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Importance: Opioid-induced ventilatory depression and hypoxemia is common, severe, and often unrecognized in postoperative patients. To the extent that nonopioid analgesics reduce opioid consumption, they may decrease postoperative hypoxemia.Objective: To test the hypothesis that duration of hypoxemia is less in patients given intravenous acetaminophen than those given placebo.Design, Setting, and Participants: Randomized, placebo-controlled, double-blind trial conducted at 2 US academic hospitals among 570 patients who were undergoing abdominal surgery, enrolled from February 2015 through October 2018 and followed up until February 2019.Interventions: Participants were randomized to receive either intravenous acetaminophen, 1 g (n = 289), or normal saline placebo (n = 291) starting at the beginning of surgery and repeated every 6 hours until 48 postoperative hours or hospital discharge, whichever occurred first.Main Outcomes and Measures: The primary outcome was the total duration of hypoxemia (hemoglobin oxygen saturation [Spo2] <90%) per hour, with oxygen saturation measured continuously for 48 postoperative hours. Secondary outcomes were postoperative opioid consumption, pain (0- 10-point scale; 0: no pain; 10: the most pain imaginable), nausea and vomiting, sedation, minimal alveolar concentration of volatile anesthetic, fatigue, active time, and respiratory function.Results: Among 580 patients randomized (mean age, 49 years; 48% women), 570 (98%) completed the trial. The primary outcome, median duration with Spo2 of less than 90%, was 0.7 (interquartile range [IQR], 0.1-5.1) minutes per hour among patients in the acetaminophen group and 1.1 (IQR, 0.1-6.6) minutes per hour among patients in the placebo group (P = .29), with an estimated median difference of -0.04 (95% CI,-0.18 to 0.11) minutes per hour. None of the 8 secondary end points differed significantly between the acetaminophen and placebo groups. Mean pain scores within initial 48 postoperative hours were 4.2 (SD, 1.8) in the acetaminophen group and 4.4 (SD, 1.8) in the placebo group (difference, -0.28; 95% CI, -0.71 to 0.15); median opioid use in morphine equivalents was 50 mg (IQR, 18-122 mg) and 58 mg (IQR, 24-151 mg) , respectively, with a ratio of geometric means of 0.86 (95% CI, 0.61-1.21).Conclusions and Relevance: Among patients who underwent abdominal surgery, use of postoperative intravenous acetaminophen, compared with placebo, did not significantly reduce the duration of postoperative hypoxemia over 48 hours. The study findings do not support the use of intravenous acetaminophen for this purpose.Trial Registration: ClinicalTrials.gov Identifier: NCT02156154. [ABSTRACT FROM AUTHOR]