The Stewart approach-the application of basic physicalchemical principles of aqueous solutions to blood-is an appealing method for analyzing acid-base disorders. These principles mainly dictate that p H is determined by three independent variables, which change primarily and independently of one other. In blood plasma in vivo these variables are:(1) the PCO2;(2) the strong ion difference(SID)-the difference between the sums of all the strong(i.e., fully dissociated, chemically nonreacting) cations and all the strong anions; and(3) the nonvolatile weak acids(Atot). Accordingly, the p H and the bicarbonate levels(dependent variables) are only altered when one or more of the independent variables change. Moreover, the source of H+ is the dissociation of water to maintain electroneutrality when the independent variables are modified. The basic principles of the Stewart approach in blood, however, have been challenged in different ways. First, the presumed independent variables are actually interdependent as occurs in situations such as:(1) the Hamburger effect(a chloride shift when CO2 is added to venous blood from the tissues);(2) the loss of Donnan equilibrium(a chloride shift from the interstitium to the intravascular compartment to balance the decrease of Atot secondary to capillary leak; and(3) the compensatory response to a primary disturbance in either independent variable. Second, the concept of water dissociation in response to changes in SID is controversial and lacks experimental evidence. In addition, the Stewart approach is not better than the conventional method for understanding acid-base disorders such as hyperchloremic metabolic acidosis secondary to a chloride-rich-fluid load. Finally, several attempts were performed to demonstrate the clinical superiority of the Stewart approach. These studies, however, have severe methodological drawbacks. In contrast, the largest study on this issue indicated the interchangeability of the Stewart and conventional methods. Although the introduction of the Stewart approach was a new insight into acid-base physiology, the method has not significantly improved our ability to understand, diagnose, and treat acid-base alterations in critically ill patients. The Stewart approach-the application of basic physical chemical principles of aqueous solutions to blood-is an appealing method for analyzing acid-base disorders. These principles mainly dictate that p H is determined by three independent variables, which change and and of of one other. In blood plasma in vivo these variables are: (1) the PCO2; (2) the strong ion difference (SID) -the difference between the sums of all the strong (ie, fully dissociated, chemically nonreacting) cations and all the strong anions ; and (3) the nonvolatile weak acids (Atot)., the p H and the bicarbonate levels (dependent variables) are only altered when one or more of the independent variables change. to maintain electroneutrality when the independent variables are modified. The basic principles of the Stewart approach in blood, however, have been challenged in different ways. First, the presumed independent variables are actually (2) the loss of Donnan equilibrium (a chloride shift from the interstitium to the intravascular compartment to balance the decrease of Atot secondary to capillary leak; and (3) the compensatory response to a primary disturbance in either independent variable. Second, the concept of water dissociation in response to changes in SID is controversial and lacks experimental evidence. Stewart approach is not better than the conventional method for understanding acid-base disorders such as hyperchloremic metabolic acidosis secondary to a chloride-rich-fluid load. Finally, several clinical were of demonstrating the clinical superiority of the Stewart approach. These studies, however In contrast, the largest study on this issue indicated the interchangeability of the Stewart and conventional methe introduction of the Stewart approach was a new insight into acid-base physiology, the method has significantly significantly improved our ability to understand, diagnose, and treat acid-base alterations in critically ill patients.