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Stewart used physicochemical principles of aqueous solutions to develop an understanding of variables that control hydrogen ion concentration (H+) in body fluids. He proposed that H+ concentration in body fluids was determined by PCO2, strong ion difference (SID = sum of strong positive ion concentrations minus the sum of the strong anion concentrations) and the total concentration of nonvolatile weak acid (Atot) under normal circumstances. Albumin is the major weak acid in plasma and represents the majority of Atot. These 3 variables were defined as independent variables, which determined the values of all other relevant variables (dependent) in plasma, including H+. The major strong ions in plasma are sodium and chloride. The difference between Na+ and Cl- may be used as an estimation of SID. A decrease in SID below normal results in acidosis (increase in H+) and an increase in SID above normal results in alkalosis (decrease in H+). Unidentified strong anions such as lactate will decrease the SID, if present. Equations developed by Fencl allow Stewart's work to be easily applied clinically for evaluating the metabolic (nonrespiratory) contribution to acid-base balance. This approach separates the net metabolic abnormality into components, and allows one to easily detect mixed metabolic acid-base abnormalities. The Fencl approach provides insight into the nature and severity of the disturbances that exist in the patient. Sodium, chloride, protein, and unidentified anion derangements may contribute to the observed metabolic acid-base imbalance.