Abstract Purpose Partial pressure of carbon dioxide (P co2 ), strong ion difference (SID), and total amount of weak acids independently regulate pH. When blood passes through an extracorporeal membrane lung, P co2 decreases. Furthermore, changes in electrolytes, potentially affecting SID, were reported. We analyzed these phenomena according to Stewart's approach. Methods Couples of measurements of blood entering (venous) and leaving (arterial) the extracorporeal membrane lung were analyzed in 20 patients. Changes in SID, P co2 , and pH were computed and pH variations in the absence of measured SID variations calculated. Results Passing from venous to arterial blood, P co2 was reduced (46.5 ± 7.7 vs 34.8 ± 7.4 mm Hg, P < .001), and hemoglobin saturation increased (78 ± 8 vs 100% ± 2%, P < .001). Chloride increased, and sodium decreased causing a reduction in SID (38.7 ± 5.0 vs 36.4 ± 5.1 mEq/L, P < .001). Analysis of quartiles of ∆ P co2 revealed progressive increases in chloride ( P < .001), reductions in sodium ( P < .001), and decreases in SID ( P < .001), at constant hemoglobin saturation variation ( P = .12). Actual pH variation was lower than pH variations in the absence of measured SID variations (0.09 ± 0.03 vs 0.12 ± 0.04, P < .001). Conclusions When P co2 is reduced and oxygen added, several changes in electrolytes occur. These changes cause a P co2 -dependent SID reduction that, by acidifying plasma, limits pH correction caused by carbon dioxide removal. In this particular setting, P co2 and SID are interdependent.