Nasa P.van Meenen D.M.P.Paulus F.Ferrando C.Bluth T.Gama de Abreu M.Ball L.Bossers S.M.Schober P.Schultz M.J.Serpa Neto A.Hemmes S.N.T.Campos N.S.Bluth T.Hemmes S.N.T.Librero J.Pozo N.Ferrando C.Ball L.Mazzinari G.Pelosi P.Gama de Abreu M.Schultz M.J.Neto A.S.Hemmes S.N.T.Gama de Abreu M.Severgnini P.Hollmann M.W.Binnekade J.M.Wrigge H.Canet J.Hiesmayr M.Schmid W.Tschernko E.Jaber S.Hedenstierna G.Putensen C.Pelosi P.Schultz M.J.Marti A.Bacuzzi A.Brodhun A.Molin A.Merten A.Parera A.Brunelli A.Cortegiani A.Güldner A.Reske A.W.Gratarola A.Giarratano A.Bastin B.Heyse B.Mazul-Sunko B.Amantea B.Barberis B.Putensen C.Uhlig C.Marín C.M.Celentano C.La Bella D.D'Antini D.Velghe D.Sulemanji D.De Robertis E.Hartmann E.Montalto F.Tropea F.Mills G.H.Cinnella G.Della Rocca G.Caggianelli G.Pellerano G.Mollica G.Bugedo G.Wrigge H.Mulier J.P.Vandenbrande J.Geib J.Yaqub J.Florez J.Mayoral J.F.Sprung J.Van Limmen J.Bos L.D.J.de Baerdemaeker L.Jamaer L.Spagnolo L.Strys L.Gil M.G.Gama de Abreu M.Vidal Melo M.F.Schultz M.J.Unzueta M.C.Moral M.V.Ferner M.Hollmann M.W.Weiss M.Vanoni M.Schaefer M.S.Mahidol University2025-09-222025-09-222025-01-01British Journal of Anaesthesia (2025)00070912https://repository.li.mahidol.ac.th/handle/123456789/112115Background: The relationship between intraoperative end-tidal CO<inf>2</inf> (etCO<inf>2</inf>) levels and postoperative outcomes remains unclear. We conducted a post hoc analysis of two randomised trials in adults undergoing major surgery under general anaesthesia. Methods: We re-analysed individual participant data comparing high or low positive end-expiratory pressure with low tidal volume intraoperative ventilation using a merged database derived from two randomised trials in non-obese (PROVHILO: ISRCTN70332574) and obese (PROBESE: NCT02148692) patients. The exposure of interest was low etCO<inf>2</inf> (<4.7 kPa) vs normal-high etCO<inf>2</inf> (≥4.7 kPa). The primary outcome was postoperative pulmonary complications within 5 days. A time-weighted etCO<inf>2</inf> analysis and propensity score matching were also performed to adjust for confounding. Results: Of 2793 participants, 891 (29.4%; 52% female) had low etCO<inf>2</inf>, compared with 1972/2793 (70.6%; 65% female) participants with normal-high etCO<inf>2</inf>. Compared with participants with normal-high etCO<inf>2</inf>, higher minute volumes (normalised to body weight) were delivered in participants with low etCO<inf>2</inf>. Postoperative pulmonary complications developed in 278/821 (34%) participants with low etCO<inf>2</inf>, compared with 462/1972 (23%) participants who had normal-high etCO<inf>2</inf> (adjusted hazard ratio, 1.3; 95% confidence interval, 1.1–1.6; P<0.001). The time-weighted analysis showed an inverse linear relationship between the mean etCO<inf>2</inf> and postoperative pulmonary complications, which was also confirmed by propensity matching. Conclusions: Low etCO<inf>2</inf> occurs often during intraoperative ventilation and is associated with a higher rate of PPCs. The etCO<inf>2</inf> level has an inverse dose-dependent relationship with postoperative pulmonary complications. Clinical trial registration: NCT05550181.MedicineArticleSCOPUS10.1016/j.bja.2025.07.0762-s2.0-1050155993291471677140930872