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<div><p>In critically ill patients, endotracheal intubation (ETI) is lifesaving but carries a high risk of adverse events, notably hypoxemia. Preoxygenation is performed before introducing the tube to increase the safe apnea time. Oxygenation is monitored by pulse oximeter measurement of peripheral oxygen saturation (SpO<sub>2</sub>). However, SpO<sub>2</sub> is unreliable at the high oxygenation levels produced by preoxygenation and, in the event of desaturation, may not decrease sufficiently early to allow preventive measures. The oxygen reserve index (ORI) is a dimensionless parameter that can also be measured continuously by a fingertip monitor and reflects oxygenation in the moderate hyperoxia range. The ORI ranges from 0 to 1 when arterial oxygen saturation (PaO<sub>2</sub>) varies between 100 to 200 mmHg, as occurs during preoxygenation. No trial has assessed the potential effects of ORI monitoring to guide preoxygenation for ETI in unstable patients. We designed a multicenter, two-arm, parallel-group, randomized, superiority, open trial in 950 critically ill adults requiring ETI. The intervention consists in monitoring ORI values and using an ORI target for preoxygenation of at least 0.6 for at least 1 minute. In the control group, preoxygenation is guided by SpO<sub>2</sub> values recorded by a standard pulse oximeter, according to the standard of care, the goal being to obtain 100% SpO<sub>2</sub> during preoxygenation, which lasts at least 3 minutes. The standard-of-care ETI technique is used in both arms. Baseline parameters, rapid-sequence induction medications, ETI devices, and physiological data are recorded. The primary outcome is the lowest SpO<sub>2</sub> value from laryngoscopy to 2 minutes after successful ETI. Secondary outcomes include cognitive function on day 28. Assuming a 10% standard deviation for the lowest SpO<sub>2</sub> value in the control group, no missing data, and crossover of 5% of patients, with the bilateral alpha risk set at 0.05, including 950 patients will provide 85% power for detecting a 2% between-group absolute difference in the lowest SpO<sub>2</sub> value. Should ORI monitoring with a target of ≥0.6 be found to increase the lowest SpO<sub>2</sub> value during ETI, then this trial may change current practice regarding preoxygenation for ETI.</p><p><b>Trial registration</b>: Registered on ClinicalTrials.gov (<a href="https://clinicaltrials.gov/ct2/show/NCT05867875" target="_blank">NCT05867875</a>) on April 27, 2023.</p></div>