Association of intraoperative end-tidal CO₂ levels with postoperative outcomes: a patient-level analysis of two randomised clinical trials

Background: The relationship between intraoperative end-tidal CO₂ (etCO₂) 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 etCO₂ (<4.7 kPa) vs normal-high etCO₂ (≥4.7 kPa). The primary outcome was postoperative pulmonary complications within 5 days. A time-weighted etCO₂ analysis and propensity score matching were also performed to adjust for confounding. Results: Of 2793 participants, 891 (29.4%; 52% female) had low etCO₂, compared with 1972/2793 (70.6%; 65% female) participants with normal-high etCO₂. Compared with participants with normal-high etCO₂, higher minute volumes (normalised to body weight) were delivered in participants with low etCO₂. Postoperative pulmonary complications developed in 278/821 (34%) participants with low etCO₂, compared with 462/1972 (23%) participants who had normal-high etCO₂ (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 etCO₂ and postoperative pulmonary complications, which was also confirmed by propensity matching. Conclusions: Low etCO₂ occurs often during intraoperative ventilation and is associated with a higher rate of PPCs. The etCO₂ level has an inverse dose-dependent relationship with postoperative pulmonary complications. Clinical trial registration: NCT05550181.