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Supplemental perioperative oxygen increases tissue oxygen tension and decreases incidence of wound infection in colorectal surgery patients. Mild intraoperative hypercapnia also increases subcutaneous tissue oxygen tension. However, the effect of hypercapnia in patients already receiving supplemental oxygen is unknown, as is the effect of mild hypercapnia on intestinal oxygenation in humans—although the intestines are presumably the tissue of interest for colon surgeries. The authors tested the hypothesis that mild intraoperative hypercapnia increases both subcutaneous tissue and intramural intestinal oxygen tension in patients given supplemental oxygen.Patients undergoing elective colon resection were randomly assigned to normocapnia (n = 15, end-tidal carbon dioxide tension 35 mmHg) or mild hypercapnia (n = 15, end-tidal carbon dioxide tension 50 mmHg). Intraoperative inspired oxygen concentration was 80%. The authors measured subcutaneous tissue oxygen tension in the right upper arm and intramural oxygen tension in the left colon. Measurements were averaged over time within each patient and, subsequently, among patients. Data were compared with chi-square, unpaired t, or Mann–Whitney rank sum tests; P < 0.05 was significant.Morphometric characteristics and other possible confounding factors were similar in the groups. Intraoperative tissue oxygen tension in hypercapnic patients was significantly greater in the arm (mean ± SD: 116 ± 29 mmHg vs. 84 ± 25 mmHg; P = 0.006) and colon (median [interquartile range]: 107 [81–129] vs. 53 [41–104] mmHg; P = 0.020).During supplemental oxygen administration, mild intraoperative hypercapnia increased tissue oxygen tension in the arm and colon. Previous work suggests that improved tissue oxygenation will reduce infection risk via the proposed pathomechanism, although only an outcome study can confirm this.