Rationale: There is no universal objective measure of the effect of sedation on brain activity and how to differentiate it from sleep. In patients with early acute hypoxemic respiratory failure (AHRF) we used the Odds Ratio Product (ORP), an electroencephalography (EEG)-based metric used to quantify the sleep-wake continuum. Despite patients behaviorally appearing asleep, we observed and quantified novel EEG patterns previously unobserved during natural sleep, and hypothesized these unnatural EEG patterns (EEG Ups ) reflect the effect of sedation. Objectives: To explore the relevance of EEG Ups (never or extremely rarely seen in sleep studies) and their association with sedation at the early phase of AHRF. Methods and Measurements: prospective cohort study including patients mechanically ventilated for AHRF and PaO 2 /FiO 2 <200 mmHg receiving various sedation-opioids regimens and doses as per clinical indication. Continuous EEG monitoring was performed from study inclusion until extubation, death, or up to seven days. EEG quantified the relative power of each frequency band (slow delta, fast delta + theta, alpha-sigma, beta) and determine the frequency of EEG Ups . Main Results: 1832 hours of EEG recordings were analyzed (mean±SD 43±25 hours/patient) from 23 patients (median[25-75% IQR] 58[48-70] years; 87% male PaO 2 /FiO 2 150[116-198] mmHg; ICU mortality 22%). EEG Ups accounted for 42% of the total recording time overall, differed among drug combinations and exceeded 50% with some sedation-opioid combinations. Brief wake intrusions, a marker of physiological sleep, were extremely low. EEG Ups prevalence was higher with sedation-opioid combinations (P≤0.029), high sedation dose (P≤0.035), deeper clinical sedation score (P≤0.024), and was associated with ICU mortality (P<0.001). Conclusions: Continuous intravenous sedation results in EEG Ups which are not present in natural sleep, correlate with dose of sedation, clinical sedation score and clinical outcomes. ClinicalTrials.gov ID: NCT03447288