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June 2019 • Volume 128 • Number 6 www.anesthesia-analgesia.org 1071 DOI: 10.1213/ANE.4163 In recent time, the perioperative administration of high fraction of inspired oxygen (Fio2) has been of great interest to surgeons and anesthesiologists alike. Surgical wounds tend to have lower oxygen tension than normal tissue, and impaired oxygenation is associated with adverse clinical outcomes. Conversely, it has been hypothesized that increasing tissue oxygen tension might exert beneficial effects.1 This, in turn, can be achieved relatively easy by administering higher Fio2. After extensive experimental work, the first large randomized controlled trial was published in 2000.2 Investigators from Austria, Germany, and the United States collaboratively randomized 500 participants across several trial sites to receive 80% or 30% Fio2 and evaluated wounds for signs of infection. In the 80% group, surgical site infections fell to nearly half of that of the 30% group. However, subsequent trials could not consistently reproduce these results.3,4 Meanwhile, concerns on potential adverse effects such as atelectasis, respiratory failure, cardiovascular complications, and even mortality due to the use of high Fio2 were raised.5 In 2016, when both the World Health Organization and the Centers for Disease Control and Prevention independently strongly recommended the use of high perioperative Fio2 for the prevention of surgical site infections, it sparked an academic debate.6,7 The validity of the evidence for the benefits was challenged, and concerns of potential harms were raised.8 Not much later, the critical care world was shaken up by a systematic review that indicated liberal oxygen therapy increased mortality in critically ill patients.9 Although these data were not representative of the perioperative use of high Fio2, it did fuel the discussion. Since the initial recommendations, new evidence had emerged,10 and some published trials had come under scrutiny.11,12 The World Health Organization decided to update its analysis and issued an independent systematic review, specifically on the adverse effect of the use of high Fio2. The updated analysis did not show a definite beneficial effect of the use of high perioperative Fio2 overall, but there was evidence of a reduction of surgical site infection risk in surgical patients under general anesthesia with tracheal intubation.13 However, the evidence for this beneficial effect became weaker.13 The other review, specifically on adverse events, demonstrated no definite signal of harm with 80% Fio2 in adult surgical patients undergoing general anesthesia, and concluded that there is little evidence on safety-related issues to discourage its use in patients undergoing surgery.14 The guidelines got revised to reflect the new evidence, now suggesting—instead of recommending—the use of high Fio2 perioperatively in patients under general anesthesia with endotracheal intubation, and concluding that additional high-quality trials are needed.15 The discussion will likely continue. In this issue of Anesthesia & Analgesia, Cohen et al16 tested an interesting new hypothesis: does the use of high perioperative Fio2 reduce postoperative pain and opioid use? Postoperative pain is common and promotes opioid use. Surgical wounds have high lactate concentration, and the corresponding acidic environment has been associated with pain. Increasing tissue oxygen tension could reduce lactate concentration and possibly the related pain. Use of hyperbaric medicine has shown promising results in the past. The authors conducted a post hoc analysis on a large, singlecenter, alternating cohort study that assigned 30% (or the lowest Fio2 to maintain hemoglobin saturation at ≥95%) or 80% O2 to adults undergoing colorectal surgery. Further anesthetic management, such as the use of proactive recruitment manoeuvres or optimization of positive end-expiratory pressure (PEEP), was not controlled. The primary outcome was pain and opioid consumption. After exclusion of patients with regional anesthesia or missing records of pain or opioid administration, a stunning 4702 patients were eligible for analysis who were well balanced across the 2 treatment assignments. No meaningful difference was found in pain scores or opioid use. The authors concluded that supplemental oxygen does not reduce postoperative pain or opioid consumption. Notably, the underlying study with a composite outcome of deep and organ space surgical site infection, healing-related wound complications, and Perioperative Use of High Fraction of Inspired Oxygen: Another Null Result?