prespecified Participants with at least 1 serious adverse event Chest radiograph scores Atelectasis Pneumothorax Ventricular arrhythmias Mesenteric ischaemia Digital ischaemia ICU‐acquired weakness Participants with ≥ 1 nosocomial infection during ICU stay Participants with ≥ 1 nosocomial pneumonia during ICU stay
Notes	Email sent to Dr Asfar 5 December 2018 and reply was received. The trial was funded by public grants (the French ministry of health).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomization list stratified by site and presence or absence of ARDS using permuted blocks of random sizes (nQuery Advisor 6.0)
Allocation concealment (selection bias)	Low risk	The pharmacists assigned a random number to each therapeutic package. The attribution of a given therapeutic package to a participant in accordance to the randomization list was done with a web‐based secured randomization system (Clinsight software).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Unblinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Unblinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	2.7% in the experimental group and 0.9% in the control were excluded from analysis.
Selective reporting (reporting bias)	Low risk	The trial was registered prior to randomisation (NCT01722422), and all prespecified outcomes were reported on.
Other bias	High risk	Early stopping bias: the trial was stopped after a pre‐planned interim analysis, criteria for stopping not specified